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Sample records for cerebral amyloid angiopathy

  1. Cerebral amyloid angiopathy

    Science.gov (United States)

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  2. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    Science.gov (United States)

    ... prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of hereditary cerebral amyloid angiopathy is unknown. The Dutch type is the most common, with over 200 ...

  3. Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications.

    Science.gov (United States)

    Boulouis, Gregoire; Charidimou, Andreas; Greenberg, Steven M

    2016-06-01

    Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-β peptide (Aβ) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-β deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. PMID:27214698

  4. Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.

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    van Veluw, Susanne J; Biessels, Geert Jan; Bouvy, Willem H; Spliet, Wim Gm; Zwanenburg, Jaco Jm; Luijten, Peter R; Macklin, Eric A; Rozemuller, Annemieke Jm; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand; Martinez-Ramirez, Sergi

    2016-03-01

    Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3-7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity. PMID:26661250

  5. Cerebral amyloid angiopathy-related inflammation: an emerging disease.

    Science.gov (United States)

    Savoiardo, M; Erbetta, A; Di Francesco, J C; Brioschi, M; Silani, V; Falini, A; Storchi, G; Brighina, L; Ferrarese, C; Ticozzi, N; Messina, S; Girotti, F

    2011-05-15

    Three elderly patients with, respectively: mild cognitive impairment, severe and progressive neurologic involvement, and focal neurologic deficit, were observed. MRI showed multiple areas of white matter edema, at times partially involving the cortex, in the first two patients, and a single area in the third. Treatment with steroids determined the disappearance of the lesions and clinical amelioration. The key to the diagnosis of cerebral amyloid angiopathy-related inflammation (CAA-ri) was the demonstration, with appropriate MRI sequences, of microbleeds consistent with cerebral amyloid angiopathy (CAA). This diagnosis was supported by genetic analysis of APOE with demonstration of ε4/ε4 genotype, found in about 80% of CAA patients who develop inflammatory changes. In the appropriate clinical setting, MRI demonstration of microbleeds supported by results of genetic analysis of APOE may strongly support the diagnosis of CAA-ri thus avoiding cerebral biopsy. PMID:24059616

  6. Cerebrospinal Fluid Biomarkers in Dementia Patients with Cerebral Amyloid Angiopathy

    Institute of Scientific and Technical Information of China (English)

    Yan-feng Li; Fang-fang Ge; Yong Zhang; Hui You; Zhen-xin Zhang

    2015-01-01

    Objective To study the changes of biomarkers in cerebrospinal fluid (CSF) in cerebral amyloid angiopathy (CAA) dementia and Alzheimer's disease. Methods Levels of amyloid proteinβ (Aβ42, Aβ40) and phosphorylated Tau-protein (P-tau) in CSF and ratio of Aβ42/Aβ40 were tested in 5 cases with CAA dementia and 20 cases with Alzheimer's disease collected at Peking Union Medical College Hospital from December 2001 to March 2011. Results The levels of Aβ42, Aβ40, and P-tau in CSF and ratio of Aβ42/Aβ40 were (660.4±265.2) ng/L, (7111.0±1033.4) ng/L, (71.8±51.5) ng/L, and 0.077±0.033, respectively in CAA dementia and (663.6±365.6) ng/L, (5115.0±2931.1) ng/L, (47.7±38.8) ng/L, and 0.192±0.140, respectively in Alzheimer's disease patients. There were no statistically significant differences between CAA dementia and Alzheimer's disease in terms of these CSF biomarkers (allP>0.05). Conclusion Measurements of CSF biomarkers may not be helpful in differential diagnosis of CAA and Alzheimer's disease.

  7. Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

    OpenAIRE

    Ryan, N. S.; Lashley, T.; Revesz, T; Dantu, K.; Fox, N.C.; Morris, H R

    2014-01-01

    Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously du...

  8. Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy

    OpenAIRE

    Lo, P; Crouzet, C; Vasilevko, V; Choi, B

    2016-01-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involve...

  9. Clinical and pathological study on 10 cases of cerebral lobe hemorrhage related with cerebral amyloid angiopathy

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    Xiao-qi LI

    2015-07-01

    Full Text Available Objective To summarize the clinical data and pathological features of 10 cases of cerebral lobar hemorrhage related with cerebral amyloid angiopathy (CAA diagnosed pathologically, thereby to improve the knowledge and diagnosis of the disease. Methods The clinical data of 10 cases of cerebral lobar hemorrhage related with CAA, collected in the General Hospital of Shenyang Command from 1983 up to now, were retrospectively analyzed, and the clinical and neuropathological features of these cases were summarized. Results Of the 10 patients, 2 suffered from single lobar hemorrhage and 8 multiple lobar hemorrhage, all of them were confirmed pathologically to have ruptured into the subarachnoid space. Pathological examination revealed microaneurysm in 2 cases, "double barrel" change in 4 cases, multiple arteriolar clusters in 5 cases, obliterative onion-liked intima change in 4 cases, and fibrinoid necrosis of vessel wall in 7 cases. In addition, neurofibrillary tangles were found in 8 cases, and senile plaque was observed in 5 cases. Conclusions Cerebral lobar hemorrhage related with CAA is mainly located in the parietal, temporal and occipital lobes, readily breaking into the subarachnoid space, and it is often multiple and recurrent. The CAA associated microvasculopathy was found frequently in the autopsy sample of CAA related cerebral lobar hemorrhage, and it may contribute to the pathogenesis of cerebral hemorrhage. DOI: 10.11855/j.issn.0577-7402.2015.07.04

  10. The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases.

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    Mendel, T A; Wierzba-Bobrowicz, T; Lewandowska, E; Stępień, T; Szpak, G M

    2013-12-01

    The process of β-amyloid accumulation in cerebral vessels is presented. Cerebral amyloid angiopathy (CAA) was confirmed during an autopsy. It was diagnosed according to the Boston criteria. Cerebral amyloid angiopathy can involve all kinds of cerebral vessels (cortical and leptomeningeal arterioles, capillaries and veins). The development of CAA is a progressive process. β-amyloid appears first in the tunica media, surrounding smooth muscle cells, and in the adventitia. β-amyloid is progressively accumulated, causing a gradual loss of smooth muscle cells in the vessel wall and finally replacing them. Then, the detachment and delamination of the outer part of the tunica media results in the "double barrel" appearance, fibrinoid necrosis, and microaneurysm formation. Microbleeding with perivascular deposition of erythrocytes and blood breakdown products can also occur. β-amyloid can also be deposited in the surrounding of the affected vessels of the brain parenchyma, known as "dysphoric CAA". Ultrastructurally, when deposits of amyloid fibers were localized in or outside the arteriolar wall, the degenerating vascular smooth muscle cells were observed. In the Institute of Psychiatry and Neurology the study was carried out in a group of 48 patients who died due to intracerebral hemorrhage caused by sporadic CAA. PMID:24375040

  11. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

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    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  12. Cerebral amyloid angiopathy presenting as a posterior leukoencephalopathy: A case report and review of the literature

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    Maramattom Boby Varkey

    2004-10-01

    Full Text Available Cerebral amyloid angiopathy (CAA is well known to present with lobar intracerebral hemorrhage, dementia or transient neurological events. White matter changes with CAA have only been recently described and can be seen with either sporadic or familial CAA. We present a 50-year-old man with rapidly progressive dementia in whom MRI brain showed symmetrical white matter changes in the parieto-occipital regions. Brain biopsy revealed changes of CAA along with features of Alzheimer′s disease. Immunohistochemistry revealed amyloid beta protein. The subcortical lesions were thought to occur from hypoperfusion of the distal white matter. The role of amyloid in the pathogenesis of CAA and the mechanism of leukoencephalopathy are discussed.

  13. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

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    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  14. Imaging of Cerebral Amyloid Angiopathy with Bivalent 99mTc-Hydroxamamide Complexes

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    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Matsumura, Kenji; Yoshimura, Masashi; Kimura, Hiroyuki; Ishibashi-Ueda, Hatsue; Okamoto, Yoko; Ihara, Masafumi; Saji, Hideo

    2016-05-01

    Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer’s disease (AD). We previously reported 99mTc-hydroxamamide (99mTc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1–42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1–40) aggregates deposited mainly in CAA and a brain uptake study were performed for 99mTc-Ham complexes, and all 99mTc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1–40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent 99mTc-Ham complexes ([99mTc]SB2A and [99mTc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the 99mTc-Ham complex.

  15. Cerebral Amyloid Angiopathy-Related Inflammation: Report of a Case with Very Difficult Therapeutic Management

    Directory of Open Access Journals (Sweden)

    Francesca Crosta

    2015-01-01

    Full Text Available Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF. Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis.

  16. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

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    Han, Byung Hee; Zhou, Meng-liang; Johnson, Andrew W; Singh, Itender; Liao, Fan; Vellimana, Ananth K.; Nelson, James W.; Milner, Eric; Cirrito, John R.; Basak, Jacob; Yoo, Min; Dietrich, Hans H.; Holtzman, David M.; Zipfel, Gregory Joseph

    2015-01-01

    One of the hallmarks of Alzheimer’s disease (AD) is cerebral amyloid angiopathy (CAA), which is a strong and independent risk factor for cerebral hemorrhage, ischemic stroke, and dementia. However, the mechanisms by which CAA contributes to these conditions are poorly understood. Results from the present study provide strong evidence that vascular oxidative stress plays a causal role in CAA-induced cerebrovascular dysfunction, CAA-induced cerebral hemorrhage, and CAA formation, itself. They a...

  17. Imaging Findings of Cerebral Amyloid Angiopathy, Aβ-Related Angiitis (ABRA), and Cerebral Amyloid Angiopathy-Related Inflammation: A Single-Institution 25-Year Experience.

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    Salvarani, Carlo; Morris, Jonathan M; Giannini, Caterina; Brown, Robert D; Christianson, Teresa; Hunder, Gene G

    2016-05-01

    Vascular inflammation is present in a subset of patients with cerebral amyloid angiopathy (CAA) and has a major influence in determining the disease manifestations. Radiological characterization of this subset is particularly important to achieve early recognition and treatment. We conducted this study to investigate the role of imaging in differentiating CAA with and without inflammation. We reviewed neuroimaging findings for 54 patients seen at Mayo Clinic over 25 years with pathological evidence of CAA and with available neuroimaging at the time of diagnosis. Clinical data were also recorded. Patients were grouped into CAA alone (no vascular inflammation), Aβ-related angiitis or ABRA (angiodestructive inflammation), and CAA-related inflammation or CAA-RI (perivascular inflammation). Imaging findings at presentation were compared among patient subgroups. Radiological features supporting a diagnosis of ABRA or CAA-RI were identified. Radiologic findings at diagnosis were available in 27 patients with CAA without inflammation, 22 with ABRA, and 5 with CAA-RI. On MRI, leptomeningeal disease alone or with infiltrative white matter was significantly more frequent at presentation in patients with ABRA or CAA-RI compared with those with CAA (29.6% vs. 3.7%, P = 0.02; and 40.7% vs. 3.7%, P = 0.002, respectively), whereas lobar hemorrhage was more frequent in patients with CAA (62.3% vs. 7.4%, P = 0.0001). Overall, leptomeningeal involvement at presentation was present in 70.4% of patients with ABRA or CAA-RI and in only 7.4% of patients with CAA (P = 0.0001). The sensitivity and specificity of leptomeningeal enhancement to identify patients with ABRA or CAA-RI were 70.4% and 92.6%, respectively, whereas the positive likelihood ratio (LR) was 9.5. The sensitivity and specificity of intracerebral hemorrhage to identify patients with CAA were 62.9% and 92.6%, respectively, whereas the positive LR was 8.5. Microbleeds were found in 70.4% of patients with

  18. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

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    Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D; Shinohara, Motoko; DeTure, Michael; Yamazaki, Yu; Tachibana, Masaya; Atagi, Yuka; Davis, Mary D; Liu, Chia-Chen; Zhao, Na; Painter, Meghan M; Petersen, Ronald C; Fryer, John D; Crook, Julia E; Dickson, Dennis W; Bu, Guojun; Kanekiyo, Takahisa

    2016-08-01

    Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE. PMID:27179972

  19. Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome

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    Martucci, Matia [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Catholic University of Sacred Heart, ' ' A. Gemelli' ' University Hospital, Department of Radiological Sciences, Rome (Italy); Sarria, Silvana; Coscojuela, Pilar; Vert, Carla; Siurana, Sahyly; Auger, Cristina; Rovira, Alex [Vall d' Hebron University Hospital, Neuroradiology Unit, Radiology Department (IDI), Barcelona (Spain); Toledo, Manuel [Vall d' Hebron University Hospital, Epilepsy Unit, Neurology Department, Barcelona (Spain)

    2014-04-15

    We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment. (orig.)

  20. Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami

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    Martínez-Lizana, Eva; Carmona-Iragui, María; Alcolea, Daniel; Gómez-Choco, Manuel; Vilaplana, Eduard; Sánchez-Saudinós, María B; Clarimón, Jordi; Hernández-Guillamon, Mar; Munuera, Josep; Gelpi, Ellen; Gómez-Anson, Beatriz; de Juan-Delago, Manel; Delgado-Mederos, Raquel; Montaner, Joan; Ois, Angel; Amaro, Sergi; Blesa, Rafael; Martí-Fàbregas, Joan; Lleó, Alberto; Fortea, Juan

    2015-01-01

    Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology. PMID:25735919

  1. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

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    Merlini, Mario; Wanner, Debora; Nitsch, Roger M

    2016-05-01

    Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95 % CI 0.370 to 0.990, p leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD. PMID:26988843

  2. Surface-bound basement membrane components accelerate amyloid-β peptide nucleation in air-free wells: an in vitro model of cerebral amyloid angiopathy.

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    Hasegawa, Kazuhiro; Ozawa, Daisaku; Ookoshi, Tadakazu; Naiki, Hironobu

    2013-08-01

    Cerebral amyloid angiopathy is caused by deposition of the amyloid β-peptide which consists of mainly 39-40 residues to the cortical and leptomeningeal vessel walls. There are no definite in vitro systems to support the hypothesis that the vascular basement membrane may act as a scaffold of amyloid β-peptide carried by perivascular drainage flow and accelerate its amyloid fibril formation in vivo. We previously reported the critical roles of interfaces and agitation on the nucleation of amyloid fibrils at low concentrations of amyloid β-peptide monomers. Here, we reproduced the perivascular drainage flow in vitro by using N-hydroxysuccinimide-Sepharose 4 Fast flow beads as an inert stirrer in air-free wells rotated at 1rpm. We then reproduced the basement membranes in the media of cerebral arteries in vitro by conjugating Matrigel and other proteins on the surface of Sepharose beads. These beads were incubated with 5μM amyloid β(1-40) at 37°C without air, where amyloid β(1-40) alone does not form amyloid fibrils. Using the initiation time of fibril growth kinetics (i.e., the lag time of fibril growth during which nuclei, on-pathway oligomers and protofibrils are successively formed) as a parameter of the efficiency of biological molecules to induce amyloid fibril formation, we found that basement membrane components including Matrigel, laminin, fibronectin, collagen type IV and fibrinogen accelerate the initiation of amyloid β-peptide fibril growth in vitro. These data support the essential role of vascular basement membranes in the development of cerebral amyloid angiopathy. PMID:23608949

  3. MMP-2/MMP-9 plasma level and brain expression in cerebral amyloid angiopathy-associated hemorrhagic stroke.

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    Hernandez-Guillamon, Mar; Martinez-Saez, Elena; Delgado, Pilar; Domingues-Montanari, Sophie; Boada, Cristina; Penalba, Anna; Boada, Mercè; Pagola, Jorge; Maisterra, Olga; Rodriguez-Luna, David; Molina, Carlos A; Rovira, Alex; Alvarez-Sabin, José; Ortega-Aznar, Arantxa; Montaner, Joan

    2012-03-01

    Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in β-amyloid (Aβ)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aβ-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding. PMID:21707819

  4. [Diagnosis of cerebral amyloid angiopathy with cerebral hemorrhage by enzyme linked immunosorbent assay (ELISA) of cystatin C in the cerebrospinal fluid].

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    Shimode, K; Fujihara, S; Nakamura, M; Kobayashi, S; Tsunematsu, T

    1990-03-01

    The lower level of cystatin C in cerebrospinal fluid (CSF) is one of the useful diagnostic markers of hereditary cerebral hemorrhage with amyloidosis in Iceland. We attempted to establish an assay to determine the level of cystatin C in CSF for diagnosis of CAA due to the deposition of cystatin C in CSF for diagnosis of CAA due to the deposition of cystatin C. We carried out the sandwich enzyme immunosorbent assay with the use of monoclonal mouse anti-cystatin C and polyclonal rabbit anti-cystatin C antibodies. CSF from nine cases of cerebral hemorrhage and fifty reference cases with other neurological diseases were examined. Four patients with cerebral hemorrhage showed a low level of cystatin C and clinical manifestations suggestive of CAA. Our study showed the feasibility of using ELISA for the diagnosis of cerebral amyloid angiopathy that causes cerebral hemorrhage with the deposition of cystatin C. PMID:2364630

  5. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.

    Science.gov (United States)

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A; Smyth, Neil R; Smith, Colin; Al-Shahi Salman, Rustam; Samarasekera, Neshika; Nicoll, James A R; Attems, Johannes; Kalaria, Rajesh N; Weller, Roy O; Carare, Roxana O

    2016-05-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327684

  6. ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy.

    Science.gov (United States)

    Montañola, Alex; de Retana, Sofía Fernández; López-Rueda, Antonio; Merino-Zamorano, Cristina; Penalba, Anna; Fernández-Álvarez, Paula; Rodríguez-Luna, David; Malagelada, Ana; Pujadas, Francesc; Montaner, Joan; Hernández-Guillamon, Mar

    2016-03-01

    The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains. PMID:26661731

  7. Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Maeda Yasushi

    2011-09-01

    Full Text Available Abstract A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed β-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved. CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.

  8. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically-verified Alzheimer’s disease

    Science.gov (United States)

    Ringman, John M.; Sachs, Michael C.; Zhou, Yan; Monsell, Sarah E.; Saver, Jeffrey L.; Vinters, Harry V.

    2014-01-01

    Importance Though cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it is limited. Objective We sought to determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically-confirmed Alzheimer’s disease (AD). Design We compared demographic and clinical variables at the earliest visit during life at which subjects were found to have cognitive impairment, and pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and non-carriers of the APOE ε4 allele. Setting Data were obtained from the Uniform Data Set that comprises longitudinal clinical assessments performed in the Alzheimer’s Disease Centers funded by the National Institute on Aging. Participants 193 persons with severe CAA and 232 persons with no CAA. All subjects had cognitive impairment and met NIA-Reagan neuropathological criteria for AD. Main Outcome Measures Prevalence of demographic characteristics and the APOE ε4 allele and odds ratios of clinical variables for the prediction of severe CAA. Results Persons with severe CAA were more likely to carry an APOE ε4 allele (64.9% vs. 42.8%), to be Hispanic (6.8% vs. 1.3%, p = 0.003), to have had a transient ischemic attack (TIA, 12.5% vs. 6.1%, OR = 2.1, 95% CI = 1 – 4.4), and had lower degrees of diffuse amyloid plaque pathology (mean CERAD scores 1.2 vs. 1.4, p = 0.01) than persons with no CAA. Intracerebral hemorrhage (9.3% vs. 3.5%, p = 0.01), cortical microinfarcts (20.7% vs. 12.9%, p = 0.03), and subcortical leukoencephalopathy (20.5% vs. 12.1%, p = 0.02) were more common in persons with CAA. A higher prevalence of stroke (11.1% vs. 3.9%, OR = 3.8, 95% CI 1.0 – 14.6) and hypercholesterolemia (50% vs. 33.3%, OR = 2.3, CI 1.1 – 4.7) were found in non-carriers of the ε4 allele with

  9. Gelsolin amyloid angiopathy causes severe disruption of the arterial wall.

    Science.gov (United States)

    Koskelainen, Susanna; Pihlamaa, Tiia; Suominen, Sinikka; Zhao, Fang; Salo, Tuula; Risteli, Juha; Baumann, Marc; Kalimo, Hannu; Kiuru-Enari, Sari

    2016-08-01

    Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi-quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA. PMID:27198069

  10. Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease.

    Science.gov (United States)

    Ryan, Natalie S; Biessels, Geert-Jan; Kim, Lois; Nicholas, Jennifer M; Barber, Philip A; Walsh, Phoebe; Gami, Priya; Morris, Huw R; Bastos-Leite, António J; Schott, Jonathan M; Beck, Jon; Mead, Simon; Chavez-Gutierrez, Lucia; de Strooper, Bart; Rossor, Martin N; Revesz, Tamas; Lashley, Tammaryn; Fox, Nick C

    2015-12-01

    Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD. PMID:26410308

  11. Unusual cerebral vascular prion protein amyloid distribution in scrapie-infected transgenic mice expressing anchorless prion protein

    OpenAIRE

    Rangel, Alejandra; Race, Brent; Klingeborn, Mikael; Striebel, James; Chesebro, Bruce

    2013-01-01

    Background In some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy. Small diffusible precursors of PrPres amyloid might flow with brain interstitial fluid (ISF), possibly accounting for the perivascular and intravascular distribution of PrPres amyloid. We previously reported that PrPres amyloid in scrapie-infected transgenic mice appeared to delay clearance of microinjected brain ISF trace...

  12. Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty

    International Nuclear Information System (INIS)

    Postpartum cerebral angiopathy (PCA) is an uncommon cause of ischemic and hemorrhagic stroke in young women. It is usually clinically benign and not relapsing. We describe a patient with non-hemorrhagic PCA who had an atypical progressive neurological deficit from bilateral hemisphere watershed ischemia despite treatment with aggressive medical therapy and intracranial balloon angioplasty. (orig.)

  13. Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty

    Energy Technology Data Exchange (ETDEWEB)

    Song, J.K. [Center for Endovascular Surgery, Hyman-Newman Inst. for Neurology and Neurosurgery, New York, NY (United States); Cacayorin, E.D. [Interventional Neuroradiology, Dept. of Radiology, Univ. of Texas Medical School, Houston, TX (United States); Fisher, S.; Seifert, T.D.; Alexandrov, A.V.; Malkoff, M.D.; Grotta, J.C.; Campbell, M.S. [Div. of Stroke Neurology, Dept. of Neurology, Univ. of Texas Medical School, Houston, TX (United States)

    2004-12-01

    Postpartum cerebral angiopathy (PCA) is an uncommon cause of ischemic and hemorrhagic stroke in young women. It is usually clinically benign and not relapsing. We describe a patient with non-hemorrhagic PCA who had an atypical progressive neurological deficit from bilateral hemisphere watershed ischemia despite treatment with aggressive medical therapy and intracranial balloon angioplasty. (orig.)

  14. A case of postvaricella cerebral angiopathy with a good outcome in a child

    OpenAIRE

    Maria Cristina Magagnini; Luisa La Spina; Daniela Gioé; G Del Campo; G Belfiore; Smilari, P.; Filippo Greco

    2015-01-01

    Cerebral vasculopathy is a serious but uncommon complication of varicella-zoster-virus (VZV) infection. Diagnosis is based on a recent history of VZV infection, signs and symptoms of transient ischemic attack or stroke, and vascular anomalies on neuroimaging. We report a case of postvaricella cerebral angiopathy in a 5-year-old child, who was admitted after three episodes of transient right hemiplegia, each one lasting a few minutes. He had contracted chicken pox, the month prior to admission...

  15. A case of postvaricella cerebral angiopathy with a good outcome in a child

    Directory of Open Access Journals (Sweden)

    Maria Cristina Magagnini

    2015-01-01

    Full Text Available Cerebral vasculopathy is a serious but uncommon complication of varicella-zoster-virus (VZV infection. Diagnosis is based on a recent history of VZV infection, signs and symptoms of transient ischemic attack or stroke, and vascular anomalies on neuroimaging. We report a case of postvaricella cerebral angiopathy in a 5-year-old child, who was admitted after three episodes of transient right hemiplegia, each one lasting a few minutes. He had contracted chicken pox, the month prior to admission. Brain magnetic resonance imaging showed hyperintense signals in the left lenticular and caudate nuclei, which can be considered to be a result of vasculopathy.

  16. A case of postvaricella cerebral angiopathy with a good outcome in a child.

    Science.gov (United States)

    Magagnini, Maria Cristina; Spina, Luisa La; Gioé, Daniela; Campo, G Del; Belfiore, G; Smilari, P; Greco, Filippo

    2015-01-01

    Cerebral vasculopathy is a serious but uncommon complication of varicella-zoster-virus (VZV) infection. Diagnosis is based on a recent history of VZV infection, signs and symptoms of transient ischemic attack or stroke, and vascular anomalies on neuroimaging. We report a case of postvaricella cerebral angiopathy in a 5-year-old child, who was admitted after three episodes of transient right hemiplegia, each one lasting a few minutes. He had contracted chicken pox, the month prior to admission. Brain magnetic resonance imaging showed hyperintense signals in the left lenticular and caudate nuclei, which can be considered to be a result of vasculopathy. PMID:26167223

  17. Vitamin E but not 17B-estradiol protect against vascular toxicity induced by B-amyloid wild type and the Dutch amyploid variant

    OpenAIRE

    Mu??oz L??pez, Francisco Jos??, 1964-; Opazo, Carlos; Gil G??mez, Gabriel; Tapia, Gladys; Fern??ndez, Virginia; Valverde, M A; Nibaldo C Inestrosa

    2002-01-01

    Amyloid ??-peptide (A??) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in A?? yielding A??Glu22???Gln. The present study addresses the effect of amyloid fibrils from both wild-type and mutated A?? on vascular cells, as well as the putative protect...

  18. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy☆

    Science.gov (United States)

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A.; Smyth, Neil R.; Smith, Colin; Salman, Rustam Al-Shahi; Samarasekera, Neshika; Nicoll, James A.R.; Attems, Johannes; Kalaria, Rajesh N.; Weller, Roy O.; Carare, Roxana O.

    2016-01-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327684

  19. Postpartum cerebral angiopathy presenting with non-aneurysmal subarachnoid hemorrhage and interval development of neurological deficits: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Li Yang

    2013-01-01

    Full Text Available Postpartum cerebral angiopathy (PCA is a cerebrovascular disease that occurs during the postpartum period. It is characterized by reversible multifocal vasoconstriction of the cerebral arteries. We report a patient with PCA proven by cerebral angiography that revealed multifocal, segmental narrowing of the cerebral arteries and non-aneurysmal subarachnoid hemorrhage. The patient suddenly deteriorated with focal neurological deficits on the 5 th day of hospitalization. She was treated with calcium-channel blockers and monitored with daily transcranial Doppler ultrasound. Her symptoms gradually improved and she was discharged on the 11 th day of hospitalization. At 1-month follow-up, patient was completely symptom-free with no neurological deficits.

  20. Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach

    Directory of Open Access Journals (Sweden)

    Björn Reuter

    2016-01-01

    Full Text Available Background: Cerebral amyloid angiopathy (CAA is characterized by vascular deposition of amyloid β (Aβ with a higher incidence of cerebral microbleeds (cMBs and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13, 12 months (n = 7, and 16 months (n = 6, respectively. Controls (n = 16 received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation, compared to 29.3 ± 9.8 in mice with eight months (p = 0.49, 24.9 ± 21.3 with 12 months (p = 0.26, and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27. In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16 compared to controls and also after adjustment for cMB size (p = 0.13. Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed.

  1. Prevalence of cerebral amyloid pathology in persons without dementia

    DEFF Research Database (Denmark)

    Jansen, Willemijn J; Ossenkoppele, Rik; Knol, Dirk L;

    2015-01-01

    IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies...... searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for...... biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20...

  2. Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy—A 9.4 Tesla MRI Study

    Science.gov (United States)

    Reuter, Björn; Venus, Alexander; Heiler, Patrick; Schad, Lothar; Ebert, Anne; Hennerici, Michael G.; Grudzenski, Saskia; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid β (Aβ) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. Materials and Methods: APP23-transgenic mice demonstrate cerebrovascular Aβ deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. Results: T2* imaging demonstrated cMBs (diameter 50–300 μm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 ± 2 (median ± interquartilrange) at 16 months, 15 ± 6 at 20 months, and 31.5 ± 17 at 24 months of age, respectively. Conclusion: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID:27458375

  3. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography

    OpenAIRE

    Palmqvist, Sebastian; Mattsson, Niklas; Hansson, Oskar; ,

    2016-01-01

    See Rabinovici (doi:10.1093/brain/aww025) for a scientific commentary on this article. Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer’s disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET ...

  4. Amyloid-Beta Related Angiitis of the Central Nervous System: Case Report and Topic Review

    Directory of Open Access Journals (Sweden)

    JoseBiller

    2014-02-01

    Full Text Available Amyloid-beta related angiitis (ABRA of the central nervous system (CNS is a rare disorder with overlapping features of primary angiits of the CNS (PACNS and cerebral amyloid angiopathy (CAA. We evaluated a 74-year-old man with intermittent left sided weakness and MRI findings of leptomeningeal enhancement, vasogenic edema and subcortical white matter disease proven to have ABRA. We discuss clinicopathological features and review the topic of ABRA.

  5. The Significance of Small Cerebral Bleeds in Neurodegenerative Dementia Syndromes

    OpenAIRE

    De Reuck, Jacques L.

    2012-01-01

    Small cerebral bleeds are frequently observed in brains of patients with Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, they are also observed in patients with other neurodegenerative dementias and in persons without cognitive impairment. The aim of this survey is to compare the bleeding load in brains with different dementia syndromes and in age-matched controls. Hundred sixty-five brains were examined. The prevalence and the severity of the different cerebrovascular ...

  6. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders.

    Science.gov (United States)

    Batarseh, Yazan S; Duong, Quoc-Viet; Mousa, Youssef M; Al Rihani, Sweilem B; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer's disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  7. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    Science.gov (United States)

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  8. Cerebral Hemorrhage and APOE genotype

    Institute of Scientific and Technical Information of China (English)

    Sun xiaojiang; Wu ping; Zhang jing; Lu shanqing; Li bing

    2000-01-01

    Background and Purpose: Current evidence Suggests that the apolipoprotein E (APOE)ε 4 allele predisposes to cerebral amyloid angiopathy (CAA) whereas ε 2 is associated with CAA-zelated hemorrhage. In this study we examined potential clinical risk factors inpatients with cerebral hemorrhage and assessed these with respect to APOE genotype. Methoeds: 146 patinas with cerebral hemorrhage and 70 normal controls were investigated. APOE genotypes were determined with use of polymerase Chain reaction techniques.Results: The frequency of allele gene ( 0.180 ) and the percentage of the APOE ε 4 genotype in the cerebral hemorrhage group were Significantly higher as compared with the e 4 prequency ( O.O72 ) in the control group respectively ( p=O.O389 ) .Conelusious: APOE ε 4 :allele is a risk gene for cerebral hemorrhage.

  9. Modeling Cerebrovascular Pathophysiology in Amyloid-β Metabolism using Neural-Crest-Derived Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Christine Cheung

    2014-10-01

    Full Text Available There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.

  10. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    Directory of Open Access Journals (Sweden)

    Yazan S. Batarseh

    2016-03-01

    Full Text Available Amyloid-β (Aβ pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia.

  11. POST VARICELLA ANGIOPATHY- A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Nita R Sutay, Md Ashfaque Tinmaswala, Shilpa Hegde

    2015-07-01

    Full Text Available Chickenpox is a common viral illness in children. In most of the immunocompitent children it’s a self-limiting disease and seldom causes complications. Neurological complications are one of the rare complications of chickenpox. These complications may present as hemiparesis, focal deficits and arterial ischemic strokes (AIS. These Ischemic strokes may be a manifestation of post varicella angiopathy. Here we present a case of 11 year old girl who presented with left hemiparesis with left sided facial nerve palsy 15 days after chickenpox. An MRI was done which was suggestive of multiple infarcts in cortical and subcortical regions and MR angiography was suggestive of narrowing of right middle cerebral artery. Patient was treated with aspirin and LMW heparin in addition to supportive measures.

  12. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Madsen, Karine; Neumann, Wolf-Julian; Holst, Klaus Kähler;

    2011-01-01

    The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-ß (Aß) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early...... Alzheimer disease (AD) patients in relation to cortical Aß burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19–27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD...

  13. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Saak V. Ovsepian

    2013-12-01

    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  14. Absence of beta-amyloid in cortical cataracts of donors with and without Alzheimer's disease.

    Science.gov (United States)

    Michael, Ralph; Rosandić, Jurja; Montenegro, Gustavo A; Lobato, Elvira; Tresserra, Francisco; Barraquer, Rafael I; Vrensen, Gijs F J M

    2013-01-01

    Eye lenses from human donors with and without Alzheimer's disease (AD) were studied to evaluate the presence of amyloid in cortical cataract. We obtained 39 lenses from 21 postmortem donors with AD and 15 lenses from age-matched controls provided by the Banco de Ojos para Tratamientos de la Ceguera (Barcelona, Spain). For 17 donors, AD was clinically diagnosed by general physicians and for 4 donors the AD diagnosis was neuropathologically confirmed. Of the 21 donors with AD, 6 had pronounced bilateral cortical lens opacities and 15 only minor or no cortical opacities. As controls, 7 donors with pronounced cortical opacities and 8 donors with almost transparent lenses were selected. All lenses were photographed in a dark field stereomicroscope. Histological sections were analyzed using a standard and a more sensitive Congo red protocol, thioflavin staining and beta-amyloid immunohistochemistry. Brain tissue from two donors, one with cerebral amyloid angiopathy and another with advanced AD-related changes and one cornea with lattice dystrophy were used as positive controls for the staining techniques. Thioflavin, standard and modified Congo red staining were positive in the control brain tissues and in the dystrophic cornea. Beta-amyloid immunohistochemistry was positive in the brain tissues but not in the cornea sample. Lenses from control and AD donors were, without exception, negative after Congo red, thioflavin, and beta-amyloid immunohistochemical staining. The results of the positive control tissues correspond well with known observations in AD, amyloid angiopathy and corneas with lattice dystrophy. The absence of staining in AD and control lenses with the techniques employed lead us to conclude that there is no beta-amyloid in lenses from donors with AD or in control cortical cataracts. The inconsistency with previous studies of Goldstein et al. (2003) and Moncaster et al. (2010), both of which demonstrated positive Congo red, thioflavin, and beta-amyloid

  15. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  16. Oligomeric Amyloid-β Peptide on Sialylic Lewisx–Selectin Bonding at Cerebral Endothelial Surface

    Directory of Open Access Journals (Sweden)

    Sholpan Askarova

    2014-12-01

    Full Text Available Introduction: Alzheimer’s disease (AD is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB plays an important role in the onset and progression of the disease. Increased deposition of amyloid b peptide (Aβ in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains and are some of the pathological hallmarks of the diseases. Since the transmigration of monocytes across the BBB is both a mechanical and a biochemical process, the expression of adhesion molecules and mechanical properties of endothelial cells are the critical factors that require investigation.Methods: Because of recent advances in the biological applications of atomic force microscopy (AFM, we applied AFM with cantilever tips bio-functionalized by sLex in combination with the advanced immunofluorescent microscopy (QIM to study the direct effects of Aβ42 oligomers on the selectins expression, actin polymerization, and cellular mechanical and adhesion properties in cerebral endothelial cells (mouse bEnd3 line and primary human CECs and find a possible way to attenuate these effects. Results: QIM results showed that Aβ42 increased the expressions of P-selectin on the cell surface and enhanced actin polymerization. Consistent with our QIM results, AFM data showed that Aβ42 increased the probability of cell adhesion with sLex-coated cantilever and cell stiffness. These effects were counteracted by lovstatin, a cholesterol-lowering drug.  Surprisingly, the apparent rupture force of sLex-selectin bonding was significantly lower after treatment with Aβ42, as compared with the control (i.e. no treatment

  17. Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Dahyun eYi

    2015-02-01

    Full Text Available Despite potential implications for the early detection of impending AD, very little is known about the differences of large scale brain networks between amnestic MCI (aMCI with high cerebral amyloid beta protein (Aβ deposition (i.e., aMCI+ and aMCI with no or very little Aβ deposition (i.e., aMCI-. We first aimed to extend the current literature on altering intrinsic functional connectivity (FC of the default mode network (DMN and salience network (SN from CN to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI-, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI-, and 11 AD dementia subjects were included. All participants received clinical and neuropsychological assessment, resting state functional MRI, structural MRI, and Pittsburgh compound-B-PET scans. FC data were preprocessed using Multivariate Exploratory Linear Optimized Decomposition into Independent Components of FSL. Group comparisons were carried out using the dual-regression approach. In addition, to verify presence of grey matter (GM volume changes with intrinsic functional network alterations, Voxel Based Morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (in precuneus and cingulate gyrus. The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI- exhibited increased FC in the DMN compared to CN (in precuneus as well as aMCI+. In terms of the SN, aMCI- exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI- showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite of the similarity in cross-sectional cognitive features aMCI- has quite different functional brain connectivity compared to

  18. Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan C.

    2001-01-01

    Full Text Available Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.

  19. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    Science.gov (United States)

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD. PMID:26324099

  20. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    Directory of Open Access Journals (Sweden)

    Gary W Arendash

    Full Text Available Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

  1. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

    OpenAIRE

    Ghiso, J.; Jensson, O; Frangione, B

    1986-01-01

    A gamma-trace variant protein is the major constituent of the amyloid fibrils in patients from Iceland with hereditary cerebral hemorrhage with amyloidosis. The protein consists of 110 residues and is similar to human urinary gamma-trace basic protein (or cystatin C) beginning at its 11th amino-terminal residue. It has an amino acid substitution (glutamine for leucine) at position 58 (position 68 in gamma-trace numbering), which is near the proposed active site of related proteins--namely, cy...

  2. Micro-MRI study of cerebral aging: ex vivo detection of hippocampal sub-field reorganization, micro-hemorrhages and amyloid plaques in mouse lemur primates

    International Nuclear Information System (INIS)

    Mouse lemurs are non-human primate models of cerebral aging and neuro-degeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 μm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral micro-hemorrhages. (authors)

  3. Thiazine Red(+) platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer's Disease mouse model.

    Science.gov (United States)

    Kniewallner, Kathrin M; Wenzel, Daniela; Humpel, Christian

    2016-01-01

    Strong evidence shows an association between cerebral vascular diseases and Alzheimer´s disease (AD). In order to study the interaction of beta-amyloid (Aβ) plaques with brain vessels, we crossbred an AD mouse model (overexpressing amyloid precursor protein with the Swedish-Dutch-Iowa mutations, APP_SweDI) with mice expressing green fluorescent protein (GFP) under the flt-1/VEGFR1 promoter in vessels (GFP_FLT1). Our data show, that only very few Aβ plaques were seen in 4-months old mice, focused in the mammillary body and in the lateral septal nucleus. The number of plaques markedly increased with age being most prominent in 12-months old mice. Thiazine Red was used to verify the plaques. Several Thiazine Red(+) inclusions were found in GFP(+) vessels, but only in non-perfused 4-months old mice. These inclusions were verified by Resorufin stainings possibly representing cerebral amyloid angiopathy. The inclusions were also seen in non-crossbred APP_SweDI but not in wildtype and GFP_FLT1 mice. In order to characterize these inclusions Flow Cytometry (FACS) analysis demonstrated that platelets were specifically stained by Thiazine Red(+), more pronounced when aggregated. In conclusion, our data show that Thiazine Red(+) inclusions representing aggregated platelets are a first pathological sign in AD before plaque development and may become important therapeutic targets in early AD. PMID:27345467

  4. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.

    Science.gov (United States)

    Rosen, Rebecca F; Tomidokoro, Yasushi; Farberg, Aaron S; Dooyema, Jeromy; Ciliax, Brian; Preuss, Todd M; Neubert, Thomas A; Ghiso, Jorge A; LeVine, Harry; Walker, Lary C

    2016-08-01

    The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloidangiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. PMID:27318146

  5. Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.

    Directory of Open Access Journals (Sweden)

    Bruce Chesebro

    2010-03-01

    Full Text Available Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres. PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen, a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI. Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

  6. Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition

    Directory of Open Access Journals (Sweden)

    DeFilippis Kelly

    2007-09-01

    Full Text Available Abstract The deposition of amyloid β-protein (Aβ in cerebral vasculature, known as cerebral amyloid angiopathy (CAA, is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β precursor protein transgenic mice harboring two CAA Aβ mutations (Dutch E693Q and Iowa D694N that mimic the prevalent cerebral microvascular Aβ deposition observed in those patients, and the Swedish mutations (K670N/M671L to increase Aβ production. In these Tg-SwDI mice, we have reported predominant fibrillar Aβ along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular Aβ in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular Aβ. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus, C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular Aβ deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular Aβ deposition that is

  7. PiB fails to map amyloid deposits in cerebral cortex of aged dogs with Canine Cognitive Dysfunction

    DEFF Research Database (Denmark)

    Fast, Rikke; Rodell, Anders; Gjedde, Albert; Mouridsen, Kim; Alstrup, Aage Kristian Olsen; Bjarkam, Carsten Reidies; West, Mark J.; Berendt, Mette; Møller, Arne

    2013-01-01

    Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to...

  8. Ischaemic stroke in children secondary to post varicella angiopathy.

    LENUS (Irish Health Repository)

    Hayes, B

    2007-01-01

    Varicella in childhood is a self-limiting disease, which usually follows a benign course. However, complications, although rare, may have serious consequences. Ischaemic stroke secondary to post varicella angiopathy is a well-described complication and is estimated to account for up to a third of all strokes in infants. We present three previously healthy children who presented to our centre with ischaemic cerebrovascular infarction due to varicella angiopathy. All three children first presented within six weeks after onset of varicella infection and had MRI changes characteristic of ischaemic stroke secondary to post varicella angiopathy. While one child made an excellent recovery being left with only a minor deficit, the remaining two children were left with considerable morbidity severely affecting quality of life. The varicella vaccine has been proven to be well tolerated, safe and effective. We conclude that varicella vaccination should be considered for inclusion in the vaccination schedule to prevent serious complications which while rare may have devastating consequences.

  9. 78 FR 38352 - Government-Owned Inventions; Availability for Licensing

    Science.gov (United States)

    2013-06-26

    ..., neurofibrillary tangles, cerebral amyloid angiopathy, hyperphosphorylated tau, paired-helical filaments, Hirano...). Publication: Akagi I, et al. Combination of protein coding and non- coding gene expression as a...

  10. Beta-Amyloid Downregulates MDR1-P-Glycoprotein (Abcb1 Expression at the Blood-Brain Barrier in Mice

    Directory of Open Access Journals (Sweden)

    Anja Brenn

    2011-01-01

    Full Text Available Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic β-amyloid (Aβ peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1 is involved in the export of Aβ from the brain into the blood. To determine whether Aβ influences the expression of key Aβ transporters, we studied the effects of 1-day subcutaneous Aβ1-40 and Aβ1-42 administration via Alzet mini-osmotic pumps on P-gp, BCRP, LRP1, and RAGE expression in the brain of 90-day-old male FVB mice. Our results demonstrate significantly reduced P-gp, LRP1, and RAGE mRNA expression in mice treated with Aβ1-42 compared to controls, while BCRP expression was not affected. The expression of the four proteins was unchanged in mice treated with Aβ1-40 or reverse-sequence peptides. These findings indicate that, in addition to the age-related decrease of P-gp expression, Aβ1-42 itself downregulates the expression of P-gp and other Aβ-transporters, which could exacerbate the intracerebral accumulation of Aβ and thereby accelerate neurodegeneration in Alzheimer's disease and cerebral β-amyloid angiopathy.

  11. Quercetin protects human brain microvascular endothelial cells from fibrillar β-amyloid1–40-induced toxicity

    Directory of Open Access Journals (Sweden)

    Yongjie Li

    2015-01-01

    Full Text Available Amyloid beta-peptides (Aβ are known to undergo active transport across the blood-brain barrier, and cerebral amyloid angiopathy has been shown to be a prominent feature in the majority of Alzheimer׳s disease. Quercetin is a natural flavonoid molecule and has been demonstrated to have potent neuroprotective effects, but its protective effect on endothelial cells under Aβ-damaged condition is unclear. In the present study, the protective effects of quercetin on brain microvascular endothelial cells injured by fibrillar Aβ1–40 (fAβ1–40 were observed. The results show that fAβ1–40-induced cytotoxicity in human brain microvascular endothelial cells (hBMECs can be relieved by quercetin treatment. Quercetin increases cell viability, reduces the release of lactate dehydrogenase, and relieves nuclear condensation. Quercetin also alleviates intracellular reactive oxygen species generation and increases superoxide dismutase activity. Moreover, it strengthens the barrier integrity through the preservation of the transendothelial electrical resistance value, the relief of aggravated permeability, and the increase of characteristic enzyme levels after being exposed to fAβ1–40. In conclusion, quercetin protects hBMECs from fAβ1–40-induced toxicity.

  12. Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: Relevance to accumulation of Aβ in Alzheimer's disease.

    Science.gov (United States)

    Zekonyte, Jurgita; Sakai, Kenji; Nicoll, James A R; Weller, Roy O; Carare, Roxana O

    2016-05-01

    Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer's disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. The motive force for the elimination of Aβ along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, Aβ rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E ε4 (ApoE4) mice. For drainage of Aβ to occur in a direction contrary to the pulse wave, some form of attachment to basement membrane would be required to prevent reflux of Aβ back into the brain during the passage of the subsequent pulse wave. In this study, we show first that apolipoprotein E co-localizes with Aβ in basement membrane drainage pathways in the walls of arteries. Secondly, we show by Atomic Force Microscopy that attachment of ApoE4/Aβ complexes to basement membrane laminin is significantly weaker than ApoE3/Aβ complexes. These results suggest that perivascular elimination of ApoE4/Aβ complexes would be less efficient than with other isoforms of apolipoprotein E, thus endowing a higher risk for Alzheimer's disease. Therapeutic correction for ApoE4/Aβ/laminin interactions may increase the efficiency of elimination of Aβ in the prevention of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327683

  13. In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Rob J A Nabuurs

    Full Text Available This study investigated the in vivo properties of two heavy chain antibody fragments (V(HH, ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(HH in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled V(HH by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All V(HH showed rapid renal clearance (10-20 min. Twenty-four hours post-injection (99mTc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for (99mTc-ni3A or DTPA((111In-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ was confirmed for both fluorescently labeled V(HH, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both V(HH showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that V(HH detect Aβ deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aβ deposits.

  14. In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

    Science.gov (United States)

    Nabuurs, Rob J A; Rutgers, Kim S; Welling, Mick M; Metaxas, Athanasios; de Backer, Maaike E; Rotman, Maarten; Bacskai, Brian J; van Buchem, Mark A; van der Maarel, Silvère M; van der Weerd, Louise

    2012-01-01

    This study investigated the in vivo properties of two heavy chain antibody fragments (V(H)H), ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(H)H in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled V(H)H by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All V(H)H showed rapid renal clearance (10-20 min). Twenty-four hours post-injection (99m)Tc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for (99m)Tc-ni3A or DTPA((111)In)-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ was confirmed for both fluorescently labeled V(H)H, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both V(H)H showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that V(H)H detect Aβ deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aβ deposits. PMID:22675537

  15. Dementia with non-hereditary cystatin C angiopathy

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Blöndal, H; Jóhannesson, G;

    1989-01-01

    Brain biopsies from two patients with non-hereditary cerebral hemorrhages and eighty autopsied cases with the clinical diagnosis of dementia are presented. The biopsied cases, both males aged 64 and 59, had a sudden onset of cerebral hemorrhage, mild progressive dementia and cystatin C cerebral...

  16. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

    Directory of Open Access Journals (Sweden)

    Anckarsäter Henrik

    2010-06-01

    Full Text Available Abstract Background The metabolism of amyloid precursor protein (APP and β-amyloid (Aβ is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB. Methods The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau, phosphorylated tau (P-tau and neurofilament protein (NFL were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. Results In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up. Conclusions Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

  17. Operative neurosurgery. Personal view and historical backgrounds. (9) Moyamoya angiopathy (MMA). Past history and status presens

    International Nuclear Information System (INIS)

    The second international meeting on the Moyamoya angiopathy (MMA) was held in mid. July 2011 at the children's hospital Zurich by Frau PD Dr.Khan and Prof.Meuli. On this occasion I was asked to give a survey of this disease, so the following points were presented and discussed: Who was the person who discovered this disease. How has the Research Committee of the Ministry of Health and Welfare, Japan (RCMHWJ) contributed to clarify the epidemiology, etiology, pathophysiology and treatments. What is the current situation in foreign countries especially Euroamerican to date on these topics. How the treatment technique developed and who did the initial revascularization procedures for the first. Update of the disease. Established view; discovery of the disease by Tekeuchi and Shimizu in 1955 could have been called somewhat into question as they described neither abnormal vasculature nor transdural anastomosis. Kudo who described ''spontaneous occlusion of the circle of Willis'' more precisely, but seemed to have thought that the occlusion site of the internal carotid artery (ICA) is around the origin of the ophthalmic artery. Suzuki and Takaku who coined the name Moyamoya disease (MMD) in 1969 and described 6 stages of progression on the basis of observation on 20 cases. The RCMHWJ founded in 1977 has contributed to clarifying the epidemiology, pathophysiology, treatment and etiology by interdisciplinary cooperative study having some epoch making events especially; by setting the guide lines -diagnostic criteria of the disease at the end of 1970, applying MRI and MR angiography (MRA) at the beginning of 1990 for the diagnosis instead of angiography used until then. By finding and focusing, therefore, on the cases of asymptomatic or oligosymptomatic presentation around the middle of 2000, which have almost doubled or tripled in incidence and/or prevalence and also changed the age distribution with the higher peak for adult cases. Achievements of research for the

  18. In vivo amyloid imaging in Alzheimer's disease

    International Nuclear Information System (INIS)

    Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies. (orig.)

  19. B-Amyloid Precursor Protein Staining of the Brain in Sudden Infant and Early Childhood Death

    DEFF Research Database (Denmark)

    Jensen, Lisbeth Lund; Banner, Jytte; Ulhøi, Benedicte Parm;

    2013-01-01

    To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children.......To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children....

  20. Proteólisis cerebral del péptido amiloide-ß: Relevancia de la enzima degradadora de insulina en la enfermedad de Alzheimer Cerebral proteolysis of amyloid-ß peptide: Relevance of insulin-degrading enzyme in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2009-10-01

    Full Text Available El aumento global de la expectativa de vida convierte a la enfermedad de Alzheimer (EA en un problema creciente. Una de las características distintivas de EA es la acumulación excesiva del péptido amiloide ß (Aß en el cerebro. En los últimos años se ha fortalecido el concepto de que la degradación de Aß por proteasas in situ es un mecanismo importante que previene su acumulación cerebral. Datos bioquímicos y genéticos mostraron que la enzima degradadora de insulina (IDE participa en la homeostasis de Aß e insulina. La expresión y la actividad de IDE están significativamente disminuidas en cerebros con EA comparados con controles de igual edad. Además, IDE se deposita con Aß en placas seniles y vasos, indicando un grosero cambio conformacional producto de distintos mecanismos post-traduccionales. Estas alteraciones en la distribución y actividad de IDE resultan en una insuficiente degradación de Aß e insulina y promueven la formación de oligómeros de Aß y la resistencia a la hormona, procesos que convergen hacia la neurodegeneración. El estudio de los mecanismos de eliminación de Aß cerebral no sólo ayudará a comprender la patogenia de EA sino que permitirá una mejor interpretación de los ensayos clínicos en curso y el desarrollo de nuevas estrategias terapéuticas.The global increase in life expectancy turns Alzheimer's disease (AD into a growing problem. One of the distinctive features of AD is the excessive accumulation of amyloid-ß (Aß peptide in the brain. In recent years, a concept that has gained strength is that degradation of Aß by proteases in situ is an important mechanism that prevents cerebral peptide accumulation. Biochemical and genetic data have shown that insulin-degrading enzyme (IDE participates in Aß and insulin homeostasis. IDE expression and activity are significantly decreased in AD brains compared to age-matched controls. Also, IDE is deposited with Aß in senile plaques and blood vessels

  1. Clinical significance of changes of serum levels of sICAM-1 and HA in patients with type-2 diabetes complicated with angiopathy

    International Nuclear Information System (INIS)

    Objective: To study the significance of changes of serum soluble intercellular adhesion molecule-1 (sICAM-1) and hyaluronic acid (HA) levels in patients with type-2 diabetes complicated with angiopathy. Methods: Serum levels of sICAM-1 (by ELISA) and HA (by RIA) were measured in 66 cases of type-2 diabetes complicated with angiopathy and 35 controls. Contents of fasting blood glucose (FBG), glycosylated hemoglobin (HbAIC) and urine microalbumin (MAlb) were also measured for correlation analysis studies. Results: Serum sICAM-1 and HA levels in patients with type-2 diabetic angiopathy were significantly higher than those in controls (p<0.01) and were closely positively correlated to the contents of FBG, HbAIC and MAlb (p<0.01). Conclusion: Higher serum sICAM-1 and HA levels may play some role in the pathogenesis of type-2 diabetic angiopathy

  2. Cerebral Hypoxia

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  3. In vivo amyloid imaging in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Sair, H.I.; Doraiswamy, P.M.; Petrella, J.R. [Department of Radiology, Box 3808, Duke University Medical Center, NC 27710, Durham (United States)

    2004-02-01

    Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies. (orig.)

  4. In situ hybridization of nucleus basalis neurons shows increased β-amyloid mRNA in Alzheimer disease

    International Nuclear Information System (INIS)

    To determine which cells within the brain produce β-amyloid mRNA and to assess expression of the β-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that β-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more β-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the β-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease

  5. Tuberculoma cerebral Cerebral tuberculoma

    OpenAIRE

    ELIZABETH CLARA BARROSO; TÂNIA REGINA BRÍGIDO DE OLIVEIRA; ANA MARIA DANTAS DO AMARAL; VALÉRIA GÓES FERREIRA PINHEIRO; ANA LÚCIA DE OLIVEIRA SOUSA

    2002-01-01

    Relata-se o caso de paciente com crises convulsivas de início recente. A tomografia computadorizada cerebral evidenciou imagem sugestiva de lesão expansiva metastática frontoparietal direita. A investigação de tumor primário ou outra doença foi negativa e o exame histopatológico do tecido cerebral diagnosticou tuberculoma. As convulsões foram controladas com a associação de hidantoína 300mg/dia ao esquema específico, utilizado por 18 meses. A tuberculose do sistema nervoso central representa ...

  6. Amyloid Fibril Solubility.

    Science.gov (United States)

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general. PMID:26496385

  7. Amyloid Fibril Solubility

    CERN Document Server

    Rizzi, L G

    2015-01-01

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain side-chain interactions, backbone hydrogen bonding and temperature affect amyloid fibril solubility, which might prove a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  8. Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Abeta40 (DAbeta(1-40)) are modulated by sulfate moieties of heparin.

    NARCIS (Netherlands)

    Timmer, N.M.; Schirris, T.J.J.; Bruinsma, I.B.; Otte-Holler, I.; Kuppevelt, A.H.M.S.M. van; Waal, R.M.W. de; Verbeek, M.M.

    2010-01-01

    Glycosaminoglycans (GAGs), in particular as part of heparan sulfate proteoglycans, are associated with cerebral amyloid angiopathy (CAA). Similarly, GAGs are also associated with the severe CAA found in patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-

  9. Cerebral Palsy

    Science.gov (United States)

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  10. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...

  11. Cerebral Atrophy

    Science.gov (United States)

    ... Alzheimer’s disease, Pick’s disease, and fronto-temporal dementia cerebral palsy , in which lesions (damaged areas) may impair motor ... lead to cerebral atrophy. NIH Patient Recruitment for Cerebral Atrophy Clinical Trials ... by: Office of Communications and Public Liaison National Institute of Neurological Disorders ...

  12. Amyloids here, amyloids there…What’s wrong with them?

    OpenAIRE

    Gharibyan, Anna

    2012-01-01

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical...

  13. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Yanjun Zhang; Shuai Du; Mixia Zhang

    2011-01-01

    Berberine, a major constituent of Coptidis rhizoma, exhibits neural protective effects. The present study analyzed the potential protective effect of berberine against amyloid G-induced cytotoxicity in rat cerebral cortical neurons. Alzheimer's disease cell models were treated with 0.5 and 2 μmol/Lberberine for 36 hours to inhibit amyloid G-induced toxicity. Methyl thiazolyl tetrazolium assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining results showed that berberine significantly increased cell viability and reduced cell apoptosis in primary cultured rat cortical neurons. In addition, western blot analysis revealed a protective effect of berberine against amyloid β-induced toxicity in cultured cortical neurons, which coincided with significantly decreased abnormal up-regulation of activated caspase-3. These results showed that berberine exhibited a protective effect against amyloid 13-induced cytotoxicity in cultured rat cortical neurons.

  14. Alzheimer’s Disease and Glaucoma: Mechanistic Similarities and Differences

    OpenAIRE

    Ghiso, Jorge A.; Doudevski, Ivo; Ritch, Robert; Agueda A. Rostagno

    2013-01-01

    Alzheimer’s disease (AD) is the most common form of dementia. Intraneuronal neurofibrillary tangles, extracellular Aβ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy, and synaptic and neuronal loss co-exist in the brain parenchyma, with the limbic areas being the most severely affected. The classic clinical findings are personality changes, progressive cognitive dysfunction, and loss of ability to perform activities of daily living. Visual impairment is common ...

  15. Novel immunological approaches for the treatment of Alzheimer's disease

    OpenAIRE

    Priyanka Sabharwal; Thomas Wisniewski

    2014-01-01

    Alzheimer's disease (AD), the most prevalent form of dementia worldwide, can be deemed as the next global health epidemic. The biochemistry underlying deposition of amyloid beta (A β) and hyperphosphorylated tau aggregates in AD has been extensively studied. The oligomeric forms of Aβ that are derived from the normal soluble Aβ peptides are believed to be the most toxic. However, it is the fibrillar Aβ form that aggregates as amyloid plaques and cerebral amyloid angiopathy, which serve as pat...

  16. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Wanhong Zhao; Chao Luo; Jue Wang; Jian Gong; Bin Li; Yingxia Gong; Jun Wang; Hanqin Wang

    2014-01-01

    3-N-butylphthalide is an effective drug for acute ischemic stroke. However, its effects on chronic cerebral ischemia-induced neuronal injury remain poorly understood. Therefore, this study li-gated bilateral carotid arteries in 15-month-old rats to simulate chronic cerebral ischemia in aged humans. Aged rats were then intragastrically administered 3-n-butylphthalide. 3-N-butylphtha-lide administration improved the neuronal morphology in the cerebral cortex and hippocampus of rats with chronic cerebral ischemia, increased choline acetyltransferase activity, and decreased malondialdehyde and amyloid beta levels, and greatly improved cognitive function. These findings suggest that 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby im-proving cerebral neuronal injury and cognitive deifcits.

  17. Houshiheisan compound prescription protects neurovascular units after cerebral ischemia.

    Science.gov (United States)

    Wang, Haizheng; Wang, Lei; Zhang, Nan; Zhang, Qi; Zhao, Hui; Zhang, Qiuxia

    2014-04-01

    Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-β 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-β 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra. PMID:25206882

  18. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons

    OpenAIRE

    Guo, Shuzhen; Kim, Woo Jean; Lok, Josephine; Lee, Sun-Ryung; Besancon, Elaine; Luo, Bing-Hao; Stins, Monique F.; Wang, Xiaoying; Dedhar, Shoukat; Lo, Eng H.

    2008-01-01

    The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This ph...

  19. Tuberculoma cerebral Cerebral tuberculoma

    Directory of Open Access Journals (Sweden)

    ELIZABETH CLARA BARROSO

    2002-01-01

    Full Text Available Relata-se o caso de paciente com crises convulsivas de início recente. A tomografia computadorizada cerebral evidenciou imagem sugestiva de lesão expansiva metastática frontoparietal direita. A investigação de tumor primário ou outra doença foi negativa e o exame histopatológico do tecido cerebral diagnosticou tuberculoma. As convulsões foram controladas com a associação de hidantoína 300mg/dia ao esquema específico, utilizado por 18 meses. A tuberculose do sistema nervoso central representa 5-15% das formas extrapulmonares e é reconhecida como de alta letalidade. Apresentação tumoral como a relatada é rara, particularmente em imunocompetentes. Quando tratada, pode ter bom prognóstico e deve entrar sempre no diagnóstico diferencial de massas cerebrais.It is reported a case of a previously healthy man with seizures of sudden onset. A contrast head computerized tomogram (CT showed a right frontoparietal expanding lesion suggesting to be metastatic. No prior disease was found on investigation. The histologic exam of the brain revealed tuberculoma. The seizures were controlled with Hidantoin 300 mg/day and antituberculosis chemotherapy for 18 months. Central nervous system tuberculosis (5-15% of the extrapulmonary forms is highly lethal. The case reported herein is specially rare in immunocompetent patients. It may have good prognosis and should be considered in the differential diagnosis of brain tumours.

  20. Musculoskeletal amyloid disease: MRI features

    International Nuclear Information System (INIS)

    A case of arthropathy and soft tissue masses due to amyloid deposition in a patient with myeloma is reported. The radiologic and magnetic resonance findings of musculoskeletal amyloidosis are described. The amyloid masses show heterogeneous signal intensity, with a signal lower than muscle and intermingled areas of marked hyperintensity on T 2-weighted images. (authors). 7 refs., 2 figs

  1. Musculoskeletal amyloid disease: MRI features

    Energy Technology Data Exchange (ETDEWEB)

    Del Castillo, M.; Guerra, J.L. [Hospital Arquitecto Marcide, Ferrol (Spain); Comesana, L.; Martin, R. [Hospital Arquitecto Marcide, Ferrol (Spain)]|[Hospital Juan Canalejo, La Coruna (Spain); Rodriguez, E.; Soler, R. [Hospital Juan Canalejo, La Coruna (Spain)

    1995-12-31

    A case of arthropathy and soft tissue masses due to amyloid deposition in a patient with myeloma is reported. The radiologic and magnetic resonance findings of musculoskeletal amyloidosis are described. The amyloid masses show heterogeneous signal intensity, with a signal lower than muscle and intermingled areas of marked hyperintensity on T 2-weighted images. (authors). 7 refs., 2 figs.

  2. Cerebral Palsy

    Science.gov (United States)

    ... 1 • 2 • 3 For Teens For Kids For Parents MORE ON THIS TOPIC Cerebral Palsy: Keith's Story Physical Therapy I Have Cerebral Palsy. Can I Babysit? Body Image and Self-Esteem Contact Us Print Resources Send to a friend ...

  3. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    International Nuclear Information System (INIS)

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.)

  4. Cerebral palsy.

    Science.gov (United States)

    Graham, H Kerr; Rosenbaum, Peter; Paneth, Nigel; Dan, Bernard; Lin, Jean-Pierre; Damiano, Diane L; Becher, Jules G; Gaebler-Spira, Deborah; Colver, Allan; Reddihough, Dinah S; Crompton, Kylie E; Lieber, Richard L

    2016-01-01

    Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging. PMID:27188686

  5. How Ionic Strength Affects the Conformational Behavior of Human and Rat Beta Amyloids - A Computational Study

    OpenAIRE

    Kriz Z.; Klusak J.; Kristofikova Z.; Koca J.

    2016-01-01

    Progressive cerebral deposition of amyloid beta occurs in Alzheimeŕs disease and during the aging of certain mammals (human, monkey, dog, bear, cow, cat) but not others (rat, mouse). It is possibly due to different amino acid sequences at positions 5, 10 and 13. To address this issue, we performed series of 100 ns long trajectories (each trajectory was run twice with different initial velocity distribution) on amyloid beta (1–42) with the human and rat amino acid sequence in three different e...

  6. Corkscrew angiopathy of intracranial vessels in a young stroke patient: a case report

    OpenAIRE

    Alurkar Anand; Karanam Lakshmi Sudha P; Oak Sagar P

    2012-01-01

    Abstract Introduction We present a rare finding of a ‘corkscrew appearance’ of the distal cerebral vessels in a young Asian woman who presented with acute stroke. Case presentation A 32-year-old Asian woman presented with a 3-month history of recurrent right-sided transient ischemic attacks. Her clinical workup and brain imaging results were normal. A digital subtraction angiogram revealed an abnormal corkscrew appearance of all intracranial distal vessels. She was discharged on a single anti...

  7. Cerebral hypoxia

    Science.gov (United States)

    ... the veins ( deep vein thrombosis ) Lung infections (pneumonia) Malnutrition When to Contact a Medical Professional Cerebral hypoxia ... References Bernat JL. Coma, vegetative state, and brain death. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

  8. Drug: D06202 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 0303 139.1735 D06202.gif Treatment of mild-to-moderate Alzheimer's disease, treatment of cerebral amyloid an...giopathy Same as: C03349 map07056 Agents for Alzheimer-type dementia CAS: 3687-18-1 PubChem: 47207860 PDB-CC

  9. Cerebral Palsy (For Parents)

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Cerebral Palsy KidsHealth > For Parents > Cerebral Palsy Print A A ... kids who are living with the condition. About Cerebral Palsy Cerebral palsy is one of the most common ...

  10. Towards a Pharmacophore for Amyloid

    Energy Technology Data Exchange (ETDEWEB)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David (UCLA)

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a

  11. Polyfluorinated bis-styrylbenzenes as amyloid-β plaque binding ligands.

    Science.gov (United States)

    Nabuurs, Rob J A; Kapoerchan, Varsha V; Metaxas, Athanasios; de Jongh, Sanne; de Backer, Maaike; Welling, Mick M; Jiskoot, Wim; Windhorst, Albert D; Overkleeft, Hermen S; van Buchem, Mark A; Overhand, Mark; van der Weerd, Louise

    2014-04-15

    Detection of cerebral β-amyloid (Aβ) by targeted contrast agents remains of great interest to aid the in vivo diagnosis of Alzheimer's disease (AD). Bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. To further explore their potency as (19)F MRI contrast agents we synthetized several novel fluorinated bis-styrylbenzenes and studied their fluorescent properties and amyloid-β binding characteristics. The compounds showed a high affinity for Aβ plaques on murine and human brain sections. Interestingly, competitive binding experiments demonstrated that they bound to a different binding site than chrysamine G. Despite their high logP values, many bis-styrylbenzenes were able to enter the brain and label murine amyloid in vivo. Unfortunately initial post-mortem (19)F NMR studies showed that these compounds as yet do not warrant further MRI studies due to the reduction of the (19)F signal in the environment of the brain. PMID:24657049

  12. Tuberculoma cerebral

    OpenAIRE

    BARROSO ELIZABETH CLARA; OLIVEIRA TÂNIA REGINA BRÍGIDO DE; AMARAL ANA MARIA DANTAS DO; PINHEIRO VALÉRIA GÓES FERREIRA; SOUSA ANA LÚCIA DE OLIVEIRA

    2002-01-01

    Relata-se o caso de paciente com crises convulsivas de início recente. A tomografia computadorizada cerebral evidenciou imagem sugestiva de lesão expansiva metastática frontoparietal direita. A investigação de tumor primário ou outra doença foi negativa e o exame histopatológico do tecido cerebral diagnosticou tuberculoma. As convulsões foram controladas com a associação de hidantoína 300mg/dia ao esquema específico, utilizado por 18 meses. A tuberculose do sistema nervoso central representa ...

  13. Phenolic Compounds Prevent Amyloid β-Protein Oligomerization and Synaptic Dysfunction by Site-specific Binding*

    OpenAIRE

    Ono, K.; Li, L.; Takamura, Y; Yoshiike, Y; L. Zhu; Han, F.; Mao, X; Ikeda, T; Takasaki, JI; Nishijo, H; Takashima, A.; Teplow, DB; Zagorski, MG; Yamada, M.

    2012-01-01

    Cerebral deposition of amyloid β protein (Aβ) is an invariant feature of Alzheimer disease (AD), and epidemiological evidence suggests that moderate consumption of foods enriched with phenolic compounds reduce the incidence of AD. We reported previously that the phenolic compounds myricetin (Myr) and rosmarinic acid (RA) inhibited Aβ aggregation in vitro and in vivo. To elucidate a mechanistic basis for these results, we analyzed the effects of five phenolic compounds in the Aβ aggregation pr...

  14. Is Verbal Episodic Memory in Elderly with Amyloid Deposits Preserved Through Altered Neuronal Function?

    OpenAIRE

    Ossenkoppele, Rik; Madison, Cindee,; Oh, Hwamee; Wirth, Miranka; van Berckel, Bart N. M.; Jagust, William J.

    2013-01-01

    A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [11C]Pittsburgh Compound-B and [18F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aβ (n = 53), intermediate-Aβ ...

  15. Corkscrew angiopathy of intracranial vessels in a young stroke patient: a case report

    Directory of Open Access Journals (Sweden)

    Alurkar Anand

    2012-10-01

    Full Text Available Abstract Introduction We present a rare finding of a ‘corkscrew appearance’ of the distal cerebral vessels in a young Asian woman who presented with acute stroke. Case presentation A 32-year-old Asian woman presented with a 3-month history of recurrent right-sided transient ischemic attacks. Her clinical workup and brain imaging results were normal. A digital subtraction angiogram revealed an abnormal corkscrew appearance of all intracranial distal vessels. She was discharged on a single antiplatelet drug. She had no further transient ischemic attacks on clinical follow-up. A digital subtraction angiogram performed 1 year later revealed no changes in the appearance of these vessels. Conclusion To the best of our knowledge no similar previous reports exist in the literature. The present report describes a unique case of an unusual corkscrew appearance of the distal intracranial vessels. However, the underlying etiology in the present case remains unknown.

  16. Cerebral Microcirculation during Experimental Normovolaemic Anemia

    Science.gov (United States)

    Bellapart, Judith; Cuthbertson, Kylie; Dunster, Kimble; Diab, Sara; Platts, David G.; Raffel, O. Christopher; Gabrielian, Levon; Barnett, Adrian; Paratz, Jenifer; Boots, Rob; Fraser, John F.

    2016-01-01

    Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain. PMID:26869986

  17. Cerebral Arteriosclerosis

    Science.gov (United States)

    ... the brain can cause a hemorrhagic stroke. Both types of stroke can be fatal. Cerebral arteriosclerosis is also related to a condition known as vascular dementia, in which small, symptom-free strokes cause cumulative damage and death to neurons (nerve cells) in the brain. Personality changes in ...

  18. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission.

    Science.gov (United States)

    Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo

    2016-06-01

    Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID:26002948

  19. Functional Amyloid Formation within Mammalian Tissue.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  20. Nanomechanical properties of single amyloid fibrils

    Science.gov (United States)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  1. Employees with Cerebral Palsy

    Science.gov (United States)

    ... Resources Home | Accommodation and Compliance Series: Employees with Cerebral Palsy (CP) By Eddie Whidden, MA Preface Introduction Information ... SOAR) at http://AskJAN.org/soar. Information about Cerebral Palsy (CP) What is CP? Cerebral palsy is a ...

  2. Amyloid formation: functional friend or fearful foe?

    Science.gov (United States)

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  3. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study.

    Science.gov (United States)

    Leuzy, Antoine; Chiotis, Konstantinos; Hasselbalch, Steen G; Rinne, Juha O; de Mendonça, Alexandre; Otto, Markus; Lleó, Alberto; Castelo-Branco, Miguel; Santana, Isabel; Johansson, Jarkko; Anderl-Straub, Sarah; von Arnim, Christine A F; Beer, Ambros; Blesa, Rafael; Fortea, Juan; Herukka, Sanna-Kaisa; Portelius, Erik; Pannee, Josef; Zetterberg, Henrik; Blennow, Kaj; Nordberg, Agneta

    2016-09-01

    The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference

  4. Renal vascular reverse could stratify angiopathy in diabetic patients using baseline an acetazolamide Tc99mMAG-3 renography

    International Nuclear Information System (INIS)

    Purpose: The aim of this study was to determine whether or not Tc99mMAG-3 renography can stratify the severity of renal parenchymal damage related to angiopathy in patients with normal, hypertension and diabetes with hypertension by combining baseline with Acetazolamide (ACZ), an inhibitor of carbonic anhydrase, renography. Methods: We obtained the informed consent of 30 patients to participate in this study of baseline and ACZ renography. There were divided into three groups of 10 each as follows: normal (NR), essential hypertension (EH) and Type 2 diabetes with hypertension (DM). We performed baseline renography for 20 min after an injection of 370 MBq Tc99mMAG-3, followed by ACZ renography performed in the same manner 10 min after a 1g injection ACZ. Quantitative analyses included tubular extraction rate (TER), effective renal plasma flow (ERPF) and time to the maximum activity of the renal curve (Tmax) determined using the deconvolution method applied to the time activity curve of Tc99mMAG-3 in the kidneys. The percent change in TER (ERPF and Tmax) between the baseline and ACZ renography was obtained in the following manner: %TER (%ERPF and %Tmax) = [ACZ TER (ERPF and Tmax) - baseline TER (ERPF and Tmax)] x 100/baseline TER (ERPF and Tmax) Corrected %TER (%ERPF and % Tmax) was then obtained by subtracting the variation in %TER (%ERPF and % Tmax) between baseline and sequential renograms derived from 10 control patients (CR group) injected with distilled water, from those injected with ACZ. Results: These parameters did not significantly differ between the Nr and Eh groups, but the differences between the Dm and Nr groups and between the Dm and Eh groups were significant (p<0.01). Conclusion: Combined baseline and ACZ Tc99mMAG-3 renography can evaluate renal vascular reverse, a loss of which could represent microangiopathy in diabetic patients (au)

  5. Cerebral palsy

    International Nuclear Information System (INIS)

    This paper reviews cranial MR findings in patients with cerebral palsy (CP) to clarify and categorize this disorder. The MR images of 40 patients with clinical CP were retrospectively reviewed. All patients suffered either varying spastic plegias, hypotonicity, or choreoathetosis. Concomitantly, the patients suffered from static encephalopathy, developmental delay, and/or microcephaly. Twenty-four patients were born at or near term, 10 were premature, and incomplete birth histories were available in six. The MR images revealed mild to severe degrees of white matter damage in 24 patients (12 term, nine premature, three unknown)

  6. Amyloid Goiter Secondary to Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Bunyamin Aydin

    2016-01-01

    Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

  7. Amyloid Goiter Secondary to Ulcerative Colitis.

    Science.gov (United States)

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  8. In vivo amyloid imaging with PET in frontotemporal dementia

    Energy Technology Data Exchange (ETDEWEB)

    Engler, Henry [Uruguay University Hospital of Clinics and Faculty of Science, Department of Nuclear Medicine, Montevideo (Uruguay); Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Uppsala (Sweden); GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena [Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Wang, Shu Xia [Guangdong Provincial People' s Hospital, Weilun PET Centre, Guangzhou (China); Savitcheva, Irina [Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Nordberg, Agneta [Karolinska Institute, Division of Molecular Neuropharmacology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Laangstroem, Bengt [GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Uppsala University, Departments of Biochemistry and Organic Chemistry, Uppsala (Sweden)

    2008-01-15

    N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

  9. In vivo amyloid imaging with PET in frontotemporal dementia

    International Nuclear Information System (INIS)

    N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

  10. DNA aptamers detecting generic amyloid epitopes

    OpenAIRE

    Mitkevich, Olga V.; Kochneva-Pervukhova, Natalia V; Surina, Elizaveta R.; Benevolensky, Sergei V.; Kushnirov, Vitaly V.; Ter-Avanesyan, Michael D.

    2012-01-01

    Amyloids are fibrillar protein aggregates resulting from non-covalent autocatalytic polymerization of various structurally and functionally unrelated proteins. Previously we have selected DNA aptamers, which bind specifically to the in vitro assembled amyloid fibrils of the yeast prionogenic protein Sup35. Here we show that such DNA aptamers can be used to detect SDS-insoluble amyloid aggregates of the Sup35 protein, and of some other amyloidogenic proteins, including mouse PrP, formed in yea...

  11. Amyloid myopathy: a diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Heli Tuomaala

    2009-08-01

    Full Text Available Amyloid myopathy (AM is a rare manifestation of primary systemic amyloidosis (AL. Like inflammatory myopathies, it presents with proximal muscle weakness and an increased creatine kinase level. We describe a case of AL with severe, rapidly progressive myopathy as the initial symptom. The clinical manifestation and muscle biopsy were suggestive of inclusion body myositis. AM was not suspected until amyloidosis was seen in the gastric mucosal biopsy. The muscle biopsy was then re-examined more specifically, and Congo red staining eventually showed vascular and interstitial amyloid accumulation, which led to a diagnosis of AM. The present case illustrates the fact that the clinical picture of AM can mimic that of inclusion body myositis.

  12. Towards a Pharmacophore for Amyloid

    Science.gov (United States)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  13. Cerebral malaria.

    Science.gov (United States)

    Postels, Douglas G; Birbeck, Gretchen L

    2013-01-01

    Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood-brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed. PMID:23829902

  14. The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice

    OpenAIRE

    Vidal, Ruben; Sammeta, Neeraja; Garringer, Holly J.; Sambamurti, Kumar; Miravalle, Leticia; Lamb, Bruce T.; Ghetti, Bernardino

    2012-01-01

    Genetically engineered mice have been generated to model cerebral β-amyloidosis, one of the hallmarks of Alzheimer disease (AD) pathology, based on the overexpression of a mutated cDNA of the amyloid-β precursor protein (AβPP) or by knock-in of the murine Aβpp gene alone or with presenilin1 mutations. Here we describe the generation and initial characterization of a new mouse line based on the presence of 2 copies of the human genomic region encoding the wild-type AβPP and the L166P presenili...

  15. Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  16. Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  17. Synthetic peptide homologous to β protein from Alzheimer's disease forms amyloid-like fibrils in vitro

    International Nuclear Information System (INIS)

    Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to β protein of brain amyloid: β-(1-28), residues 1-28 of the β protein; [Ala1-β-(1-28), β-(1-28) with alanine substituted for lysine at position 16; and β-(18-28), residues 18-28 of the β protein. β-(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-β-conformation. [Ala16]β-(1-28) formed β-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the β-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. Β-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer's-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis

  18. Cerebral cysticercosis

    International Nuclear Information System (INIS)

    Two cases of histologically proven cerebral cysticercosis are presented. In both cases subcutaneous tissue nodules, a rare feature, were present. Several disease patterns are apparent - meningeal, parenchymatous and ventricular, spinal cord lesions and mixed patterns. Epilepsy is by far the major presenting symptom of cysticercosis, which in turn plays a significant role in the causation of adult-onset epilepsy in Blacks. Despite its drawbacks, the haemag-glutination inhibition test remains the most satisfactory serological method at present available for the diagnosis of cysticercosis; it is positive in up to 85% of cases of proven cysticercosis. With the advent of computed tomography many cases of unsuspected cysticercosis (symptomatic or asymptomatic) are being discovered

  19. Dynamic changes of beta-amyloid protein deposition in hippocampus of female ovariectomized rats

    Institute of Scientific and Technical Information of China (English)

    Huiqing Xie; Jianda Zhou; Shaodan Sun; Xuhong Li; Liming Deng; Fengmei Li

    2008-01-01

    BACKGROUND: To evaluate and summarize the effects of cerebral perfusion and vascular reserve on the treatment of SICAS. Recently, research on β-amyloid protein has focused on the regulatory effects of es-trogen or phytoestrogen on its deposition. However, there have been only a few reports on dynamic changes of β-amyloid protein deposition in hippocampus of ovariectomized rats.OBJECTIVE: To measureβ-amyloid protein deposition in the hippocampal formation of ovariectomized rats by using immunohistochemistry; to observe time-dependent dynamic changes. DESIGN: Randomized controlled animal study.SETTING: Third Xiangya Hospital of Central South University.MATERIALS: The experiment was carried out in the Central Laboratory of the Third Xiangya Hospital of Central South University from November 2005 to December 2006. Fifty healthy female Sprague Dawley (SD) rats, weighing (293 ± 10) g, were provided by the Animal Laboratory of Xiangya Medical College, Central South University. All rats had neither a childbearing history nor hepatic or renal disease, or skeletal deformity. Β-amyloid protein immunohistochemical kit was provided by Wuhan Boster Company. The ex-periment was in accordance with animal ethics standards.METHODS: All rats were randomly divided into five groups, including normal control group (n = 10), sham operation group (n = 10), and ovariectomized group (n = 30). After anesthesia in the ovariectomized group, the bilateral ovaries were separated and resected. The same volume of fat was resected in the sham operation group. Rats from the normal control group, however, did not receive any surgical treatments. Rats in the normal control group and sham operation group were sacrificed by anesthesia 7 weeks after surgery. Every ten rats from the ovariectomized group was respectively sacrificed at 7, 15, and 30 weeks after surgery. Immunohistochemistry was used to detectβ-amyloid protein deposition in hippocampal sections. Cell counting and gray value

  20. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    Science.gov (United States)

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-04-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. PMID:3924450

  1. Cerebroprotective effect of Huanglian Jiedu decoction on amyloid protein precursor/presenilin-1 double transgenic mice

    Institute of Scientific and Technical Information of China (English)

    Xin Qiu; Guohua Chen; Gui Mei; Yuegu Wang; Kaixin Wang; Tao Wang; Pei Feng

    2011-01-01

    Huanglian Jiedu decoction (HLJDD) has been shown to improve cerebral blood flow, and reduce lipid peroxidation damage to the brain and its energy metabolism. The present study was designed to observe the cerebroprotective effect of HLJDD on an Alzheimer's disease rodent model,presenilin-1/amyloid protein precursor double transgenic mice. HLJDD reduced serum interleukin-6 and interleukin-1β levels, decreased β-amyloid precursor protein gene and senile plaque expression, resisted oxidation, and reduced free radical-induced injury, thereby improving the learning and memory of these mice. Moreover, HLJDD at 433 mg/kg per day exhibited better effects compared with that at 865 or 216 mg/kg per day, and donepezil hydrochloride at 30 mg/kg per day.Thus, these results suggest that HLJDD may have protective effects against Alzheimer's disease.

  2. Amyloid-β efflux from the CNS into the plasma

    Science.gov (United States)

    Roberts, Kaleigh Filisa; Elbert, Donald L.; Kasten, Tom P.; Patterson, Bruce W.; Sigurdson, Wendy C.; Connors, Rose E.; Ovod, Vitaliy; Munsell, Ling Y.; Mawuenyega, Kwasi G.; Miller-Thomas, Michelle M.; Moran, Christopher J.; Cross, Dewitte T.; Derdeyn, Colin P.; Bateman, Randall J.

    2015-01-01

    Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans. PMID:25205593

  3. Appropriate use criteria for amyloid PET imaging cannot replace guidelines: On behalf of the European association of nuclear medicine

    International Nuclear Information System (INIS)

    The recent approval of [18F]florbetapir by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in April and January 2013, respectively, for PET imaging of cerebral amyloid underlines the achievement of an important goal of molecular imaging, and emphasizes the potential role of this tool in the early diagnosis and management of patients with dementia. There are, however, some cautions concerning the use of brain amyloid radiotracers in clinical practice that have to be addressed. Therefore, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) convened the Amyloid Imaging Taskforce (AIT). The AIT recently published their guidance report in which they describe 'specific use criteria' which underlines their vision of the clinical utility of amyloid PET. Since we believe that amyloid imaging will be an important new tool for routine clinical studies in the near future, we resolved to provide a brief description and evaluation of this new technique and the most important topics described in the report. In addition we provide some comments on the report

  4. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Science.gov (United States)

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  5. [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey

    International Nuclear Information System (INIS)

    Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood–brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC50=10.5±1.3 nM). Conclusions: [18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

  6. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  7. Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Merz, G S; Schwenk, V;

    1999-01-01

    amyloidogenic mutation on the intracellular processing of its protein product. The protein, a mutant of the cysteine protease inhibitor cystatin C, is the amyloid precursor protein in Hereditary Cerebral Hemorrhage with Amyloidosis--Icelandic type (HCHWA-I). The amyloid fibers are composed of mutant cystatin C...... (L68Q) that lacks the first 10 amino acids. We have previously shown that processing of wild-type cystatin C entails formation of a transient intracellular dimer that dissociates prior to secretion, such that extracellular cystatin C is monomeric. We report here that the cystatin C mutation engenders...

  8. Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome.

    Directory of Open Access Journals (Sweden)

    Juliet A Moncaster

    Full Text Available Down syndrome (DS, trisomy 21 is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21 encoding the Alzheimer's disease (AD amyloid precursor protein (APP. Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta, early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta

  9. United Cerebral Palsy

    Science.gov (United States)

    ... Voices of UCP blog for the latest updates. United Cerebral Palsy UCP educates, advocates and provides support ... Our Partners Merz Logo Sprint Relay Copyright © 2015 United Cerebral Palsy 1825 K Street NW Suite 600 ...

  10. Cerebral palsy and epilepsy

    OpenAIRE

    Knežević-Pogančev Marija

    2010-01-01

    Introduction. Cerebral palsy is the most common cause of physical disability in early childhood. Epilepsy is known to have a high association with cerebral palsy. All types of epileptic seizures can be seen in patients with cerebral palsy. Complex partial and secondary generalized ones are the most frequent seizure types. In persons with cerebral palsy and mental retardation, the diagnosis of epilepsy presents unique difficulties. Generally they are not able to describe the epileptic ev...

  11. Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo

    Directory of Open Access Journals (Sweden)

    G. D. Rabinovici

    2009-01-01

    Full Text Available Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET with ^{11}carbon-labelled Pittsburgh Compound-B (11C-PIB, the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI and Alzheimer’s disease (AD. PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

  12. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    Science.gov (United States)

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (pCerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all pCerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction. PMID:24315581

  13. Molecular mechanisms of amyloid self-regulation

    OpenAIRE

    Landreh, Michael

    2012-01-01

    Amyloid is associated with both pathological protein deposits and the formation of functional protein structures. Therefore, several strategies have evolved to control the formation or inhibition of amyloid in vivo. In this thesis, three separate systems were investigated in which amyloidogenic protein segments are coupled to regulatory elements that prevent or promote fibrillation. We describe the molecular mechanism for how (a) a propeptide segment prevents the uncontrolled a...

  14. Amyloid myopathy presenting with respiratory failure.

    OpenAIRE

    Ashe, J.; Borel, C O; Hart, G.; Humphrey, R L; Derrick, D A; Kuncl, R W

    1992-01-01

    Amyloidosis is a rare cause of myopathy. Its prominent or presenting feature may be respiratory failure. Physiological measurement of transdiaphragmatic pressure and biopsy specimens of muscle show the pathological mechanism to be diaphragm weakness due to amyloid infiltration of the diaphragm rather than parenchymal lung involvement. Thus amyloid myopathy even without the typical macroglossia and muscle pseudohypertrophy should be considered as one of the neurological causes of respiratory f...

  15. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    Science.gov (United States)

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane. PMID:26673736

  16. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  17. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  18. Preferential Transport Theory for Beta-Amyloid Clearance from the Brain

    Science.gov (United States)

    Coloma, Mikhail; Schaffer, David; Chiarot, Paul; Huang, Peter

    2015-11-01

    The failure to clear beta-amyloid from the aging brain leads to its accumulation within the walls of arteries and to Alzheimer's disease. However, the transport mechanism for beta-amyloid clearance is not well understood. In this study, we propose a preferential transport theory for flow within the vascular walls in the cerebral arterial basement membrane. The flow conduit within the arterial basement membrane is modeled as an annulus between deformable concentric cylinders filled with an incompressible, single-phase Newtonian fluid. The transport is driven by arterial lumen deformation induced by heart pulsations superimposed with reflected boundary waves. Our theory predicts that while the overall arterial wave propagation is in the same direction as the blood flow toward the capillaries, a reverse flow in the basement membrane can be preferentially induced toward larger arteries. This has been suggested as a potential clearance pathway for beta-amyloid. We estimate the magnitude of the reverse transport through a control volume analysis which is corroborated by numerical solutions of the Navier-Stokes equations. Bench-top experiments to validate our computational models are presented.

  19. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    Science.gov (United States)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  20. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ilaria Canobbio

    2015-03-01

    Full Text Available Alzheimer’s disease (AD is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of the AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD. According to the vascular hypothesis, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorragic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review we analyse the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.

  1. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    Science.gov (United States)

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  2. Posttherapeutic cerebral radionecrosis: a complication of head and neck tumor therapy

    International Nuclear Information System (INIS)

    Patients with treated head and neck cancer may have focal neurologic symptoms and personality changes due to delayed cerebral radionecrosis. A history of past treatment should direct the physician to consider these lesions in the differential diagnosis. Craniotomy is the management recommended. Histopathologic changes include fibrotic response of the meninges with pleomorphic and vacuolated fibroblasts, capillary hyperplasia, reactive astrocytes, and fibrosis of the blood vessels. Amyloid is deposited in the arteriolar walls and extracellular space. Ischemic, autoimmune, or vascular mechanisms, and glial alterations have all been considered in the pathogensis of delayed cerebral radionecrosis. Some researchers have concluded that chemotherapeutic agents, such as methotrexate, may contribute to its production

  3. Posttherapeutic cerebral radionecrosis: a complication of head and neck tumor therapy

    Energy Technology Data Exchange (ETDEWEB)

    Araoz, C.; Weems, A.M.

    1981-12-01

    Patients with treated head and neck cancer may have focal neurologic symptoms and personality changes due to delayed cerebral radionecrosis. A history of past treatment should direct the physician to consider these lesions in the differential diagnosis. Craniotomy is the management recommended. Histopathologic changes include fibrotic response of the meninges with pleomorphic and vacuolated fibroblasts, capillary hyperplasia, reactive astrocytes, and fibrosis of the blood vessels. Amyloid is deposited in the arteriolar walls and extracellular space. Ischemic, autoimmune, or vascular mechanisms, and glial alterations have all been considered in the pathogensis of delayed cerebral radionecrosis. Some researchers have concluded that chemotherapeutic agents, such as methotrexate, may contribute to its production.

  4. Cerebral angiography in leptomeningitis and cerebritis

    International Nuclear Information System (INIS)

    This is a report of the cerebral angiographic findings in cases of meningitis and cerebritis. Fifty-nine patients, 38 of whom were under 1 year of age, underwent cerebral angiography by means of femoral catheterization. All the patients had signs of increased intracranial pressure, seizures, focal cerebral signs, positive transillumination of the head, and or abnormal brain scan findings. A few patients who did not respond to systemic antibiotics as was expected were also evaluated by means of cerebral angiography. The following characteristic angiographic findings were observed in 18 cases of active meningitis: (1) A hasy appearance around the arteries (halo formation) between the late arterial and capillary phases. (2) Narrowing of the arteries in the basal cistern. This sometimes extended to the peripheral arteries. (3) Irregular caliber following the narrowing of arteries (in few cases). (4) Circulation time so slow that veins could be seen in the late arterial phase. (5) Halo formation around the anterior chroidal artery and the clear appearance of the choroid plexus in the venous phase (when the infectious process reached the choroid plexus). Cerebritis could be identified on the angiograms by two signs: (1) local swelling of the brain (mainly the temporal lobe) and (2) staining around the veins without any abnormal signs in the arterial phase (laminar staining). In conclusion, angiography is a meaningful test by which to determine the phase of meningitis and cerebritis. These two conditions should be treated based on valid information obtained by means of CSF examinations and neuroradiological tests, especially CT scan and cerebral angiography. (author)

  5. Contemporary treatment of amyloid heart disease.

    Science.gov (United States)

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  6. Associations between white matter hyperintensities and β amyloid on integrity of projection, association, and limbic fiber tracts measured with diffusion tensor MRI.

    Directory of Open Access Journals (Sweden)

    Linda L Chao

    Full Text Available The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0-0.5 and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume were assessed with positron emission tomography (PET with Pittsburg compound B (PiB and magnetic resonance and diffusion tensor imaging (DTI. Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix. WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi fiber tracts. Aβ deposition (i.e., PiB positivity was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity and in blood vessels (resulting in amyloid angiopathy and WMH pathology, and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies

  7. In vivo detection of prion amyloid plaques using [11C]BF-227 PET

    International Nuclear Information System (INIS)

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  8. In vivo detection of prion amyloid plaques using [{sup 11}C]BF-227 PET

    Energy Technology Data Exchange (ETDEWEB)

    Okamura, Nobuyuki; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Shiga, Yusei; Itoyama, Yasuhito [Tohoku University School of Medicine, Department of Neurology, Sendai (Japan); Furumoto, Shozo [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tsuboi, Yoshio [Fukuoka University School of Medicine, Department of Neurology, Fukuoka (Japan); Furukawa, Katsutoshi; Arai, Hiroyuki [Institute of Development, Aging, and Cancer, Tohoku University, Department of Geriatrics and Gerontology, Division of Brain Sciences, Sendai (Japan); Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan); Doh-ura, Katsumi [Tohoku University School of Medicine, Department of Prion Research, 2-1 Seiryo-machi, Aoba-ku, Sendai (Japan)

    2010-05-15

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [{sup 11}C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [{sup 11}C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  9. Extrahepatic production of acute phase serum amyloid A

    OpenAIRE

    Upragarin, N.; Landman, W.J.M.; Gaastra, W; Gruys, E.

    2005-01-01

    Amyloidosis is a group of diseases characterized by the extracellular deposition of protein that contains non-branching, straight fibrils on electron microscopy (amyloid fibrils) that have a high content of ß-pleated sheet conformation. Various biochemically distinct proteins can undergo transformation into amyloid fibrils. The precursor protein of amyloid protein A (AA) is the acute phase protein serum amyloid A (SAA). The concentration of SAA in plasma increa...

  10. STIMULATED PLATELETS RELEASE AMYLOID β–PROTEIN PRECURSOR

    OpenAIRE

    Cole, Gregory M.; Galasko, Douglas; Shapiro, I. Paul; Saitoh, Tsunao

    1990-01-01

    Human platelets can be stimulated by thrombin or ionomycin to secrete soluble truncated amyloid β–protein precursor and particulate membrane fragments which contain C-terminal and N-terminal immunoreactive amyloid β–protein precursor. This suggests a possible circulating source of β–protein in serum which may play a role in the formation of amyloid deposits. The release of soluble amyloid β-protein precursor could be involved in normal platelet physiology.

  11. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu

    2013-01-01

    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

  12. Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

    Directory of Open Access Journals (Sweden)

    Langen Ralf

    2008-10-01

    Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

  13. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  14. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  15. [Treatment of familial amyloid polyneuropathy].

    Science.gov (United States)

    Adams, David; Samuel, Didier; Slama, Michel

    2012-09-01

    The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the

  16. Cerebral Palsy (CP) Quiz

    Science.gov (United States)

    ... Submit Button Past Emails CDC Features Pop Quiz: Cerebral Palsy Language: English Español (Spanish) Recommend on Facebook Tweet ... Sandy is the parent of a child with cerebral palsy and the Board President of Gio’s Garden , a ...

  17. Reversible cerebral vasoconstriction syndrome

    Directory of Open Access Journals (Sweden)

    Saini Monica

    2009-01-01

    Full Text Available Reversible cerebral vasoconstriction syndromes (RCVS are a group of disorders that have in common an acute presentation with headache, reversible vasoconstriction of cerebral arteries, with or without neurological signs and symptoms. In contrast to primary central nervous system vasculitis, they have a relatively benign course. We describe here a patient who was diagnosed with RCVS.

  18. Effective screen for amyloid β aggregation inhibitor using amyloid β-conjugated gold nanoparticles

    OpenAIRE

    Han, Sun-Ho; Chang, Yu Jin; Jung, Eun Sun; Kim, Jong-Won; Na, Duk Lyul; Mook-Jung, Inhee

    2010-01-01

    The abnormal aggregation of amyloid β (Aβ) and its subsequent intra- and extracellular accumulation constitute the disease-causing cascade of Alzheimer’s disease (AD). The detection of Aβ aggregates and senile plaque formation, however, is nearly impossible during early pathogenesis, and the absence of a convenient screen to validate the activity of Aβ aggregation regulators impedes the development of promising drug targets and diagnostic biomarkers for AD. Here, we conjugated amyloid β42 (Aβ...

  19. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R;

    2000-01-01

    -Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases...

  20. Serum amyloid P inhibits dermal wound healing

    Science.gov (United States)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  1. Is amyloid A (AA) amyloidosis always secondary?

    OpenAIRE

    Maury, C P; Törnroth, T; Wegelius, O

    1985-01-01

    The case is reported of a patient with systemic AA amyloidosis associated with non-specific mesenteric lymphadenitis and chronic sideropenia. Renal, small bowel, and rectal biopsies showed amyloid deposits containing AA protein, as defined by potassium permanganate sensitivity and by reactivity with AA antiserum. Reversal of the nephrotic syndrome occurred during steroid-azathioprine therapy.

  2. Cerebral haematocrit measurement

    International Nuclear Information System (INIS)

    Regional cerebral haematocrit was measured in a group of sixteen subjects by the single-photon emission computerized tomography method. This group included three normal subjects as controls and thirteen patients affected with ischaemic cerebral disease presenting clinically with transient ischaemic attacks-six patients - or recent cerebral stroke - seven patients. Two intravenous radioactive tracers - technetium-99m labelled autologous red blood cells and Tc-99m human serum albumin were used. Cerebral tomographic imaging was performed using a rotating scintillation camera. The values of cerebral haematocrit obtained, taken as a ratio to venous haematocrit, range between 0.65-0.88 in the subjects studied. As a general finding in normal subjects and in patients with transient ischaemic attacks, no significant difference between right and left hemispheric haematocrit value was noted. However, in the group of patients affected with stroke, a significant difference in the right versus left hemispheric Hct was observed in 3 patients, the higher Hct value corresponding to the affected side. The clinical implication is on the emphasis of cerebral Hct measurement when the measurement of cerebral blood flow or volume is sought. Also the variation in regional Hct value observed in patients with stroke, above mentioned, points to a regulation mechanism of the blood composition for optimal oxygen delivery to the brain that is impaired in these patients. 14 refs. (Author)

  3. Unilateral cerebral polymicrogyria with ipsilateral cerebral hemiatrophy

    International Nuclear Information System (INIS)

    We evaluated six children in whom MR imaging showed unilateral cerebral polymicrogyria associated with ipsilateral cerebral atrophy and ipsilateral brain stem atrophy. The aim of this study was to clarify whether this disorder based on neuroimaging constitutes a new homogeneous clinical entity. The subjects were six children whose ages at the time of MR imaging ranged from 8 months to 11 years. Their clinical and MR features were analyzed. All of the children were born between 38 and 42 weeks gestation, without any significant perinatal events. Spastic hemiplegia and epilepsy were observed in all of the patients, and mental retardation was observed in four. The MR findings included unilateral cerebral polymicrogyria associated with ipsilateral cerebral hemiatrophy and ipsilateral brain stem atrophy in all patients. The ipsilateral sylvian fissure was hypoplastic in four patients. These patients showed relatively homogeneous clinical and neuroimaging features. Although the additional clinical features varied according to the site and the extent affected by the polymicrogyria, this disorder could constitute a new relatively homogeneous clinical entity. (orig.)

  4. Unilateral cerebral polymicrogyria with ipsilateral cerebral hemiatrophy

    Energy Technology Data Exchange (ETDEWEB)

    Hayakawa, Katsumi [Department of Radiology, Kyoto City Hospital, 1-2 Higashi-Takada-cho, Mibu, Nakagyo-ku, 604-8845 Kyoto (Japan); Kanda, Toyoko; Yamori, Yuriko [Department of Pediatric Neurology, St. Joseph Hospital for Handicapped Children, 603-8323 Kyoto (Japan)

    2002-10-01

    We evaluated six children in whom MR imaging showed unilateral cerebral polymicrogyria associated with ipsilateral cerebral atrophy and ipsilateral brain stem atrophy. The aim of this study was to clarify whether this disorder based on neuroimaging constitutes a new homogeneous clinical entity. The subjects were six children whose ages at the time of MR imaging ranged from 8 months to 11 years. Their clinical and MR features were analyzed. All of the children were born between 38 and 42 weeks gestation, without any significant perinatal events. Spastic hemiplegia and epilepsy were observed in all of the patients, and mental retardation was observed in four. The MR findings included unilateral cerebral polymicrogyria associated with ipsilateral cerebral hemiatrophy and ipsilateral brain stem atrophy in all patients. The ipsilateral sylvian fissure was hypoplastic in four patients. These patients showed relatively homogeneous clinical and neuroimaging features. Although the additional clinical features varied according to the site and the extent affected by the polymicrogyria, this disorder could constitute a new relatively homogeneous clinical entity. (orig.)

  5. Current and future treatment of amyloid diseases.

    Science.gov (United States)

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  6. The value of incomplete mouse models of Alzheimer's disease

    International Nuclear Information System (INIS)

    To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Aβ42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral β-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging. (orig.)

  7. Nuclear imaging of amyloid deposits based upon thioflavins

    International Nuclear Information System (INIS)

    Full text: Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo in living mice; and 4) one of these compounds has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies and

  8. Nuclear imaging of amyloid deposits based upon thioflavins

    International Nuclear Information System (INIS)

    Alzheimer's Disease (AD) is a chronic neurodegenerative disorders characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding. assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo iri living mice; and 4) One of these compounds, termed PIB, has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies

  9. Neonatal Cerebral Sinovenous Thrombosis

    OpenAIRE

    J Gordon Millichap

    2006-01-01

    The presentation, treatment, and outcome of neonatal cerebral sinovenous thrombosis (SVT) were studied in 42 children, using neurology clinic records (1986-2005) at Indiana University School of Medicine.

  10. Cerebral Aneurysms Fact Sheet

    Science.gov (United States)

    ... cerebral aneurysm from forming. People with a diagnosed brain aneurysm should carefully control high blood pressure, stop smoking, and avoid cocaine use or other stimulant drugs. They should also ...

  11. Acute ischemic cerebral attack

    OpenAIRE

    Franco-Garcia Samir; Barreiro-Pinto Belis

    2010-01-01

    The decrease of the cerebral blood flow below the threshold of autoregulation led to changes of cerebral ischemia and necrosis that traduce in signs and symtoms of focal neurologic dysfunction called acute cerebrovascular symdrome (ACS) or stroke. Two big groups according to its etiology are included in this category the hemorragic that constitue a 20% and the ischemic a 80% of cases. Great interest has wom the ischemic ACS because of its high social burden, being the third cause of no violen...

  12. Cerebral aneurysms and inflammation

    Directory of Open Access Journals (Sweden)

    Toshihiro Yokoi

    2015-06-01

    Full Text Available Multiple inflammatory factors, playing a crucial role in cerebral aneurysm formation, have been identified. tumor necrosis factor-alpha (TNF-α has been revealed to have a close connection with several risk factors that affect aneurysm formation. Remarkable expression in aneurysm walls of mRNA for TNF-α has been observed in humans. Possible therapeutic interventions to reduce the formation of cerebral aneurysms may include the inhibition of mediators of inflammation.

  13. Rehabilitation in cerebral palsy.

    OpenAIRE

    Molnar, G. E.

    1991-01-01

    Cerebral palsy is the most frequent physical disability of childhood onset. Over the past four decades, prevalence has remained remarkably constant at 2 to 3 per 1,000 live births in industrialized countries. In this article I concentrate on the rehabilitation and outcome of patients with cerebral palsy. The epidemiologic, pathogenetic, and diagnostic aspects are highlighted briefly as they pertain to the planning and implementation of the rehabilitation process.

  14. Cerebral Palsy Litigation

    OpenAIRE

    Sartwelle, Thomas P.; Johnston, James C.

    2015-01-01

    The cardinal driver of cerebral palsy litigation is electronic fetal monitoring, which has continued unabated for 40 years. Electronic fetal monitoring, however, is based on 19th-century childbirth myths, a virtually nonexistent scientific foundation, and has a false positive rate exceeding 99%. It has not affected the incidence of cerebral palsy. Electronic fetal monitoring has, however, increased the cesarian section rate, with the expected increase in mortality and morbidity risks to mothe...

  15. Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised.

    OpenAIRE

    Landreth Gary E; Heneka Michael T; Breidert Tilo; Schmidt Stephen D; Mathews Paul M; Lacombe Pierre; Feinstein Douglas L; Galea Elena

    2004-01-01

    Abstract Background The over-expression of transforming growth factor β-1(TGF-β1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidβ (Aβ) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-β1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-β1. This idea was in accordance with the view that...

  16. Fold modulating function: Bacterial toxins to functional amyloids

    Directory of Open Access Journals (Sweden)

    AdnanKhawajaSyed

    2014-08-01

    Full Text Available Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  17. Prevalence of amyloid PET positivity in dementia syndromes

    DEFF Research Database (Denmark)

    Ossenkoppele, Rik; Jansen, Willemijn J; Rabinovici, Gil D;

    2015-01-01

    IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use...... individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION: Case reports and studies on....... The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status...

  18. Atomic View of a Toxic Amyloid Small Oligomer

    Energy Technology Data Exchange (ETDEWEB)

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David (UCI); (UCLA)

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  19. Simulations of nucleation and elongation of amyloid fibrils

    OpenAIRE

    Zhang, Jianing; Muthukumar, M.

    2009-01-01

    We present a coarse-grained model for the growth kinetics of amyloid fibrils from solutions of peptides and address the fundamental mechanism of nucleation and elongation by using a lattice Monte Carlo procedure. We reproduce the three main characteristics of nucleation of amyloid fibrils: (1) existence of lag time, (2) occurrence of a critical concentration, and (3) seeding. We find the nucleation of amyloid fibrils to require a quasi-two-dimensional configuration, where a second layer of β ...

  20. Inhibition of Alzheimer amyloid β aggregation by polyvalent trehalose

    International Nuclear Information System (INIS)

    A glycopolymer carrying trehalose was found to suppress the formation of amyloid fibrils from the amyloid β peptide (1-42) (Aβ), as evaluated by thioflavin T assay and atomic force microscopy. Glycopolymers carrying sugar alcohols also changed the aggregation properties of Aβ, and the inhibitory effect depended on the type of sugar and alkyl side chain. Neutralization activity was confirmed by in vitro assay using HeLa cells. The glycopolymer carrying trehalose strongly inhibited amyloid formation and neutralized cytotoxicity.

  1. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors

    OpenAIRE

    Villar-Piqué Anna; Espargaró Alba; Sabaté Raimon; de Groot Natalia S; Ventura Salvador

    2012-01-01

    Abstract Background The amyloid-β peptide (Aβ42) is the main component of the inter-neuronal amyloid plaques characteristic of Alzheimer's disease (AD). The mechanism by which Aβ42 and other amyloid peptides assemble into insoluble neurotoxic deposits is still not completely understood and multiple factors have been reported to trigger their formation. In particular, the presence of endogenous metal ions has been linked to the pathogenesis of AD and other neurodegenerative disorders. Results ...

  2. New Insights in the Amyloid-Beta Interaction with Mitochondria

    OpenAIRE

    Carlos Spuch; Saida Ortolano; Carmen Navarro

    2012-01-01

    Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both...

  3. Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

    Directory of Open Access Journals (Sweden)

    Nina Stemmer

    Full Text Available Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the γ-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the γ-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-β42 levels in culture supernatants, while transfection with the P-domain increases amyloid-β40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-β40 and amyloid-β42 levels, respectively. These findings indicate that the interaction of

  4. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

    Science.gov (United States)

    Ferretti, M T; Merlini, M; Späni, C; Gericke, C; Schweizer, N; Enzmann, G; Engelhardt, B; Kulic, L; Suter, T; Nitsch, R M

    2016-05-01

    Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease. PMID:26872418

  5. Nanomedicine in cerebral palsy

    Directory of Open Access Journals (Sweden)

    Balakrishnan B

    2013-11-01

    Full Text Available Bindu Balakrishnan,1 Elizabeth Nance,1 Michael V Johnston,2 Rangaramanujam Kannan,3 Sujatha Kannan1 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University; Baltimore, MD, USA; 2Department of Neurology and Pediatrics, Kennedy Krieger Institute, Baltimore, MD, USA; 3Department of Ophthalmology, Center for Nanomedicine, Johns Hopkins University, Baltimore, MD, USA Abstract: Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed. Keywords: dendrimer, cerebral palsy, neuroinflammation, nanoparticle, neonatal brain injury, G4OH-PAMAM

  6. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    Science.gov (United States)

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  7. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    Science.gov (United States)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  8. Amyloid β protein and Alzheimer disease

    OpenAIRE

    Square, D

    1997-01-01

    Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view o...

  9. Prions, amyloids, and RNA: Pieces of a puzzle.

    Science.gov (United States)

    Nizhnikov, Anton A; Antonets, Kirill S; Bondarev, Stanislav A; Inge-Vechtomov, Sergey G; Derkatch, Irina L

    2016-05-01

    Amyloids are protein aggregates consisting of fibrils rich in β-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self-propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions. PMID:27248002

  10. Clinical Neuroimaging of cerebral ischemia

    International Nuclear Information System (INIS)

    Notice points in clinical imaging of cerebral ischemia are reviewed. When cerebral blood flow is determined in acute stage of cerebral embolism (cerebral blood flow SPECT), it is important to find area of ischemic core and ischemic penumbra. When large cortex area is assigned to ischemic penumbra, thrombolytic therapy is positively adapted, but cautious correspondence is necessary when ischemic core is recognized. DWI is superior in the detection of area equivalent to ischemic core of early stage, but, in imaging of area equivalent to ischemic penumbra, perfusion image or distribution image of cerebral blood volume (CBV) by MRI need to be combined. Luxury perfusion detected by cerebral blood flow SPECT in the cases of acute cerebral embolism suggests vascular recanalization, but a comparison with CT/MRI and continuous assessment of cerebral circulation dynamics were necessary in order to predict brain tissue disease (metabolic abnormality). In hemodynamic cerebral ischemia, it is important to find stage 2 equivalent to misery perfusion by quantification of cerebral blood flow SPECT. Degree of diaschisis can indicate seriousness of brain dysfunction for lacuna infarct. Because cerebral circulation reserve ability (perfusion pressure) is normal in all areas of the low cerebral blood flow by diaschisis mechanism, their areas are easily distinguished from those of hemodynamic cerebral ischemia. (K.H.)

  11. Amyloid-beta Alzheimer targets — protein processing, lipid rafts, and amyloid-beta pores

    Science.gov (United States)

    Arbor, Sage C.; LaFontaine, Mike; Cumbay, Medhane

    2016-01-01

    Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.

  12. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.

    Science.gov (United States)

    Arbor, Sage C; LaFontaine, Mike; Cumbay, Medhane

    2016-03-01

    Amyloid beta (Aβ), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review. PMID:27505013

  13. Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters

    Directory of Open Access Journals (Sweden)

    Katsumi Matsuzaki

    2011-01-01

    Full Text Available It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1–40 and Aβ-(1–42 in membrane interaction and amyloidogenesis are also emphasized.

  14. Design and Construction of Large Amyloid Fibers

    Directory of Open Access Journals (Sweden)

    Devin M. Ridgley

    2015-04-01

    Full Text Available Mixtures of “template” and “adder” proteins self-assemble into large amyloid fibers of varying morphology and modulus. Fibers range from low modulus, rectangular cross-sectioned tapes to high modulus, circular cross-sectioned cylinders. Varying the proteins in the mixture can elicit “in-between” morphologies, such as elliptical cross-sectioned fibers and twisted tapes, both of which have moduli in-between rectangular tapes and cylindrical fibers. Experiments on mixtures of proteins of known amino acid sequence show that control of the large amyloid fiber morphology is dependent on the amount of glutamine repeats or “Q-blocks” relative to hydrophobic side chained amino acids such as alanine, isoleucine, leucine, and valine in the adder protein. Adder proteins with only hydrophobic groups form low modulus rectangular cross-sections and increasing the Q-block content allows excess hydrogen bonding on amide groups that results in twist and higher modulus. The experimental results show that large amyloid fibers of specific shape and modulus can be designed and controlled at the molecular level.

  15. Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid

    OpenAIRE

    Castellani, Rudy J.; Lee, Hyoung-gon; Siedlak, Sandra L.; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused on amyloid-β as the major pathogenic mechanisms with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectac...

  16. Cerebral palsy and multiple births.

    OpenAIRE

    Pharoah, P. O.; Cooke, T

    1996-01-01

    AIM: To compare the birthweight specific prevalence of cerebral palsy in singleton and multiple births. METHODS: Registered births of babies with cerebral palsy born to mothers resident in the counties of Merseyside and Cheshire during the period 1982 to 1989 were ascertained. RESULTS: The crude prevalence of cerebral palsy was 2.3 per 1000 infant survivors in singletons, 12.6 in twins, and 44.8 in triplets. The prevalence of cerebral palsy rose with decreasing birthweight. The birthweight sp...

  17. Experimental Focal Cerebral Ischemia

    DEFF Research Database (Denmark)

    Christensen, Thomas

    2007-01-01

    Focal cerebral ischemia due to occlusion of a major cerebral artery is the cause of ischemic stroke which is a major reason of mortality, morbidity and disability in the populations of the developed countries. In the seven studies summarized in the thesis focal ischemia in rats induced by occlusion...... of the middle cerebral artery (MCAO) was used as an experimental model of ischemic stroke. MCAO produces an acute lesion consisting of an ischemic core or focus with severely reduced blood flow surrounded by a borderzone or ischemic penumbra with less pronounced blood flow reduction. Cells in the...... radical scavenger α-PBN on the periinfarct depolarizations and infarct volume was investigated. In study number six, the activity of the mitochondrial electron transport complexes I, II and IV was evaluated histochemically during reperfusion after MCAO in order to assess the possible role of mitochondrial...

  18. Cerebral hemodynamics in migraine

    DEFF Research Database (Denmark)

    Hachinski, V C; Olesen, Jes; Norris, J W;

    1977-01-01

    Clinical and angiographic findings in migraine are briefly reviewed in relation to cerebral hemodynamic changes shown by regional cerebral blood flow (rCBF) studies. Three cases of migraine studied by the intracarotid xenon 133 method during attacks are reported. In classic migraine, with typical...... prodromal symptoms, a decrease in cerebral blood flow has been demonstrated during the aura. Occasionally, this flow decrease persists during the headache phase. In common migraine, where such prodromata are not seen, a flow decrease has not been demonstrated. During the headache phase of both types of...... migraine, rCBF has usually been found to be normal or in the high range of normal values. The high values may represent postischemic hyperemia, but are probably more frequently secondary to arousal caused by pain. Thus, during the headache phase rCBF may be subnormal, normal or high. These findings do not...

  19. Cerebral abscess in children

    International Nuclear Information System (INIS)

    A cerebral abscess (CA) is a focal, infectious process only or multiple, located in the cerebral parenchyma that produces tisular lysis and it behaves like a lesion of space occupative, being a suppurative illness, who origin is a distant infection, or for continuity that studies initially as an area of focal cerebritis and it is developed to a collection surrounded purulent. At the moment they are perfecting technical and protocols diagnoses and therapeutic and measures for allow to control the natural history of the illness, making from the confrontation to this pathology a necessarily interdisciplinary complicated art, stiller in the infantile population, due to their difficulty in the diagnosis and the relevance of the same one. The paper includes epidemiology, etiology, risk factors, localization, pathology, clinic, diagnoses, treatment and diagnostic images

  20. Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry.

    Science.gov (United States)

    Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P N

    2016-05-01

    Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multitargeting small molecules as therapeutic options. The pathophysiology of Alzheimer's disease is attributed to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of beta-amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia. The two commonly used approaches to prevent beta-amyloid accumulation in the brain include (i) development of beta-secretase inhibitors and (ii) designing direct inhibitors of beta-amyloid (self-induced) aggregation. This review highlights the amyloid cascade hypothesis and the key chemical features required to design small molecules that inhibit lower and higher order beta-amyloid aggregates. Several recent examples of small synthetic molecules with disease-modifying properties were considered and their molecular docking studies were conducted using either a dimer or steric-zipper assembly of beta-amyloid. These investigations provide a mechanistic understanding on the structural requirements needed to design novel small molecules with anti-amyloid aggregation properties. Significantly, this work also demonstrates that the structural requirements to prevent aggregation of various amyloid species differs considerably, which explains the fact that many small molecules do not exhibit similar inhibition profile toward diverse amyloid species such as dimers, trimers, tetramers, oligomers, protofibrils and fibrils. PMID:26945113

  1. The effects of beta-amyloid protein and presenilin on potassium channel%淀粉样蛋白及早老素对钾通道的影响

    Institute of Scientific and Technical Information of China (English)

    佟晓永; 王晓良

    2001-01-01

    Alzheimer病目前是痴呆的最常见原因,病理学特征是:神经纤维缠结,神经斑块,神经元丢失,淀粉样血管改变。临床上最显著的特点是学习记忆障碍。钾通道在学习记忆中起着重要作用。Alzheimer病人成纤维细胞以及嗅成纤维细胞113pS四已胺敏感的钾通道缺失。记忆相关蛋白Cp20以及与Alzheimer病遗传密切相关的淀粉样蛋白前体蛋白及早老素均能调节钾通道活性。Alzheimer病时钾通道亚型的改变尚需进一步的理论研究。钾通道在Alzhe imer病治疗方面有可能成为重要靶点。%Alzheimer disease(AD) is the most common cau se of dementia today. Th e characteristic histopathologic changes include neurofibrillary tangles, neurit ic plaques, neuronal loss, and amyloid angiopathy. The noted Alzheimer symptom is the dysfunction of learning a nd memory. Potassium channels play a key role in it. A 113-pS tetraethylammoniu m-sensitive potassium channel was consistently absent from AD fibroblasts and o lfactory neuroblasts. Cp20, a memory-associated protein, amyloid precuror prote in and presenilin which are all tightly associated with genetic Alzheimer diseas e can regulate the activities of potassium channels. The changes of potassium ch annels subtype need further study. Potassium channels are maybe the important dr ug targets in the treatment of Alzheimer disease.

  2. Cerebral fat embolism

    International Nuclear Information System (INIS)

    A case of cerebral fat embolism is reported. A 18-year-old patient with multiple bone fractures was in semiconma immediately after an injury. Brain CT showed no brain swelling or intracranial hematoma. Hypoxemia and alcoholemia were noted on admission, which returned to normal without improvement of consciousness level. In addition, respiratory symptoms with positive radiographic changes, tachycardia, pyrexia, sudden drop in hemoglobin level, and sudden thrombocytopenia developed. These symptoms were compatible with Gurd's criteria of systemic fat embolism. Eight days after injury, multiple low density areas appeared on CT and disappeared within the subsequent two weeks, and subdural effusion with cerebral atrophy developed. These CT findings were not considered due to cerebral trauma. Diagnosis of cerebral fat embolism was made. The subdural effusion was drained. Neurologic and pulmonary recoveries took place slowly and one month following the injury the patient became alert and exhibited fully coordinated limb movement. The CT scans of the present case well corresponded with hitherto reported pathological findings. Petechiae in the white matter must have developed on the day of injury, which could not be detected by CT examination. It is suggested that some petechial regions fused to purpuras and then gradually resolved when they were detected as multiple low density areas on CT. CT in the purpuras phase would have shown these lesions as high density areas. These lesions must have healed with formation of tiny scars and blood pigment which were demonstrated as the disappearance of multiple low density areas by CT examination. Cerebral atrophy and subsequent subdural effusion developed as a result of demyelination. The patient took the typical clinical course of cerebral fat embolism and serial CT scans served for its assessment. (author)

  3. Cerebral palsy and congenital malformations

    DEFF Research Database (Denmark)

    Garne, Ester; Dolk, Helen; Krägeloh-Mann, Inge;

    2007-01-01

    were reported to have a congenital malformation. The majority (8.6% of all children) were diagnosed with a cerebral malformation. The most frequent types of cerebral malformations were microcephaly and hydrocephaly. Non-cerebral malformations were present in 97 CP children and in further 14 CP children...

  4. Quantitative Analysis of the Flavonoid Glycosides and Terpene Trilactones in the Extract of Ginkgo biloba and Evaluation of Their Inhibitory Activity towards Fibril Formation of β-Amyloid Peptide

    OpenAIRE

    Haiyan Xie; Jing-Rong Wang; Lee-Fong Yau; Yong Liu; Liang Liu; Quan-Bin Han; Zhongzhen Zhao; Zhi-Hong Jiang

    2014-01-01

    The standard extract of Ginkgo biloba leaves (EGb761) is used clinically in Europe for the symptomatic treatment of impaired cerebral function in primary degenerative dementia syndromes, and the results of numerous in vivo and in vitro studies have supported such clinical use. The abnormal production and aggregation of amyloid β peptide (Aβ) and the deposition of fibrils in the brain are regarded as key steps in the onset of Alzheimer’s Disease (AD), and the inhibition of Aβ aggregation and d...

  5. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    Science.gov (United States)

    Cai, Zhiyou; Yan, Yong; Wang, Yonglong

    2013-01-01

    Background Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions

  6. Cerebral atrophic and degenerative changes following various cerebral diseases, (1)

    International Nuclear Information System (INIS)

    Patients having cerebral atrophic and degenerative changes following hypoglycemia, cerebral contusion, or cerebral hypoxia including cerebrovascular disorders were reported. Description was made as to cerebral changes visualized on CT images and clinical courses of a patient who revived 10 minutes after heart stoppage during neurosurgery, a newborn with asphyxia, a patient with hypoglycemia, a patient who suffered from asphyxia by an accident 10 years before, a patient with carbon monoxide poisoning at an acute stage, a patient who had carbon monoxide poisoning 10 years before, a patient with diffuse cerebral ischemic changes, a patient with cerebral edema around metastatic tumor, a patient with respiration brain, a patient with neurological sequelae after cerebral contusion, a patient who had an operation to excise right parietal lobe artery malformation, and a patient who was shooted by a machine gun and had a lead in the brain for 34 years. (Tsunoda, M.)

  7. The Effect of Glycosaminoglycans (GAGs on Amyloid Aggregation and Toxicity

    Directory of Open Access Journals (Sweden)

    Clara Iannuzzi

    2015-02-01

    Full Text Available Amyloidosis is a protein folding disorder in which normally soluble proteins are deposited extracellularly as insoluble fibrils, impairing tissue structure and function. Charged polyelectrolytes such as glycosaminoglycans (GAGs are frequently found associated with the proteinaceous deposits in tissues of patients affected by amyloid diseases. Experimental evidence indicate that they can play an active role in favoring amyloid fibril formation and stabilization. Binding of GAGs to amyloid fibrils occurs mainly through electrostatic interactions involving the negative polyelectrolyte charges and positively charged side chains residues of aggregating protein. Similarly to catalyst for reactions, GAGs favor aggregation, nucleation and amyloid fibril formation functioning as a structural templates for the self-assembly of highly cytotoxic oligomeric precursors, rich in β-sheets, into harmless amyloid fibrils. Moreover, the GAGs amyloid promoting activity can be facilitated through specific interactions via consensus binding sites between amyloid polypeptide and GAGs molecules. We review the effect of GAGs on amyloid deposition as well as proteins not strictly related to diseases. In addition, we consider the potential of the GAGs therapy in amyloidosis.

  8. Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness

    DEFF Research Database (Denmark)

    Zeng, Guanghong; Vad, Brian Stougaard; Dueholm, Morten Simonsen;

    2015-01-01

    and increases biofilm stiffness 20-fold. Deletion of any one of the individual members of in the fap operon (except the putative chaperone FapA) abolishes this ability to increase biofilm stiffness and correlates with the loss of amyloid. We conclude that amyloid makes major contributions to biofilm...

  9. The Tubular Sheaths Encasing Methanosaeta thermophila Filaments Are Functional Amyloids.

    Science.gov (United States)

    Dueholm, Morten S; Larsen, Poul; Finster, Kai; Stenvang, Marcel R; Christiansen, Gunna; Vad, Brian S; Bøggild, Andreas; Otzen, Daniel E; Nielsen, Per Halkjær

    2015-08-14

    Archaea are renowned for their ability to thrive in extreme environments, although they can be found in virtually all habitats. Their adaptive success is linked to their unique cell envelopes that are extremely resistant to chemical and thermal denaturation and that resist proteolysis by common proteases. Here we employ amyloid-specific conformation antibodies and biophysical techniques to show that the extracellular cell wall sheaths encasing the methanogenic archaea Methanosaeta thermophila PT are functional amyloids. Depolymerization of sheaths and subsequent MS/MS analyses revealed that the sheaths are composed of a single major sheath protein (MspA). The amyloidogenic nature of MspA was confirmed by in vitro amyloid formation of recombinant MspA under a wide range of environmental conditions. This is the first report of a functional amyloid from the archaeal domain of life. The amyloid nature explains the extreme resistance of the sheath, the elastic properties that allow diffusible substrates to penetrate through expandable hoop boundaries, and how the sheaths are able to split and elongate outside the cell. The archaeal sheath amyloids do not share homology with any of the currently known functional amyloids and clearly represent a new function of the amyloid protein fold. PMID:26109065

  10. Amyloid imaging in Alzheimer's disease: a literature review.

    Science.gov (United States)

    Saidlitz, P; Voisin, T; Vellas, B; Payoux, P; Gabelle, A; Formaglio, M; Delrieu, J

    2014-07-01

    Therapies targeting amyloid-β peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aβ immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-β peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation. PMID:25226113

  11. Rational design of potent human transthyretin amyloid disease inhibitors.

    Science.gov (United States)

    Klabunde, T; Petrassi, H M; Oza, V B; Raman, P; Kelly, J W; Sacchettini, J C

    2000-04-01

    The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases. PMID:10742177

  12. Development of (F-18)-Labeled Amyloid Imaging Agents for PET

    International Nuclear Information System (INIS)

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the 'amyloid cascade hypothesis' which holds that amyloid accumulation is the primary cause of AD.

  13. Development of [F-18]-Labeled Amyloid Imaging Agents for PET

    Energy Technology Data Exchange (ETDEWEB)

    Mathis, CA

    2007-05-09

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the "amyloid cascade hypothesis" which holds that amyloid accumulation is the primary cause of AD.

  14. Glycosaminoglycans in extracts of cardiac amyloid fibrils from familial amyloid cardiomyopathy of Danish origin related to variant transthyretin Met 111.

    Science.gov (United States)

    Magnus, J H; Stenstad, T; Kolset, S O; Husby, G

    1991-07-01

    We have previously demonstrated an association between secondary AA type amyloid fibrils and glycosaminoglycans (GAGs) in human liver. The present study was aimed at investigating whether a similar association could be demonstrated in isolated cardiac amyloid fibrils from a unique Danish family with amyloid cardiomyopathy related to variant transthyretin (TTR) with a single amino acid substitution of a methionin for leucine at position 111 (TTR Met 111). Using gel filtration and ion exchange chromatography, significant amounts of GAGs were detected in close association with purified myocardial amyloid fibrils, whereas only trace amounts of polysaccharides were present in the corresponding normal preparation. The GAGs were identified as 50% chondroitin sulfate, 33% heparin/heparan sulfate, and 17% hyaluronan. With the methods used the amyloid associated GAGs appeared as high molecular weight free polysaccharide chains, and not as part of intact proteoglycans (PGs) in the fibril extracts. We conclude that the association between purified amyloid fibrils and GAGs may be a general feature of amyloid deposits. Also, we suggest that the proportion of different GAGs in the amyloid deposits may depend both on the organ or tissues affected and the type of proteins making up the fibrils. PMID:2068532

  15. Imaging of dialysis-related amyloid (AB-amyloid) deposits with 131I-beta 2-microglobulin

    International Nuclear Information System (INIS)

    The diagnosis of dialysis-related amyloid (AB-amyloid) has been based usually on clinical and radiological criteria. Following the discovery that beta 2-microglobulin was the major protein of this amyloid, we isolated and radiolabelled uremic plasma beta 2-microglobulin. After intravenous injection, gamma-camera images of selected joint areas were obtained from 42 patients who were on regular hemodialysis therapy. Positive scans involving the shoulder, hip, knee and carpal regions were found in 13 of 14 patients treated for more than 10 years and 10 of 16 patients treated for 5 to 10 years. Patients treated for less time had negative scans. Specificity was indicated by negative scans in non-amyloid inflammatory lesions in control hemodialysis patients. Up to 48-fold tracer enrichment was detected in excised AB-amyloid containing tissue as compared to amyloid-free tissue. These findings suggest that circulating radiolabelled beta 2-microglobulin is taken up by the amyloid deposits. This method may non-invasively detect tissue infiltrates of amyloid. It may also permit prospective evaluation of the efficacy of prophylactic dialysis strategies which are designed to prevent or delay the onset of this complication of long-term dialysis

  16. Recurrent cerebral thrombosis

    International Nuclear Information System (INIS)

    Neuroradiological techniques were used to elucidate pathophysiology of recurrent cerebral thrombosis. Twenty-two patients with cerebral thrombosis who suffered a second attack under stable conditions more than 22 days after the initial stroke were studied. Hypertension, diabetes mellitus, and hypercholesterolemia were also seen in 20, 8, and 12 patients, respectively. The patients were divided into three groups according to their symptoms: (I) symptoms differed between the first and second strokes (n=12); (II) initial symptoms were suddenly deteriorated (n=6); and (III) symptoms occurring in groups I and II were seen (n=4). In group I, contralateral hemiparesis or suprabulbar palsy was often associated with the initial hemiparesis. The time of recurrent stroke varied from 4 months to 9 years. CT and MRI showed not only lacunae in both hemispheres, but also deep white-matter ischemia of the centrum semi-ovale. In group II, hemiparesis or visual field defect was deteriorated early after the initial stroke. In addition, neuroimaging revealed that infarction in the posterior cerebral artery was progressed on the contralateral side, or that white matter lesion in the middle artery was enlarged in spite of small lesion in the left cerebral hemisphere. All patients in group III had deterioration of right hemiparesis associated with aphasia. CT, MRI, SPECT, and angiography indicated deep white-matter ischemia caused by main trunk lesions in the left hemisphere. Group III seemed to be equivalent to group II, except for laterality of the lesion. Neuroradiological assessment of the initial stroke may help to predict the mode of recurrence, although pathophysiology of cerebral thrombosis is complicated and varies from patient to patient. (N.K.)

  17. Calumenin interacts with serum amyloid P component

    DEFF Research Database (Denmark)

    Vorum, H; Jacobsen, Christian; Honoré, Bent

    secretory pathway that include reticulocalbin, ERC-55, Cab45 and crocalbin. In order to further investigate the extracellular functions of calumenin we immobilized the recombinant protein to a column. After application of a placental tissue extract we were able to elute one protein that interacts with...... calumenin in the presence of Ca(2+). Amino acid sequencing identified this protein as serum amyloid P component (SAP). Furthermore, we verified and characterized the calumenin-SAP interaction by the surface plasmon resonance technique. The findings indicate that calumenin may participate in the...

  18. A catalytic surface for amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Hammarstroem, P; Ali, M M; Mishra, R; Tengvall, P; Lundstroem, I [Department of Physics, Biology and Chemistry, Linkoeping University, SE-581 83 Linkoeping (Sweden); Svensson, S [Astra Zeneca R and D, SE-151 85 Soedertaelje (Sweden)], E-mail: ingemar@ifm.liu.se

    2008-03-15

    A hydrophobic surface incubated in a solution of protein molecules (insulin monomers) was made into a catalytic surface for amyloid fibril formation by repeatedly incubate, rinse and dry the surface. The present contribution describes how this unexpected transformation occurred and its relation to rapid fibrillation of insulin solutions in contact with the surface. A tentative model of the properties of the catalytic surface is given, corroborated by ellipsometric measurements of the thickness of the organic layer on the surface and by atomic force microscopy. The surfaces used were spontaneously oxidized silicon made hydrophobic through treatment in dichlorodimethylsilane.

  19. Stability and cytotoxicity of crystallin amyloid nanofibrils

    Science.gov (United States)

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J.; Valery, Celine; Gerrard, Juliet A.; Sasso, Luigi

    2014-10-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils.Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. Electronic supplementary information (ESI) available: ThT fluorescence graphs of buffers and solvents used for

  20. Imaging of amyloid deposition in human brain using positron emission tomography and [{sup 18}F]FACT: comparison with [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Shinotoh, Hitoshi; Shimada, Hitoshi; Miyoshi, Michie; Takano, Harumasa; Takahashi, Hidehiko; Arakawa, Ryosuke; Kodaka, Fumitoshi; Ono, Maiko; Eguchi, Yoko; Higuchi, Makoto; Fukumura, Toshimitsu; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); Yanai, Kazuhiko; Okamura, Nobuyuki [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan)

    2014-04-15

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The {sup 18}F-labeled amyloid tracer, [{sup 18}F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ {sup 11}C ]Pittsburgh compound B (PIB) and [ {sup 18}F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ {sup 11}C ]PIB and [ {sup 18}F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ {sup 18}F ]FACT studies without partial volume correction, while significant differences were observed in [ {sup 11}C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ {sup 18}F ]FACT studies as well as [ {sup 11}C ]PIB. Relatively lower uptakes of [ {sup 11}C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ {sup 18}F ]FACT. Relatively higher uptake of [ {sup 11}C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ {sup 18}F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ {sup 11}C ]PIB and [ {sup 18}F ]FACT might be due to differences

  1. Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB

    International Nuclear Information System (INIS)

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The 18F-labeled amyloid tracer, [18F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ 11C ]Pittsburgh compound B (PIB) and [ 18F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ 11C ]PIB and [ 18F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ 18F ]FACT studies without partial volume correction, while significant differences were observed in [ 11C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ 18F ]FACT studies as well as [ 11C ]PIB. Relatively lower uptakes of [ 11C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ 18F ]FACT. Relatively higher uptake of [ 11C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ 18F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ 11C ]PIB and [ 18F ]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic

  2. Parálisis cerebral Cerebral palsy

    OpenAIRE

    Jorge Malagon Valdez

    2007-01-01

    El término parálisis cerebral (PC) engloba a un gran número de síndromes neurológicos clínicos, de etiología diversa. Estos síndromes se caracterizan por tener una sintomatología común: los trastornos motores. Algunos autores prefieren manejar términos como "encefalopatía fija", "encefalopatías no evolutivas". Se mencionan la utilidad de programas de intervención temprana y métodos especiales de rehabilitación, así como el manejo de las deficiencias asociadas como la epilepsia, deficiencia me...

  3. Parálisis cerebral Cerebral palsy

    Directory of Open Access Journals (Sweden)

    Jorge Malagon Valdez

    2007-01-01

    Full Text Available El término parálisis cerebral (PC engloba a un gran número de síndromes neurológicos clínicos, de etiología diversa. Estos síndromes se caracterizan por tener una sintomatología común: los trastornos motores. Algunos autores prefieren manejar términos como "encefalopatía fija", "encefalopatías no evolutivas". Se mencionan la utilidad de programas de intervención temprana y métodos especiales de rehabilitación, así como el manejo de las deficiencias asociadas como la epilepsia, deficiencia mental, trastornos del lenguaje, audición, visión, déficit de la atención que mejoran el pronóstico de manera significativa. El pronóstico también depende de la gravedad del padecimiento y de las manifestaciones asociadas.The term cerebral palsy (CP, is used for a great number of clinical neurological syndromes. The syndromes are characterized by having a common cause, motor defects. It is important, because they can cause a brain damage by presenting motor defects and some associated deficiencies, such as mental deficiency, epilepsy, language and visual defects and pseudobulbar paralysis, with the nonevolving fact. Some authors prefer using terms such as "non-evolving encephalopathies". In the treatment the utility of prevention programs of early stimulation and special rehabilitation methods, and treatment of associated deficiencies such as epilepsy, mental deficiency, language, audition and visual problems, and the attention deficit improve the prognosis in an important way. The prognosis depends on the severity of the disease and the associated manifestations.

  4. Functional Hydrogel Materials Inspired by Amyloid

    Science.gov (United States)

    Schneider, Joel

    2012-02-01

    Protein assembly resulting in the formation of amyloid fibrils, assemblies rich in cross beta-sheet structure, is normally thought of as a deleterious event associated with disease. However, amyloid formation is also involved in a diverse array of normal biological functions such as cell adhesion, melanin synthesis, insect defense mechanism and modulation of water surface tension by fungi and bacteria. These findings indicate that Nature has evolved to take advantage of large, proteinaceous fibrillar assemblies to elicit function. We are designing functional materials, namely hydrogels, from peptides that self-assembled into fibrillar networks, rich in cross beta-sheet structure. These gels can be used for the direct encapsulation and delivery of small molecule-, protein- and cell-based therapeutics. Loaded gels exhibit shear-thinning/self-healing mechanical properties enabling their delivery via syringe. In addition to their use for delivery, we have found that some of these gels display antibacterial activity. Although cytocompatible towards mammalian cells, the hydrogels can kill a broad spectrum of bacteria on contact.

  5. Cerebral infarction showed hyperperfusion pattern on radionuclide cerebral angiography

    International Nuclear Information System (INIS)

    Four patients of middle cerebral infarctin showed hyperperfusion on radionuclide cerebral angiography and fan-shape accumulation at the area of middle cerebral artery on early and delayed brain scan. In these patients, bone scanning agents such as sup(99m)Tc-EHDP or sup(99m)Tc-MDP also prominently accumulated at the area of infarction. These findings were observed on the study when it was performed within seventeen days after attack, but reexamination tended to show normal or decreased perfusion on radionuclide cerebral angiography and improve abnormal accumulation on brain scans. The clinical diagnosis of these three patients were cerebral embolism with heart disease, but one patient was internal carotid artery occlusion. The prognosis of all patients were very good. The hyperperfusion on radionuclide cerebral angiography of these patients represents the luxury perfusion in the lesion and these infarction has been called hot stroke by Yarnell et al. (author)

  6. Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives

    OpenAIRE

    Šneideris, Tomas; Baranauskienė, Lina; Jonathan G Cannon; Rutkienė, Rasa; Meškys, Rolandas; Smirnovas, Vytautas

    2015-01-01

    A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrils in vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of i...

  7. A Novel liposomal nanoparticle for the imaging of amyloid plaque by MRI

    OpenAIRE

    Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L.; Annapragada, Ananth

    2016-01-01

    Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy....

  8. Pulsations with reflected boundary waves: a hydrodynamic reverse transport mechanism for perivascular drainage in the brain.

    Science.gov (United States)

    Coloma, M; Schaffer, J D; Carare, R O; Chiarot, P R; Huang, P

    2016-08-01

    Beta-amyloid accumulation within arterial walls in cerebral amyloid angiopathy is associated with the onset of Alzheimer's disease. However, the mechanism of beta-amyloid clearance along peri-arterial pathways in the brain is not well understood. In this study, we investigate a transport mechanism in the arterial basement membrane consisting of forward-propagating waves and their reflections. The arterial basement membrane is modeled as a periodically deforming annulus filled with an incompressible single-phase Newtonian fluid. A reverse flow, which has been suggested in literature as a beta-amyloid clearance pathway, can be induced by the motion of reflected boundary waves along the annular walls. The wave amplitude and the volume of the annular region govern the flow magnitude and may have important implications for an aging brain. Magnitudes of transport obtained from control volume analysis and numerical solutions of the Navier-Stokes equations are presented. PMID:26729476

  9. SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly

    Directory of Open Access Journals (Sweden)

    S. Fabio Falsone

    2012-08-01

    Full Text Available The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

  10. Accumulation of murine amyloid-β mimics early Alzheimer's disease.

    Science.gov (United States)

    Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

    2015-08-01

    Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes. PMID:25991605

  11. Amyloid plaque imaging in vivo: current achievement and future prospects

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high 11C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by 11C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD. (orig.)

  12. Phenylpropanolamine and cerebral hemorrhage

    International Nuclear Information System (INIS)

    Computerized tomography, carotid angiograms, and arteriography were used to diagnose several cases of cerebral hemorrhage following the use of phenylpropanolamine. The angiographic picture in one of the three cases was similar to that previously described in association with amphetamine abuse and pseudoephedrine overdose, both substances being chemically and pharmacologically similar to phenylpropanolamine. The study suggests that the arterial change responsible for symptoms may be due to spasm rather than arteriopathy. 14 references, 5 figures

  13. Nanomedicine in cerebral palsy

    OpenAIRE

    Balakrishnan B; Nance E; Johnston MV; Kannan R; Kannan S

    2013-01-01

    Bindu Balakrishnan,1 Elizabeth Nance,1 Michael V Johnston,2 Rangaramanujam Kannan,3 Sujatha Kannan1 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University; Baltimore, MD, USA; 2Department of Neurology and Pediatrics, Kennedy Krieger Institute, Baltimore, MD, USA; 3Department of Ophthalmology, Center for Nanomedicine, Johns Hopkins University, Baltimore, MD, USA Abstract: Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the...

  14. Cerebral palsy and aging

    OpenAIRE

    Haak, Peterson; Lenski, Madeleine; HIDECKER, MARY JO COOLEY; Li, Min; Paneth, Nigel

    2009-01-01

    Cerebral palsy (CP), the most common major disabling motor disorder of childhood, is frequently thought of as a condition that affects only children. Deaths in children with CP, never common, have in recent years become very rare, unless the child is very severely and multiply disabled. Thus, virtually all children assigned the diagnosis of CP will survive into adulthood. Attention to the adult with CP has been sparse, and the evolution of the motor disorder as the individual moves through ad...

  15. Osteopenia in cerebral palsy.

    OpenAIRE

    Shaw, N J; White, C. P.; Fraser, W. D.; ROSENBLOOM, L.

    1994-01-01

    The bone mineral density of the lumbar spine was assessed in nine non-ambulant children with cerebral palsy combined with measurements of serum 25-hydroxyvitamin D, parathyroid hormone, and urinary calcium excretion. Three children with recurrent fractures received treatment with bisphosphonates for periods ranging from 12-18 months. All the children demonstrated a severe reduction in bone mineral density even when allowance was made for their body weight. There were no consistent abnormaliti...

  16. Radiopharmaceuticals for cerebral studies

    International Nuclear Information System (INIS)

    For obtain good brain scintillation images in nuclear medicine must be used several radiopharmaceuticals. Cerebral studies give a tumors visual image as well as brain anomalities detection and are helpful in the diagnostic diseases . Are described in this work: a cerebrum radiopharmaceuticals classification,labelled compounds proceeding and Tc 99m good properties in for your fast caption, post administration and blood purification for renal way

  17. Plasticidad cerebral y lenguaje

    OpenAIRE

    Moreno-Torres Sánchez, Ignacio; Berthier Torres, Marcelo Luís

    2012-01-01

    Hace pocos años se daba por sentado que la recuperación del lenguaje tras una lesión cerebral era imposible, al igual que adquirir la lengua materna más allá de los tres primeros años de vida. Sin embargo, las últimas indagaciones muestran que nuestra capacidad de aprender es mucho mayor.

  18. Dysphagia in cerebral palsy

    OpenAIRE

    Salghetti, Annamaria; Martinuzzi, Andrea

    2013-01-01

    Abstract. Feeding problemsare often present in children with neuromotor impairment: dysphagia is usuallyseen in the most severe form of cerebral palsy and it’s defined as thedifficulty with any of the four phases of swallowing. Clinical consequences aremalnutrition and recurrent chest infections that reduce expected duration andquality of life. In order to prevent these consequences it’s important todetect with clinical and instrumental examinations dysphagia symptoms and totreat them. Clinic...

  19. Perfusion MRI in cerebral infarction

    International Nuclear Information System (INIS)

    Purpose: To investigate the hemodynamic changes in patients with acute cerebral stroke by perfusion MRI. Materials and methods: In 12 patients with acute stroke in the territory of the middle cerebral artery, perfusion MRI was performed. Peak time, mean transit time, regional cerebral blood volume and regional cerebral blood flow were calculated in the infarction, the peri-infarction area and the contralateral hemisphere. Results: In the infarction the mean blood flow was 29 ml/100 g/min, compared to about 40 ml/100 g/min in the peri-infarction area and the contralateral hemisphere. In two patients increased cortical blood flow was found in the infarction due to luxury perfusion. The cerebral blood volume was reduced in the infarction, but significantly increased, to 7.3 ml/100 g, in the peri-infarction tissue. Conclusion: Perfusion MRI allows one to differentiate various patterns of perfusion disorders in patients with acute cerebral stroke. (orig./AJ)

  20. Hyperventilation, cerebral perfusion, and syncope

    DEFF Research Database (Denmark)

    Immink, R V; Pott, F C; Secher, N H;

    2014-01-01

    dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2 the......This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon...... contribution of a low PaCO2 to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced...

  1. Ligand-binding sites in human serum amyloid P component

    DEFF Research Database (Denmark)

    Heegaard, N.H.H.; Heegaard, Peter M. H.; Roepstorff, P.; Robey, F.A.

    1996-01-01

    Amyloid P component (AP) is a naturally occurring glycoprotein that is found in serum and basement membranes, AP is also a component of all types of amyloid, including that found in individuals who suffer from Alzheimer's disease and Down's syndrome. Because AP has been found to bind strongly and...... of 25 mu M, while the IC50 of AP-(27-38)-peptide and AP-(33-38)-peptide are 10 mu M and 2 mu M, respectively, The understanding of the structure and function of active AP peptides will be useful for development of amyloid-targeted diagnostics and therapeutics....

  2. [Insomnia and cerebral hypoperfusion].

    Science.gov (United States)

    Káposzta, Zoltán; Rácz, Klára

    2007-11-18

    Insomnia is defined as difficulty with the initiation, maintenance, duration, or quality of sleep that results in the impairment of daytime functioning, despite adequate opportunity and circumstances for sleep. In most countries approximately every third inhabitant has insomnia. Insomnia can be classified as primary and secondary. The pathogenesis of primary insomnia is unknown, but available evidence suggests a state of hyperarousal. Insomnia secondary to other causes is more common than primary insomnia. Cerebral hypoperfusion can be the cause of insomnia in some cases. In such patients the cerebral blood flow should be improved using parenteral vascular therapy. If insomnia persists despite treatment, then therapy for primary insomnia should be instituted using benzodiazepine-receptor agonists such as Zolpidem, Zopiclone, or Zaleplon. In those cases Midazolam cannot be used for the treatment of insomnia due to its marked negative effect on cerebral blood flow. In Hungary there is a need to organize multidisciplinary Insomnia Clinics because insomnia is more than a disease, it is a public health problem in this century. PMID:17988972

  3. Cerebral oxygenation and hyperthermia

    Directory of Open Access Journals (Sweden)

    AnthonyRichardBain

    2014-03-01

    Full Text Available Hyperthermia is associated with marked reductions in cerebral blood flow (CBF. Increased distribution of cardiac output to the periphery, increases in alveolar ventilation and resultant hypocapnia each contribute to the fall in CBF during passive hyperthermia; however, their relative contribution remains a point of contention, and probably depends on the experimental condition (e.g. posture and degree of hyperthermia. The hyperthermia-induced hyperventilatory response reduces arterial CO2 pressure (PaCO2 causing cerebral vasoconstriction and subsequent reductions in flow. During supine passive hyperthermia, the majority of recent data indicate that reductions in PaCO2 may be the primary, if not sole, culprit for reduced CBF. On the other hand, during more dynamic conditions (e.g. hemorrhage or orthostatic challenges, an inability to appropriately decrease peripheral vascular conductance presents a condition whereby adequate cerebral perfusion pressure may be compromised secondary to reductions in systemic blood pressure. Although studies have reported maintenance of pre-frontal cortex oxygenation (assessed by near-infrared spectroscopy during exercise and severe heat stress, the influence of cutaneous blood flow is known to contaminate this measure. This review discusses the governing mechanisms associated with changes in CBF and oxygenation during moderate to severe (i.e. 1.0°C to 2.0°C increase in body core temperature levels of hyperthermia. Future research directions are provided.

  4. Cerebral malformations without antenatal diagnosis

    International Nuclear Information System (INIS)

    Cerebral malformations are usually described following the different steps in development. Disorders of neurulation (dysraphisms), or diverticulation (holoprosencephalies and posterior fossa cysts), and total commissural agenesis are usually diagnosed in utero. In contrast, disorders of histogenesis (proliferation-differentiation, migration, organization) are usually discovered in infants and children. The principal clinical symptoms that may be a clue to cerebral malformation include congenital hemiparesis, epilepsy and mental or psychomotor retardation. MRI is the imaging method of choice to assess cerebral malformations. (orig.)

  5. Cerebral malformations without antenatal diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Girard, Nadine J. [Diagnostic Neuroradiology, Hopital Timone, Marseille (France)

    2010-06-15

    Cerebral malformations are usually described following the different steps in development. Disorders of neurulation (dysraphisms), or diverticulation (holoprosencephalies and posterior fossa cysts), and total commissural agenesis are usually diagnosed in utero. In contrast, disorders of histogenesis (proliferation-differentiation, migration, organization) are usually discovered in infants and children. The principal clinical symptoms that may be a clue to cerebral malformation include congenital hemiparesis, epilepsy and mental or psychomotor retardation. MRI is the imaging method of choice to assess cerebral malformations. (orig.)

  6. Early oligomerization stages for the non-amyloid component of α-synuclein amyloid

    Science.gov (United States)

    Eugene, Cindie; Laghaei, Rozita; Mousseau, Normand

    2014-10-01

    In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.

  7. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    OpenAIRE

    Yazan S. Batarseh; Quoc-Viet Duong; Youssef M. Mousa; Al Rihani, Sweilem B.; Khaled Elfakhri; Amal Kaddoumi

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process m...

  8. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  9. Oligomeric Amyloid-β Peptide on Sialylic Lewisx–Selectin Bonding at Cerebral Endothelial Surface

    OpenAIRE

    Sholpan Askarova; Sun, Grace Y; Gerald A. Meininger; James Lee

    2014-01-01

    Introduction: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB) plays an important role in the onset and progression of the disease. Increased de...

  10. Natriuretic peptides and cerebral hemodynamics

    DEFF Research Database (Denmark)

    Guo, Song; Barringer, Filippa; Zois, Nora Elisabeth;

    2014-01-01

    decompensated disease. In contrast, their biological effects on the cerebral hemodynamics are poorly understood. In this mini-review, we summarize the hemodynamic effects of the natriuretic peptides with a focus on the cerebral hemodynamics. In addition, we will discuss its potential implications in diseases...... where alteration of the cerebral hemodynamics plays a role such as migraine and acute brain injury including stroke. We conclude that a possible role of the peptides is feasible as evaluated from animal and in vitro studies, but more research is needed in humans to determine the precise response on...... cerebral vessels....

  11. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    Directory of Open Access Journals (Sweden)

    Cai Z

    2013-08-01

    Full Text Available Zhiyou Cai,1 Yong Yan,2 Yonglong Wang2 1Department of Neurology, the Lu’an Affiliated Hospital of Anhui Medical University, Lu’an People’s Hospital, Lu’an, Anhui Province, People’s Republic of China; 2Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China Background: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results: These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting

  12. Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.

    Science.gov (United States)

    Henderson, Simon J; Andersson, Christin; Narwal, Rajesh; Janson, Juliette; Goldschmidt, Tom J; Appelkvist, Paulina; Bogstedt, Anna; Steffen, Ann-Charlott; Haupts, Ulrich; Tebbe, Jan; Freskgård, Per Ola; Jermutus, Lutz; Burrell, Matthew; Fowler, Susan B; Webster, Carl I

    2014-02-01

    Alzheimer's disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-β in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-β are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby reducing formation of plaques predominantly composed of insoluble amyloid-β; the so-called peripheral sink hypothesis. Here we describe the use of an amyloid-β degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to albumin to extend plasma half-life and has been engineered to confer increased amyloid-β degradation activity. We used this molecule to investigate the effect of degradation of peripheral amyloid-β on amyloid-β levels in the brain and cerebrospinal fluid after repeated intravenous dosing for up to 4 months in Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved highly effective at degradation of amyloid-β in the periphery but did not alter brain or cerebrospinal fluid amyloid-β levels, suggesting that the peripheral sink hypothesis is not valid and is the first time that this has been demonstrated in non-human primates. PMID:24259408

  13. Binuclear ruthenium(II) complexes for amyloid fibrils recognition

    Energy Technology Data Exchange (ETDEWEB)

    Hanczyc, Piotr, E-mail: piotr.hanczyc@chalmers.se

    2014-12-05

    Highlights: • Interactions of binuclear ruthenium(II) complexes with amyloid fibrils. • Dimer ruthenium(II) compounds are sensitive amyloid fibrils biomarkers. • Recognition of amyloid-chromophore adducts by two-photon excited emission. - Abstract: Metal–organic compounds represent a unique class of biomarkers with promising photophysical properties useful for imaging. Here interactions of insulin fibrils with two binuclear complexes [μ-(11,11′-bidppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (1) and [μ-C4(cpdppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (2) are studied by linear dichroism (LD) and fluorescence. These ruthenium(II) compounds could provide a new generation of amyloid binding chromophores with long lived lifetimes, good luminescence quantum yields for the bound molecules and photo-stability useful in multiphoton luminescence imaging.

  14. Tau/Amyloid Beta 42 Peptide Test (Alzheimer Biomarkers)

    Science.gov (United States)

    ... helpful? Also known as: Alzheimer Biomarkers Formal name: Tau Protein and Amyloid Beta 42 Peptide Related tests: Phosporylated ... should know? How is it used? Tests for Tau protein and Aß42 may be used as supplemental tests ...

  15. Phosphorylation modifies the molecular stability of β-amyloid deposits

    Science.gov (United States)

    Rezaei-Ghaleh, Nasrollah; Amininasab, Mehriar; Kumar, Sathish; Walter, Jochen; Zweckstetter, Markus

    2016-04-01

    Protein aggregation plays a crucial role in neurodegenerative diseases. A key feature of protein aggregates is their ubiquitous modification by phosphorylation. Little is known, however, about the molecular consequences of phosphorylation of protein aggregates. Here we show that phosphorylation of β-amyloid at serine 8 increases the stability of its pathogenic aggregates against high-pressure and SDS-induced dissociation. We further demonstrate that phosphorylation results in an elevated number of hydrogen bonds at the N terminus of β-amyloid, the region that is critically regulated by a variety of post-translational modifications. Because of the increased lifetime of phosphorylated β-amyloid aggregates, phosphorylation can promote the spreading of β-amyloid in Alzheimer pathogenesis. Our study suggests that regulation of the molecular stability of protein aggregates by post-translational modifications is a crucial factor for disease progression in the brain.

  16. Computational Modelling of the Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby

    2014-01-01

    specific protein into amyloid fibrils. During this process, a cytotoxic event occurs which can be a serious actor in the evolvement of the disease. This thesis is concerned with elucidating the biological processes concerning amyloid proteins, more specifically, the peptide hormone human islet amyloid...... methods to interpret results correctly. Computational studies and molecular dynamics (MD) simulations in particular have become important tools in the effort to understand biological mechanisms. The strength of these methods is the high resolution in time and space, and the ability to specifically design...... atoms are grouped into a single particle, reducing the number of particles in the system. Coarse grained MD simulations are necessary to study amyloid aggregation computationally, as the time scale and the system size needed for the process are not currently accessible with atomistic MD simulations...

  17. Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.

    Science.gov (United States)

    Zhang, Xilin; Hu, Jin; Zhong, Li; Wang, Na; Yang, Longyu; Liu, Chia-Chen; Li, Huifang; Wang, Xin; Zhou, Ying; Zhang, Yunwu; Xu, Huaxi; Bu, Guojun; Zhuang, Jiangxing

    2016-09-01

    Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also associated with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degradation in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insoluble Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy. PMID:27114256

  18. Interactions driving the collapse of islet amyloid polypeptide: Implications for amyloid aggregation

    Science.gov (United States)

    Cope, Stephanie M.

    Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-residue intrinsically disordered hormone involved in glucose regulation and gastric emptying. The aggregation of hIAPP into amyloid fibrils is believed to play a causal role in type 2 diabetes. To date, not much is known about the monomeric state of hIAPP or how it undergoes an irreversible transformation from disordered peptide to insoluble aggregate. IAPP contains a highly conserved disulfide bond that restricts hIAPP(1-8) into a short ring-like structure: N_loop. Removal or chemical reduction of N_loop not only prevents cell response upon binding to the CGRP receptor, but also alters the mass per length distribution of hIAPP fibers and the kinetics of fibril formation. The mechanism by which N_loop affects hIAPP aggregation is not yet understood, but is important for rationalizing kinetics and developing potential inhibitors. By measuring end-to-end contact formation rates, Vaiana et al. showed that N_loop induces collapsed states in IAPP monomers, implying attractive interactions between N_loop and other regions of the disordered polypeptide chain . We show that in addition to being involved in intra-protein interactions, the N_loop is involved in inter-protein interactions, which lead to the formation of extremely long and stable beta-turn fibers. These non-amyloid fibers are present in the 10 muM concentration range, under the same solution conditions in which hIAPP forms amyloid fibers. We discuss the effect of peptide cyclization on both intra- and inter-protein interactions, and its possible implications for aggregation. Our findings indicate a potential role of N_loop-N_loop interactions in hIAPP aggregation, which has not previously been explored. Though our findings suggest that N_loop plays an important role in the pathway of amyloid formation, other naturally occurring IAPP variants that contain this structural feature are incapable of forming amyloids. For example, hIAPP readily

  19. Hereditary Amyloid Cardiomyopathy Caused by a Variant Apolipoprotein A1

    OpenAIRE

    Hamidi Asl, Ladan; Liepnieks, Juris J.; Hamidi Asl, Kamran; Uemichi, Tomoyuki; Moulin, Georges; Desjoyaux, Emmanuel; Loire, Robert; Delpech, Marc; Grateau, Gilles; Benson, Merrill D.

    1999-01-01

    Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene. The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein ...

  20. Amyloid/Melanin distinctive mark in invertebrate immunity

    OpenAIRE

    A Grimaldi; R Girardello; D Malagoli; P Falabella; Tettamanti, G.; R Valvassori; E Ottaviani; M de Eguileor

    2012-01-01

    Protostomes and Deuterostomes show the same nexus between melanin production, and amyloid fibril production, i.e., the presence of melanin is indissolubly linked to amyloid scaffold that, in turn, is conditioned by the redox status/cytoplasmic pH modification, pro-protein cleavage presence, adrenocorticotropin hormone (ACTH), melanocyte-stimulating hormone (α-MSH), and neutral endopeptidase (NEP) overexpressions. These events represent the crucial component of immune response in invertebrates...

  1. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Helen P McWilliams-Koeppen

    Full Text Available Light chain (AL amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(PH-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  2. Novel β-amyloid aggregation inhibitors possessing a turn mimic.

    Science.gov (United States)

    Hamada, Yoshio; Miyamoto, Naoko; Kiso, Yoshiaki

    2015-04-01

    Amyloid β peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of β-secretase, γ-secretase, and Aβ aggregation, and anti-amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Aβ antibodies. Recently, we reported potent small-sized β-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel β-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid β peptides contain a turn structure within the molecule. Here, we designed and synthesized novel β-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid β peptides. PMID:25736996

  3. Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis

    Directory of Open Access Journals (Sweden)

    Tanya L. Poshusta

    2013-11-01

    Full Text Available Light chain (AL amyloidosis is a devastating disease characterized by amyloid deposits formed by immunoglobulin light chains. Current available treatments involve conventional chemotherapy and autologous stem cell transplant. We have recently concluded a phase III trial comparing these two treatments. AL amyloidosis patients who achieve hematological complete response (CR do not necessarily achieve organ response regardless of the treatment they received. In order to investigate the possible correlation between amyloid formation kinetics and organ response, we selected AL amyloidosis patients from the trial with kidney involvement and CR after treatment. Six patients were selected and their monoclonal immunoglobulin light chains were characterized. The proteins showed differences in their stability and their kinetics of amyloid formation. A correlation was detected at pH 7.4, showing that less stable proteins are more likely to form amyloid fibrils. AL-T03 is too unstable to form amyloid fibrils at pH 7.4. This protein was found in the only patient in the study that had organ response, suggesting that partially folded species are required for amyloid formation to occur in AL amyloidosis.

  4. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

    Science.gov (United States)

    Kurnellas, Michael P; Adams, Chris M; Sobel, Raymond A; Steinman, Lawrence; Rothbard, Jonathan B

    2013-04-01

    The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders. PMID:23552370

  5. Cerebral oxygenation after birth

    DEFF Research Database (Denmark)

    Hessel, Trine W; Hyttel-Sorensen, Simon; Greisen, Gorm

    2014-01-01

    AIM: To compare absolute values of regional cerebral tissue oxygenation (cStO2 ) during haemodynamic transition after birth and repeatability during steady state for two commercial near-infrared spectroscopy (NIRS) devices. METHODS: In a prospective observational study, the INVOS 5100C and FORE...... INVOS and FORE-SIGHT cStO2 estimates showed oxygenation-level-dependent difference during birth transition. The better repeatability of FORE-SIGHT could be due to the lower response to change in saturation....

  6. Techniques in cerebral protection

    International Nuclear Information System (INIS)

    Carotid angioplasty and stenting is a valid alternative option to conventional carotid endarterectomy in the treatment of carotid artery stenosis. During the stenting process, however, distal embolization can occur with neurological consequences. To avoid this, cerebral protection devices have been introduced. Three principal types of protection system have been developed: distal balloon occlusion, distal filters and proximal protection with or without reversal of flow. As protection devices became the focus of interest by manufactures and physicians, several trials are going on worldwide to analyze the characteristics of each of them and to evaluate their efficacy to reduce the rate of distal embolization

  7. Therapeutic interventions in cerebral palsy.

    Science.gov (United States)

    Patel, Dilip R

    2005-11-01

    Various therapeutic interventions have been used in the management of children with cerebral palsy. Traditional physiotherapy and occupational therapy are widely used interventions and have been shown to be of benefit in the treatment of cerebral palsy. Evidence in support of the effectiveness of the neurodevelopmental treatment is equivocal at best. There is evidence to support the use and effectiveness of neuromuscular electrical stimulation in children with cerebral palsy. The effectiveness of many other interventions used in the treatment of cerebral palsy has not been clearly established based on well-controlled trials. These include: sensory integration, body-weight support treadmill training, conductive education, constraint-induced therapy, hyperbaric oxygen therapy, and the Vojta method. This article provides an overview of salient aspects of popular interventions used in the management of children with cerebral palsy. PMID:16391455

  8. Cerebral hemodynamics in moyamoya disease

    International Nuclear Information System (INIS)

    Rebuild-up phenomenon, an electroencephalographic pathological finding in moyamoya disease, was evaluated in the context of dynamic changes in cerebral circulation after hyperventilation. Sequential functional angiography after hyperventilation, measurement of cerebral blood flow (CBF) by the outflow method, and Kr-81m single photon emission tomography were employed for clarification of the sequential dynamic changes in cerebral circulation after hyperventilation. In most cases there was a persistent decrease in CBF even after arterial carbon dioxide tension (PaCO2) had been normalized, which suggests that the response of the cerebral circulation to the changes in PaCO2 is delayed. Moreover, this feature was most prominent in the superficial layer of the cerebrum. For the most part, coincidence and synchronization were documented between rebuild-up and the delayed response of the cerebral circulation. These findings indicate that the delayed CBF response to hyperventilation contributes pathogenetically to rebuild-up in moyamoya disease. (author)

  9. Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer’s and Parkinson’s diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca2+-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined “membrane therapy”) targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  10. Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  11. Imaging β-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization

    International Nuclear Information System (INIS)

    The polymerization of β-amyloid (Aβ) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. Aβ molecular imaging probes (Aβ-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of Aβ with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of Aβ-MIPs with fibrils. Subsequently, we hypothesize four Aβ-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B max and K D to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions

  12. A Paired RNAi and RabGAP Overexpression Screen Identifies Rab11 as a Regulator of β-Amyloid Production

    Directory of Open Access Journals (Sweden)

    Vinod Udayar

    2013-12-01

    Full Text Available Alzheimer’s disease (AD is characterized by cerebral deposition of β-amyloid (Aβ peptides, which are generated from amyloid precursor protein (APP by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD.

  13. Cortical Amyloid beta in cognitively normal elderly adults is associated with decreased network efficiency within the cerebro-cerebellar system.

    Directory of Open Access Journals (Sweden)

    Stefanie eSteininger

    2014-03-01

    Full Text Available Deposition of cortical amyloid beta (Aβ is a correlate of aging and a risk factor for Alzheimer Disease (AD. While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using Pittsburgh Compound-B positron-emission-tomography (PiB-PET late frame signals. Volumes of brain structures were assessed by applying an automated parcellation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent (BOLD resting state functional magnetic resonance imaging (fMRI at the high field strength of 7 Tesla for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling.Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro

  14. Cerebral imaging in pediatrics

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, I. [London, Great Ormond Street Hospital for Children (United Kingdom)

    1998-06-01

    Radioisotope brain imaging has focused mainly on regional cerebral blood flow (rCBF). However the use of ligand which go to specific receptor sites is being introduced in pediatrics, mainly psychiatry. rCBF is potentially available in many institutions, especially with the availability of multi-headed gamma cameras. The use of this technique in pediatrics requires special attention to detail in the manner of data acquisition and handling the child. The interpretation of the rCBF study in a child requires knowledge of normal brain maturation. The major clinical use in pediatrics is epilepsy because of the advances in surgery and the frequency of complex partial seizures. Other indications in pediatric neurology include brain death, acute neurological loss including stroke, language disorders, cerebral palsy, hypertension due to renovascular disease, traumatic brain injury and migraine. There are pediatric physiological conditions in which rCBF has been undertaken, these include anorexia nervosa, autism, Gilles de la Tourette syndrome (GTS) and attention deficit disorder-hyperactivity (ADHD). Research using different ligands to specific receptor sites will also be reviewed in pediatrics.

  15. Cerebral imaging in pediatrics

    International Nuclear Information System (INIS)

    Radioisotope brain imaging has focused mainly on regional cerebral blood flow (rCBF). However the use of ligand which go to specific receptor sites is being introduced in pediatrics, mainly psychiatry. rCBF is potentially available in many institutions, especially with the availability of multi-headed gamma cameras. The use of this technique in pediatrics requires special attention to detail in the manner of data acquisition and handling the child. The interpretation of the rCBF study in a child requires knowledge of normal brain maturation. The major clinical use in pediatrics is epilepsy because of the advances in surgery and the frequency of complex partial seizures. Other indications in pediatric neurology include brain death, acute neurological loss including stroke, language disorders, cerebral palsy, hypertension due to renovascular disease, traumatic brain injury and migraine. There are pediatric physiological conditions in which rCBF has been undertaken, these include anorexia nervosa, autism, Gilles de la Tourette syndrome (GTS) and attention deficit disorder-hyperactivity (ADHD). Research using different ligands to specific receptor sites will also be reviewed in pediatrics

  16. Cerebral sinus venous thrombosis.

    Science.gov (United States)

    Alvis-Miranda, Hernando Raphael; Milena Castellar-Leones, Sandra; Alcala-Cerra, Gabriel; Rafael Moscote-Salazar, Luis

    2013-10-01

    Cerebral sinus venous thrombosis (CSVT) is a rare phenomenon that can be seen with some frequency in young patients. CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, the leading causes differ between developed and developing countries, converting CSVT in a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who presents with CSVT should underwent to CT-scan venography (CVT) and to the proper inquiry of the generating cause. This disease can affect the cerebral venous drainage and related anatomical structure. The symptoms may appear in relation to increased intracranial pressure imitating a pseudotumorcerebri. Prognosis depends on the early detection. Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment. PMID:24347950

  17. Cerebral sinus venous thrombosis

    Directory of Open Access Journals (Sweden)

    Hernando Raphael Alvis-Miranda

    2013-01-01

    Full Text Available Cerebral sinus venous thrombosis (CSVT is a rare phenomenon that can be seen with some frequency in young patients. CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, the leading causes differ between developed and developing countries, converting CSVT in a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who presents with CSVT should underwent to CT-scan venography (CVT and to the proper inquiry of the generating cause. This disease can affect the cerebral venous drainage and related anatomical structure. The symptoms may appear in relation to increased intracranial pressure imitating a pseudotumorcerebri. Prognosis depends on the early detection. Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment.

  18. Designed Trpzip-3 β-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems.

    Science.gov (United States)

    Hopping, Gene; Kellock, Jackson; Caughey, Byron; Daggett, Valerie

    2013-09-12

    The trpzip peptides are small, monomeric, and extremely stable β-hairpins that have become valuable tools for studying protein folding. Here, we show that trpzip-3 inhibits aggregation in two very different amyloid systems: transthyretin and Aβ(1-42). Interestingly, Trp → Leu mutations renders the peptide ineffective against transthyretin, but Aβ inhibition remains. Computational docking was used to predict the interactions between trpzip-3 and transthyretin, suggesting that inhibition occurs via binding to the outer region of the thyroxine-binding site, which is supported by dye displacement experiments. PMID:24900756

  19. Peripheral Amyloid-β Levels Regulate Amyloid-β Clearance from the Central Nervous System

    OpenAIRE

    Marques, Marcos A.; Kulstad, J. Jacob; Savard, Christopher E.; Green, Pattie S.; Lee, Sum P.; Craft, Suzanne; Watson, G. Stennis; Cook, David G.

    2009-01-01

    Amyloid-β (Aβ) is cleared from the brain by both proteolytic digestion and transport across the blood-brain-barrier into the peripheral circulatory system. To investigate the role peripheral Aβ levels play in regulating Aβ brain clearance, we measured the clearance of [125I]-Aβ-{1-40 injected into the brains of liver-ligated rats that allowed peripheral Aβ levels to be maintained at elevated levels for approximately one hour with/without a single peripheral bolus of unlabeled Aβ-{1-40. We fou...

  20. Obstructive hydrocephalus resulting from cerebral venous thrombosis

    OpenAIRE

    2011-01-01

    Cerebral venous thrombosis is a rare form of stroke in childhood. Increased intracranial pressure is a well-defined complication of cerebral venous thrombosis but obstructive hydrocephalus as a presentation finding of cerebral venous thrombosis is rarely described. A child case of cerebral sinus thrombosis presenting with obstructive hydrocephalus and management of clinical condition is presented with discussion of reported cases and treatment recommendations.

  1. Cerebrovascular hemodynamics in patients with cerebral arteriosclerosis

    Institute of Scientific and Technical Information of China (English)

    Jianbo Yang; Changcong Cui; Chengbin Wu

    2011-01-01

    The present study observed hemodynamic changes in 26 patients with cerebral arteriosclerosis using a cerebral circulation dynamics detector and transcranial Doppler.In patients with cerebral arteriosclerosis the blood supply and flow rate in the bilateral carotid arteries and the blood flow rate in the anterior cerebral and middle cerebral arteries were similar to normal controls, but the cerebral vascular resistance, critical pressure and pulsatility index were increased, and cerebral arterial elasticity and cerebral blood flow autoregulation were decreased.Compared with the lesioned hemisphere of patients with cerebral infarction, the total blood supply and blood flow rate of patients with cerebral arteriosclerosis were higher.Compared with normal subjects, patients with cerebral arteriosclerosis exhibited cognitive disturbances, mainly in short-term memory, attention, abstract capability, and spatial and executive dysfunction.Results showed that cerebral arteriosclerosis does not directly affect the blood supply of a cerebral hemisphere, but affects cognitive function.The increased cerebral vascular resistance and reduced autoregulation of cerebral blood vessels may be important hemodynamic mechanisms of arteriosclerosis-induced cerebral infarction.

  2. Liver transplantation for familial amyloid polyneuropathy.

    Science.gov (United States)

    Monteiro, E; Perdigoto, R; Furtado, A L

    1998-01-01

    Familiar Amyloid Polyneuropathy (FAP), an autosomal dominant inherited multisystemic disorder was first observed by Corino de Andrade, a Portuguese neurologist, in 1939. This disease of Portuguese origin was probably spread by fishermen, mainly to Sweden and Japan. It is characterized by a progressive peripheral polyneuropathy and autonomic neuropathy (erectile sexual disfunction, gastrointestinal disfunction, bladder dysfunction and cardio vascular disease) and malnutrition. There are neural and systemic amiloid deposits. Type I FAP, of Portuguese origin, is the most common variety. The amyloid protein is the variant transthyretin (TTR) in which methionine (MET) is a substitute for valine in position 30 (TTR MET 30). It is mainly produced by the liver (90%) and, in small amounts, by the choroidal plexus. Symptoms usually start in the 3rd and 4th decade of life and the patients usually die within 10-15 years. From the therapeutic options--plasmapheresis, immunoadsorption and liver transplantation; the latter seems to be the only one, which stops the production of TTR MET 30 in a permanent way, by means of the liver. The lack of any other effective therapy and the success of the first liver transplantation performed in Sweden arouse great hope. So far, around 300 patients have been transplanted all over the world. A hundred and thirty of them were transplanted in Portugal. A Kaplan Meier survival curve of the Portuguese patients shows a survival rate of 78% at 5 years. However, in spite of the progression of the disease being halted, the irreversibility of some neurological lesions seems to persist. This fact raises the problem of the timing of the transplantation. It seems that the patients should be transplanted as soon as the symptoms start, since mortality and severe morbidity seems to mainly involve those in whom symptomatic disease has lasted longer than six years. As the explanted liver is a morphologic normal liver, a sequential (domino) transplant has been

  3. CEREBRAL PALSY AND MUSIC ACHIEVEMENT

    Directory of Open Access Journals (Sweden)

    Miodrag L. STOSHLJEVIKJ

    2008-12-01

    Full Text Available Pupils with cerebral palsy attend elementary education accordind to a regular and special teaching plan and program. Regular school curriculum was reformed in 1992, while special plan and program has not been changed and adapted according to pupil’s needs and capacities. Music is one of the best means of expressing oneself and plays a very important role in the development of every child, the child with cerebral palsy in particular.In order to test the possibility of pupils with cerebral palsy, with and without mental retardation, to apprehend the actual program content, we have conducted research on musical achievement of children with cerebral palsy. During 2007 a research was carried out, on the sample of 27 pupils with cerebral palsy and mild mental retardation who attended classes in the school “Miodrag Matikj”, and a sample of16 students with cerebral palsy without mental retardation who attended the school “Dr. Dragan Hercog” in Belgrade.Results of the research, as well as analysis of music curriculum content, indicated that the capacities of students with cerebral palsy to carry out the curriculum tasks require special approach and methodology. Therefore, we introduced some proposals to overcome the difficulties in fulfilling music curriculum demands of those pupils. We made special emphasis on the use of computer based Assistive technology which facilitates the whole process to a large extent.

  4. CEREBRAL PALSY : ANTENATAL RISK FACTORS

    Directory of Open Access Journals (Sweden)

    Srinivasa Rao

    2015-05-01

    Full Text Available INTRODUCTION: Cerebral palsy (CP is a group of permanent movement disorders that appear in early childhood. Cerebral palsy is caused by abnormal development or damage to the parts of the brain that control movement, balance, and posture. Most often the problems occur during pregnancy; however, they may also occur during childbirth, or shortly after birth. Often the cause is unknown. AIM: To study the different antenatal maternal risk factors associated with cerebral palsy in the study group. MATERIA LS AND METHODS: Retrospective study was done to assess possible associated antenatal risk factors for cerebral palsy. Mothers of 100 cerebral palsy children were selected who are treated in Rani Chandramani Devi Hospital, a Government hospital in Visakhapa tn am, Andhra Pradesh State, India , from 2012 to 2014 and 100 controls, mothers of normal children were studied. Detailed antenatal history was obtained from the mothers of the children in both affected and control group. RESULTS: From the data, we conclude that the association of maternal anaemia with cerebral palsy is 7.3 times higher; association of maternal hypertension with cerebral palsy is 6.6 time higher, association with Pre - eclampsia is 6 times higher; association with Eclampsia is 8.6 times higher ; with antepartum haemorrhage, the association is 8.6 times higher and association of multiple pregnancy with cerebral palsy is 4.8 times higher than with controls. CONCLUSION: From this study of the role of antenatal risk factors, in the occurrence of cer ebral palsy in children it is concluded that the most common risk factor associated with cerebral palsy is the maternal anaemia and the other important risk factors associated being hypertension, pre eclampsia, eclampsia, antepartum haemorrhage and multipl e births.

  5. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    International Nuclear Information System (INIS)

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly

  6. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Energy Technology Data Exchange (ETDEWEB)

    Okumura, Hisashi [Research Center for Computational Science, Institute for Molecular Science, Okazaki, Aichi 444-8585 (Japan); Department of Structural Molecular Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585 (Japan)

    2015-12-31

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  7. The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia

    Directory of Open Access Journals (Sweden)

    Brian A. Gordon

    2015-01-01

    Conclusions: The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.

  8. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Science.gov (United States)

    Okumura, Hisashi

    2015-12-01

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  9. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.

    Science.gov (United States)

    Casarejos, Maria J; Perucho, Juan; Gomez, Ana; Muñoz, Maria P; Fernandez-Estevez, Marian; Sagredo, Onintza; Fernandez Ruiz, Javier; Guzman, Manuel; de Yebenes, Justo Garcia; Mena, Maria A

    2013-01-01

    Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders. PMID:23478312

  10. CEREBRAL PALSY AND MUSIC ACHIEVEMENT

    OpenAIRE

    Miodrag L. STOSHLJEVIKJ; EMINOVIKJ Fadilj N.; NIKIKJ Radmila M.; Gordana I. ACHIKJ; Sanela R. PACIKJ

    2015-01-01

    Pupils with cerebral palsy attend elementary education accordind to a regular and special teaching plan and program. Regular school curriculum was reformed in 1992, while special plan and program has not been changed and adapted according to pupil’s needs and capacities. Music is one of the best means of expressing oneself and plays a very important role in the development of every child, the child with cerebral palsy in particular.In order to test the possibility of pupils with cerebral pal...

  11. A potential amyloid-imaging probe for Alzheimer's disease

    International Nuclear Information System (INIS)

    Purpose: To screen out the human single-chain fragment variable (scFv) against amyloid β peptide 40 from a human synthetic antibody library, sub-clone its gene into E. coli expression system, and express and purify it for amyloid peptide imaging research. The overload of amyloid β peptide and the appearance of senile plaques in the human brain tissue is one of the hallmark of the Alzheimer's disease, and in vivo imaging of amyloidβ peptide is valuable for the earlier diagnosis of Alzheimer's disease. Methods: Amyloid β peptide 40 was bound on the solid surface of Nunc plates as antigen and a human antibody library constructed with human antibody heavy and light chain variable gene and nucleotides sequence coded (Gly4Ser)3 linker and displayed on the protein surface of filamentous phage was used to screen the binding clones. After five rounds of bio-panning, the host E. coli TG1 was infected with eluted filamentous phage from the last turn of selection. 55 well-separated colonies were picked randomly from the plates and several specific positive clones were identified by ELISA testing, and their binding sites were determined by competitive ELISA with amyloid 13 peptide 40, 1-16, 25-35. The single-chain Fv antibody gene was sequenced and their amino acids sequence was deduced. The scFv antibody gene was sub-cloned into a protokayotic expression vector pET-22b(+) and transformed into bacteria strain BL21 to express the His6-tagged single-chain antibody and the whole cell culture was subjected to SDS-PAGE analysis. The antibody was expressed in inclusion bodies and purified with serial buffers and verified with western blotting and their activity was tested by ELISA against amyloid β peptide 40. Results: ELISA testing showed that 33 clones could bind amyloid β peptide 40 and 10 of these clones could be inhibited by amyloid β peptide 40 itself to below 50% of its original binding activities. Five clones could also be inhibited by amyloid β peptide 1-16. DNA

  12. Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

    Energy Technology Data Exchange (ETDEWEB)

    Chiotis, Konstantinos [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Carter, Stephen F. [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); University of Manchester, Wolfson Molecular Imaging Centre, Institute of Brain, Behaviour and Mental Health, Manchester (United Kingdom); Farid, Karim [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); APHP, Hotel-Dieu Hospital, Department of Nuclear Medicine, Paris (France); Savitcheva, Irina [Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Collaboration: for the Diagnostic Molecular Imaging (DiMI) network and the Alzheimer' s Disease Neuroimaging Initiative

    2015-09-15

    Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

  13. Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

    International Nuclear Information System (INIS)

    Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

  14. Cerebral toxoplasmosis in AIDS

    International Nuclear Information System (INIS)

    Since 1982 (Hauser and co-workers), literature has reported focal cerebral tissue charges in AIDS patients whose diagnosis was unclear at first but which could be identified finally as florid toxoplasmosis encephalitis by biopsy and autopsy. It was found that the value of otherwise reliable serological tests (KBR, Sabin-Feldmann tests, etc.) is questionable in patients with severely impaired or incompetent immune systems, and, in particular, that a negative or uncharacteristic test result may not preclude any opportunistic infection process. Furthermore, isolation of Toxoplasma gondii or specific antibodies from the cerebrospinal fluid will be successful in exceptional cases only. In patients with AIDS or lymphadenopathy syndrome, the differential diagnosis will have to include - first and foremost - reactivated toxoplasma infection (not newly acquired, as a rule) if central neurological symptoms occur. (orig.)

  15. Cerebral white matter hypoplasia

    International Nuclear Information System (INIS)

    This paper demonstrates the MR imaging findings in children with cerebral white matter hypoplasia (CWMH). The MR studies of four children, aged 3-7 y (mean age, 2.3 y) with a diagnosis of CWMH were reviewed. In all cases multiplanar T1-weighted and T2-weighted spin-echo images were obtained. All children had similar histories of severe developmental delay and nonprogressive neurologic deficits despite normal gestational and birth histories. In two cases there was a history of maternal cocaine abuse. Autopsy correlation was available in one child. The MR images of all four children demonstrated diffuse lack of white matter and enlarged ventricles but normal-appearing gray matter. The corpus callosum, although completely formed, was severely thinned. There was no evidence of gliosis or porencephaly, and the distribution of myelin deposition was normal for age in all cases. Autopsy finding in one child correlated exactly with the MR finding

  16. Electron microscopic study on amyloid fibril formation in human lymph nodes

    OpenAIRE

    Michio Dobashi; Fumiaki Yuda; Akihiro Masuda; Kazuo Terashima; Yutaka lmai

    1986-01-01

    The purpose of this investigation was to clarify the mechanisms of amyloid fibril formation in human lymph nodes. In our present study, amyloid deposition was observed diffusely in all compartments of the lymph nodes. The deposition form showed extremely characteristic findings in its morphological features. Namely, amyloid deposits mainly consisted of clusters of round or oval nodules. Each amyloid nodule was frequently enclosed with long-stretched cytoplasmic...

  17. Studies of amyloid toxicity in Drosophila models and effects of the BRICHOS domain

    OpenAIRE

    Hermansson Wik, Erik

    2015-01-01

    Amyloid diseases involve specific protein misfolding events and formation of fibrillar deposits. The symptoms of these diseases are broad and dependent on site of accumulation, with different amyloid proteins depositing in specific tissues or systematically. One such protein is transthyretin (TTR) associated with senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. We show that the glycosaminoglycan heparan sulfate (HS) can be co-loc...

  18. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  19. Smooth muscle titin forms in vitro amyloid aggregates.

    Science.gov (United States)

    Bobylev, Alexandr G; Galzitskaya, Oxana V; Fadeev, Roman S; Bobyleva, Liya G; Yurshenas, Darya A; Molochkov, Nikolay V; Dovidchenko, Nikita V; Selivanova, Olga M; Penkov, Nikita V; Podlubnaya, Zoya A; Vikhlyantsev, Ivan M

    2016-07-01

    Amyloids are insoluble fibrous protein aggregates, and their accumulation is associated with amyloidosis and many neurodegenerative diseases, including Alzheimer's disease. In the present study, we report that smooth muscle titin (SMT; 500 kDa) from chicken gizzard forms amyloid aggregates in vitro This conclusion is supported by EM data, fluorescence analysis using thioflavin T (ThT), Congo red (CR) spectroscopy and X-ray diffraction. Our dynamic light scattering (DLS) data show that titin forms in vitro amyloid aggregates with a hydrodynamic radius (Rh) of approximately 700-4500 nm. The initial titin aggregates with Rh approximately 700 nm were observed beyond first 20 min its aggregation that shows a high rate of amyloid formation by this protein. We also showed using confocal microscopy the cytotoxic effect of SMT amyloid aggregates on smooth muscle cells from bovine aorta. This effect involves the disorganization of the actin cytoskeleton and result is cell damage. Cumulatively, our results indicate that titin may be involved in generation of amyloidosis in smooth muscles. PMID:27129292

  20. On the adsorption of magnetite nanoparticles on lysozyme amyloid fibrils.

    Science.gov (United States)

    Majorosova, Jozefina; Petrenko, Viktor I; Siposova, Katarina; Timko, Milan; Tomasovicova, Natalia; Garamus, Vasil M; Koralewski, Marceli; Avdeev, Mikhail V; Leszczynski, Błażej; Jurga, Stefan; Gazova, Zuzana; Hayryan, Shura; Hu, Chin-Kun; Kopcansky, Peter

    2016-10-01

    An adsorption of magnetic nanoparticles (MNP) from electrostatically stabilized aqueous ferrofluids on amyloid fibrils of hen egg white lysozyme (HEWL) in 2mg/mL acidic dispersions have been detected for the MNP concentration range of 0.01-0.1vol.%. The association of the MNP with amyloid fibrils has been characterized by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS) and magneto-optical measurements. It has been observed that the extent of adsorption is determined by the MNP concentration. When increasing the MNP concentration the formed aggregates of magnetic particles repeat the general rod-like structure of the fibrils. The effect is not observed when MNP are mixed with the solution of lysozyme monomers. The adsorption has been investigated with the aim to clarify previously found disaggregation activity of MNP in amyloid fibrils dispersions and to get deeper insight into interaction processes between amyloids and MNP. The observed effect is also discussed with respect to potential applications for ordering lysozyme amyloid fibrils in a liquid crystal phase under external magnetic fields. PMID:27451367

  1. MR Microimaging of amyloid plaques in Alzheimer's disease transgenic mice

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas. (orig.)

  2. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  3. Impact of amyloid imaging on drug development in Alzheimer's disease

    International Nuclear Information System (INIS)

    Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials

  4. Acute ischemic cerebral attack

    Directory of Open Access Journals (Sweden)

    Franco-Garcia Samir

    2010-12-01

    Full Text Available The decrease of the cerebral blood flow below the threshold of autoregulation led to changes of cerebral ischemia and necrosis that traduce in signs and symtoms of focal neurologic dysfunction called acute cerebrovascular symdrome (ACS or stroke. Two big groups according to its etiology are included in this category the hemorragic that constitue a 20% and the ischemic a 80% of cases. Great interest has wom the ischemic ACS because of its high social burden, being the third cause of no violent death in the world and the first of disability. Many risk factors favor the presentation of these events and some of them are susceptible of modification and therfore are objetives of primary prevention just as the control of diabetes, hypertension and the practice of healthy habits of life. The advances in the knowledge of the physiopatology, had taken to sustantial change in the nomenclature and management of ischemic ACS. Within these changes it was substituted the term cerebrovascular accident fo acute stroke, making emphasis in the key rol of a timely management with goals of time similiar to the acute coronary syndrome. It was redefined the time of acute ischemic attack to a one hour. Once stablished the cerebrovascular attack the semiology of symtoms with frecuency will led us make a topographic diagnosis of the in injury that joined to the cerebral TAC will allow us to exclude an hemorragic event and to start the treatment. In the management of these patients its essential the coordination of the differents teams of work, from the early recognition of symtoms on the part of patients andthe family, the rapid activation and response of emergency systems and the gearing of health care institutions. Are pillars of treatment: the abcde of reanimatiion, to avoid the hiperpirexis, the seizures, the hipoglicemy, the hiperglicemy, to achieve the thrombolysis in the first three hours of the begining of symtoms, to use antiplatelets, antithrombotic profilaxis

  5. Amyloid-beta Positron Emission Tomography Imaging Probes : A Critical Review

    NARCIS (Netherlands)

    Kepe, Vladimir; Moghbel, Mateen C.; Langstrom, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung-Cheng; Satyamurthy, Nagichettiar; Doudet, Doris; Mishani, Eyal; Cohen, Robert M.; Hoilund-Carlsen, Poul F.; Alavi, Abass; Barrio, Jorge R.

    2013-01-01

    The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a

  6. Anestesia e paralisia cerebral Anestesia y parálisis cerebral Anesthesia and cerebral palsy

    OpenAIRE

    Március Vinícius M Maranhão

    2005-01-01

    JUSTIFICATIVA E OBJETIVOS: A paralisia cerebral (PC) é uma doença não progressiva decorrente de lesão no sistema nervoso central, levando a um comprometimento motor do paciente. O portador de PC freqüentemente é submetido a procedimentos cirúrgicos devido a doenças usuais e situações particulares decorrentes da paralisia cerebral. Foi objetivo deste artigo revisar aspectos da paralisia cerebral de interesse para o anestesiologista, permitindo um adequado manuseio pré, intra e pós-operatório n...

  7. Diagnostic Assessment of Cerebral Palsy

    OpenAIRE

    J Gordon Millichap

    2004-01-01

    The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society have developed practice parameters for the diagnosis of cerebral palsy (CP).

  8. Learn More About Cerebral Palsy

    Centers for Disease Control (CDC) Podcasts

    2008-03-30

    This podcast describes the causes, preventions, types, and signs and symptoms of cerebral palsy.  Created: 3/30/2008 by National Center on Birth Defects and Developmental Disabilities.   Date Released: 3/21/2008.

  9. Diagnostic Assessment of Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-04-01

    Full Text Available The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society have developed practice parameters for the diagnosis of cerebral palsy (CP.

  10. ANTIAMNESIC POTENTIAL OF SOLASODINE AGAINST β-AMYLOID PROTEIN INDUCED AMNESIA IN MICE

    Directory of Open Access Journals (Sweden)

    Desai Alpesh B

    2011-05-01

    Full Text Available Alzheimer’s disease (AD, the most common form of dementia in the elderly population, is characterized by an insidious onset with memory impairment and an inexorable progression of cognitive decline. Nootropic agents are a heterogeneous groups of drugs developed for use in dementia and other cerebral disorders. Nootropics agents are being primarily used to improve memory, mood and behavior. However, the resulting adverse effects associated with these agents have limited their use. Therefore, it is worthwhile to explore the utility of traditional medicines for the treatment of various cognitive disorders. The present study was undertaken to assess the potential of solasodine on β-amyloid induced amnesia in mice. Elevated plus maze (EPM and Morris water maze (MWM was employed to evaluate learning and memory parameters. Piracetam was used as the standard drug. Solasodine (1, 2 and 4 mg/kg, p.o. was screened for claimed potential in mice. Solasodine improved both short term memory and long term memory when assessed on Elevated pluz maze and Morris Water maze respectively. Hence, solasodine might prove to be a useful memory restorative agent in the treatment of dementia seen in the Alzheimer’s disease.

  11. Gene expression profile of amyloid beta protein-injected mouse model for Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Ling-na KONG; Ping-ping ZUO; Liang MU; Yan-yong LIU; Nan YANG

    2005-01-01

    Aim: To investigate the gene expression profile changes in the cerebral cortex of mice injected icv with amyloid beta-protein (Aβ) fragment 25-35 using cDNA microarray. Methods: Balb/c mice were randomly divided into a control group and Aβ-treated group. The Morris water maze test was performed to detect the effect of Aβ-injection on the learning and memory of mice. Atlas Mouse 1.2 Expression Arrays containing 1176 genes were used to investigate the gene expression pattern of each group. Results: The gene expression profiles showed that 19 genes including TBX1, NF-κB, AP-1/c-Jun, cadherin, integrin, erb-B2, and FGFR1 were up-regulated after 2 weeks oficv administration of Aβ; while 12 genes were downregulated, including NGF, glucose phosphate isomerase 1, AT motif binding factor 1, Na+/K+-ATPase, and Akt. Conclusions: The results provide important leads for pursuing a more complete understanding of the molecular events of Aβ-injection into mice with Alzheimer disease.

  12. Cerebral venous thrombosis: diagnosis dilemma

    OpenAIRE

    2011-01-01

    Cerebral venous thrombosis is increasing common disease in daily practice with sharing clinical nonspecific symptoms. This disorder is potentially lethal but treatable, oftenly it was overlooked in both clinical and radiologic in routine practice. Whenever, clinical suspected, prompt investigation by noninvasive imaging Magnetic resonance (MR) or advanced modilities such as cerebral venous thrombosis (CVT), MRV (MR Venography) will helpful in prompt diagnosis and treatment. These imaging moda...

  13. Cerebral involvement in Whipple's disease

    International Nuclear Information System (INIS)

    Whipple's disease is a rare protean disease. Cerebral involvement occurs in ten percent of the cases. CCT findings in two patients with cerebral symptoms are presented. There was an unspecific atrophy in one patient. Patient two had hydrocephalus occlusus and a temporal lesion enhanced by contrast agent. A specific diagnosis on the sole basis of the CCT without additional clinical data does not seem possible. (orig.)

  14. Sirt1 in cerebral ischemia

    OpenAIRE

    Koronowski, Kevin B.; Perez-Pinzon, Miguel A.

    2015-01-01

    Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacylases has been shown to govern seve...

  15. NEYROPSYCHOLOGICAL CONSECUENCES OF CEREBRAL PALSY

    OpenAIRE

    ANA MARÍA NAVARRO MELENDRO; ANDREA PATRICIA RESTREPO IBIZA

    2005-01-01

    Cerebral Palsy is defined as a movement alteration result of a non progressive damage witch is permanent in anencephalon that has not acquired its final maturation. Patients that suffer cerebral palsy present learning disabilities,that varies between being completely normal to severe as a consequence of memory, gnosis, praxis, perceptive andlanguage impairments. Nevertheless the consequences of this disease are not always predictable. This paper pretendsto make a description of the cognitive ...

  16. Cerebral candidiasis. Computed tomography appearance

    International Nuclear Information System (INIS)

    A three year old child who had been suffering from oral candidiasis since the age of 1 year presented with osteitis of the clavicle, 2 cerebral frontal abscesses and an occipital abscess which extended across the calvaria and was associated with osteolysis. Histological and microbiological studies following surgery confirmed the diagnosis of candidiasis in this girl who was found to have IgA immunodefinciency. The authors report the computed tomographic appearance of the cerebral lesions and review the literature. (orig.)

  17. Cerebral candidiasis. Computed tomography appearance

    Energy Technology Data Exchange (ETDEWEB)

    Chaabane, M.; Ladeb, M.F.; Bouhaouala, M.H.; Ben Hammouda, M.; Ataalah, R.; Gannouni, A.; Krifa, H.

    1989-07-01

    A three year old child who had been suffering from oral candidiasis since the age of 1 year presented with osteitis of the clavicle, 2 cerebral frontal abscesses and an occipital abscess which extended across the calvaria and was associated with osteolysis. Histological and microbiological studies following surgery confirmed the diagnosis of candidiasis in this girl who was found to have IgA immunodefinciency. The authors report the computed tomographic appearance of the cerebral lesions and review the literature. (orig.).

  18. Cerebral palsy: classification and etiology

    OpenAIRE

    Bialik, Gad M.; Givon, Uri

    2004-01-01

    Cerebral palsy (CP), a common condition of abnormalities in the brain, arises early in life. Since the term was first introduced in 1843, many authors have tried to define and classify CP. The most recent definition was released by the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) in 2005. This article summarizes the latest and familiar classifications of, and etiologies associated with CP.

  19. Cerebral hyperperfusion following carotid endarterectomy

    DEFF Research Database (Denmark)

    Schroeder, T; Sillesen, H; Sørensen, O;

    1987-01-01

    Serial measurements of cerebral blood flow (CBF) were performed in 56 patients before and one to four times after uncomplicated carotid endarterectomy. The findings were related to the ratio between internal carotid artery (ICA) and common carotid artery (CCA) mean pressures. Within the 1st...... ratio suggests a temporary impairment of autoregulation. Special care should be taken to avoid postoperative hypertension in such patients, who typically have preoperative hypoperfusion, to avoid the occurrence of cerebral edema or hemorrhage....

  20. CEREBRAL PALSY : ANTENATAL RISK FACTORS

    OpenAIRE

    Srinivasa Rao; Vidyullatha; Subbalakshmi

    2015-01-01

    INTRODUCTION: Cerebral palsy (CP) is a group of permanent movement disorders that appear in early childhood. Cerebral palsy is caused by abnormal development or damage to the parts of the brain that control movement, balance, and posture. Most often the problems occur during pregnancy; however, they may also occur during childbirth, or shortly after birth. Often the cause is unknown. AIM: To study the different antenatal maternal risk factors associated with cere...

  1. Bone age in cerebral palsy

    OpenAIRE

    Miranda, Eduardo Régis de Alencar Bona; Palmieri, Maurício D'arc; de Assumpção, Rodrigo Montezuma César; Yamada, Helder Henzo; Rancan, Daniela Regina; Fucs, Patrícia Maria de Moraes Barros

    2013-01-01

    Objective To compare the chronological age and bone age among cerebral palsy patients in the outpatient clinic and its correlation with the type of neurological involvement, gender and functional status. Methods 401 patients with spastic cerebral palsy, and ages ranging from three months to 20 years old, submitted to radiological examination for bone age and analyzed by two independent observers according Greulich & Pyle. Results In the topographic distribution, there was a significant delay (p

  2. Atomic-resolution structures of prion AGAAAAGA amyloid fibrils

    CERN Document Server

    Zhang, Jiapu

    2011-01-01

    To the best of the author's knowledge, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113-120) of prion proteins due to the unstable, noncrystalline and insoluble nature of the amyloid fibril, although many experimental studies have shown that this region has amyloid fibril forming properties and plays an important role in prion diseases. In view of this, the present study is devoted to address this problem from computational approaches such as local optimization steepest descent, conjugate gradient, discrete gradient and Newton methods, global optimization simulated annealing and genetic algorithms, canonical dual optimization theory, and structural bioinformatics. The optimal atomic-resolution structures of prion AGAAAAGA amyloid fibils reported in this Chapter have a value to the scientific community in its drive to find treatments for prion diseases or at least be useful for the goals of medicinal chemistry.

  3. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  4. Destroying activity of magnetoferritin on lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Kopcansky, Peter; Siposova, Katarina [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Melnikova, Lucia, E-mail: melnikova@saske.sk [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Bednarikova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Institute of Chemical Sciences, Faculty of Sciences, Safarik University, Kosice (Slovakia); Timko, Milan; Mitroova, Zuzana; Antosova, Andrea [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Garamus, Vasil M. [Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, Max-Planck-Street 1, 21502 Geesthacht (Germany); Petrenko, Viktor I. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Kyiv Taras Shevchenko National University, Volodymyrska Street 64, Kyiv 01033 (Ukraine); Avdeev, Mikhail V. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Gazova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Department of Medical and Clinical Biochemistry and LABMED, Tr. SNP 1, 040 11 Kosice (Slovakia)

    2015-03-01

    Presence of protein amyloid aggregates (oligomers, protofilaments, fibrils) is associated with many diseases as diabetes mellitus or Alzheimer's disease. The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size. - Highlights: • The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. • Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size.

  5. Supramolecular amplification of amyloid self-assembly by iodination.

    Science.gov (United States)

    Bertolani, Arianna; Pirrie, Lisa; Stefan, Loic; Houbenov, Nikolay; Haataja, Johannes S; Catalano, Luca; Terraneo, Giancarlo; Giancane, Gabriele; Valli, Ludovico; Milani, Roberto; Ikkala, Olli; Resnati, Giuseppe; Metrangolo, Pierangelo

    2015-01-01

    Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents. PMID:26123690

  6. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

    Science.gov (United States)

    Demetrius, Lloyd A; Magistretti, Pierre J; Pellerin, Luc

    2014-01-01

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model. PMID:25642192

  7. The biochemical aftermath of anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Nicoll James AR

    2010-10-01

    Full Text Available Abstract Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP transgenic mice and Alzheimer's Disease (AD patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792 and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques

  8. BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis.

    Directory of Open Access Journals (Sweden)

    Allen W Bryan

    2009-03-01

    Full Text Available Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s, there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid

  9. Monitoring of cerebral haemodynamics in newborn infants

    DEFF Research Database (Denmark)

    Liem, K Djien; Greisen, Gorm

    2010-01-01

    The most important cerebrovascular injuries in newborn infants, particularly in preterm infants, are cerebral haemorrhage and ischemic injury. The typical cerebral vascular anatomy and the disturbance of cerebral haemodynamics play important roles in the pathophysiology. The term 'cerebral...... haemodynamics' includes cerebral blood flow (CBF), cerebral blood flow velocity, and cerebral blood volume (CBV). Therapy aimed at changing vascular anatomy is not available. Therefore, prevention of disturbances in CBF and CBV is pivotal. However, continuous monitoring of CBF and CBV is still unavailable for....... Using it even without knowing the exact level of CBF and CBV, it is possible to aim to keep CBF and CBV stable. Futureresearch should focus on development of monitoring tools, gaining more insight in neonatal cerebral autoregulation, and demonstrating clinical benefits of a 'cerebral perfusion...

  10. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...... rocket immunoelectrophoresis and electron microscopy. Thus, electron micrographs of purified SAP showed a predominance of decamers. However, the decamer form of SAP reversed to single pentamers when purified SAP was incorporated into SAP-depleted serum....

  11. Pathogenesis of cerebral malaria

    International Nuclear Information System (INIS)

    Full text: Cerebral Malaria (CM) is the most severe complication of malaria and a major cause of death. The mechanisms underlying human CM pathogenesis might be due to mechanical cause, as demonstrated by cytoadherence of parasitised erythrocytes pRB, or to excessive cytokine production by the host in response to Plasmodium falciparum, or a combination of the two together with neuronal injury by malaria toxins. Antibody response, genetic traits and other factors have been proposed to explain why only some episodes have life-threatening complications. The microvascular endothelial cell is a major target of inflammatory cytokines overproduced in infectious diseases. Fatal CM is associated with widespread induction of endothelial activation markers, with significant higher levels of ICAM, VCAM and E-selectin expression on vessels in the brain. 199 patients were admitted at the hospital and were classified with malaria-based neurological disfunctions, such as acute psychosis, ataxia, hallucinations, fever and convulsions, prostration or coma. On a flow chart, 65 of those patients with the most acute syndromes mentioned above, were found to have negative BSN (blood slide), compared to 124 where the BSN showed to be positive. Identically to the 10 other patients from the severe form group, also presented positive BSN. The condition of some of these two subgroup patients (15), will later evolve into a more severe form with acute neurological disfunctions attributed to the cerebral malaria. The interesting aspect in regards to the 65 patients considered as having CM, upon severe manifestations of the disease, show no or little peripheral parasitemia. This fact confirms our experimental conclusion that, in the process of pRB adhesion to the microvessels of the brain, they are sequestered by monocytes and platelets, leading to vessel rupture. This fact could be an explanation of the lower % of circulating pRB and low peripheral parasitemia. There is a relationship between

  12. Effects of Hyperglycemia and Effects of Ketosis on Cerebral Perfusion, Cerebral Water Distribution, and Cerebral Metabolism

    OpenAIRE

    Glaser, Nicole; Ngo, Catherine; Anderson, Steven; Yuen, Natalie; Trifu, Alexandra; O’Donnell, Martha

    2012-01-01

    Diabetic ketoacidosis (DKA) may cause brain injuries in children. The mechanisms responsible are difficult to elucidate because DKA involves multiple metabolic derangements. We aimed to determine the independent effects of hyperglycemia and ketosis on cerebral metabolism, blood flow, and water distribution. We used magnetic resonance spectroscopy to measure ratios of cerebral metabolites (ATP to inorganic phosphate [Pi], phosphocreatine [PCr] to Pi, N-acetyl aspartate [NAA] to creatine [Cr], ...

  13. Cerebral edema associated with acute hepatic failure.

    Directory of Open Access Journals (Sweden)

    Fujiwara,Masachika

    1985-02-01

    Full Text Available The clinicopathological findings of cerebral edema were investigated in patients with acute hepatic failure autopsied at Okayama University Hospital between 1970 and 1980 retrospectively. Nine (64% of 14 hepatic failure cases were found to have cerebral edema during a post-mortem examination of the brain. Clinical features of the patients with cerebral edema were not significantly different from those of the patients without cerebral edema. However, general convulsions were observed more frequently in patients later found to have cerebral edema. Moreover, the length of time from deep coma to death was much shorter in the brain edema cases with cerebral herniation than without herniation.

  14. Asymptomatic ischemic cerebral lesions

    International Nuclear Information System (INIS)

    For the purpose of studying the incidence, pathomorphology and etiology of asymptomatic ischemic cerebral lesions, we carried out a brain MRI study on 65 patients with diabetes mellitus accompanied with hypertension who are thought to belong to a high risk group of ischemic cerebrovascular diseases. Excluding the abnormality of tendon reflex due to diabetic neuropathy, sixty percent of the total patients had some mild neurological signs and symptoms, most of them was discrepancy in tendon reflex. The percentage of the patients in whom MRI disclosed some abnormalities was as high as 70%, they were lacunar stroke, multiple lacunar state, cortical infarct, and patchy high signal lesions visible only in the T2 weighted image. Lacunes or these patchy high signal lesions (considered to be the dilatation of the perivascular space or true lacunes) tended to be found along the border zone or the terminal zone. These results indicate that asymptomatic patients in whom MRI discloses the abnormalities should be considered as candidates for the future onset of multi-infarct. (author)

  15. Cerebral trypanosomiasis and AIDS

    Directory of Open Access Journals (Sweden)

    Antunes Apio Claudio Martins

    2002-01-01

    Full Text Available A 36 year-old black female, complaining of headache of one month's duration presented with nausea, vomiting, somnolence, short memory problems, loss of weight, and no fever history. Smoker, intravenous drugs abuser, promiscuous lifestyle. Physical examination: left homonimous hemianopsia, left hemiparesis, no papilledema, diffuse hyperreflexia, slowness of movements. Brain CT scan: tumor-like lesion in the splenium of the corpus calosum, measuring 3.5 x 1.4 cm, with heterogeneous enhancing pattern, sugesting a primary CNS tumor. Due to the possibility of CNS infection, a lumbar puncture disclosed an opening pressure of 380 mmH(20; 11 white cells (lymphocytes; glucose 18 mg/dl (serum glucose 73 mg/dl; proteins 139 mg/dl; presence of Trypanosoma parasites. Serum Elisa-HIV tests turned out to be positive. Treatment with benznidazole dramatically improved clinical and radiographic picture, but the patient died 6 weeks later because of respiratory failure. T. cruzi infection of the CNS is a rare disease, but we have an increasing number of cases in HIV immunecompromised patients. Diagnosis by direct observation of CSF is uncommon, and most of the cases are diagnosed by pathological examination. It is a highly lethal disease, even when properly diagnosed and treated. This article intends to include cerebral trypanosomiasis in the differential diagnosis of intracranial space-occupying lesions, especially in immunecompromised patients from endemic regions.

  16. [Plasma osmolarity and cerebral volume].

    Science.gov (United States)

    Boulard, G

    2001-02-01

    Under normal physiological conditions, the osmolarity of extracellular fluids (ECFs) and natremia are controlled by two regulatory mechanisms modulating the water balance and sodium outflow from information collected by the osmoreceptors and baroreceptors, respectively. As well, under normal physiological conditions, water and electrolytes of brain ECFs are secreted by the endothelial cells of brain capillaries. Furthermore, isotonicity is present on both sides of the blood-brain barrier. In the event of systemic osmolarity disorders, water transport subject to osmosis laws occurs at the level of the blood-brain barrier. In the case of plasmatic hyperosmolarity cerebral dehydration is observed, while cerebral edema occurs in the contrary case. However, plasmatic osmolarity disorders have less effect on the cerebral volume when their introduction is slow. Experimentation in acute conditions shows that measured variations of the cerebral water content are lower than calculated variations, thus suggesting the existence of an adaptive mechanism, that is, the cerebral osmoregulation which limits the variation of the volume of brain cells by modulating their osmoactive molecule content. These osmoactive molecules are, on the one hand, the electrolytes, which are early and rapidly mobilized, and, on the other hand, the organic osmoles (amino acids, etc.), whose secretion is slower and delayed. This phenomenon should be taken into account in the treatment of osmolarity disorders. Thus, the related-risk of treatment for natremia disorders is therapeutic reversal of the osmotic gradient at the level of the blood-brain barrier. This reversal, which corresponds to a second osmotic stress, requires the implementation of a new procedure of cerebral osmoregulation in the opposite direction of the preceding one. As successive osmotic stresses decrease the effectiveness of brain osmoregulation, the risk for cerebral dehydration and pontine myelinolysis increases when the treatment

  17. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition.

    Directory of Open Access Journals (Sweden)

    Sandra Arvidsson

    Full Text Available Transthyretin V30M (ATTR V30M amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007 and posterior wall thicknesses (p = 0.010, lower median LV mass indexed to height (p = 0.008, and higher septal strain (p = 0.037, as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

  18. Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid.

    Science.gov (United States)

    Sjölander, Daniel; Röcken, Christoph; Westermark, Per; Westermark, Gunilla T; Nilsson, K Peter R; Hammarström, Per

    2016-06-01

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h-FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of

  19. Difference in aggregation between functional and toxic amyloids studied by atomistic simulations

    Science.gov (United States)

    Carballo Pacheco, Martin; Ismail, Ahmed E.; Strodel, Birgit

    Amyloids are highly structured protein aggregates, normally associated with neurodegenerative diseases such as Alzheimer's disease. In recent years, a number of nontoxic amyloids with physiologically normal functions, called functional amyloids, have been found. It is known that soluble small oligomers are more toxic than large fibrils. Thus, we study with atomistic explicit-solvent molecular dynamics simulations the oligomer formation of the amyloid- β peptide Aβ25 - 35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Our simulations show that monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. In addition, we observe faster aggregation by functional amyloids than toxic amyloids, which could explain their lack of toxicity.

  20. Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby; Sørensen, Jesper; Schiøtt, Birgit

    2013-01-01

    amyloid fibrils and the disease pathology. Alzheimer’s disease is very difficult to diagnose, and much research is being performed to develop noninvasive diagnostic methods, such as imaging with small-molecule agents. The interactions between amyloid fibrils and imaging agents are challenging to examine...... experimentally due to the insoluble nature of amyloid fibrils. This study uses molecular dynamics simulations to investigate the interactions between 13 aromatic amyloid imaging agents, entailing 4 different organic scaffolds, and a model of an amyloid fibril. Clustering analysis combined with free energy...... binding modes for imaging agents is proposed to originate from subtle differences in amino acid composition of the surface grooves on an amyloid fibril, resulting in fine tuning of the binding affinities for a specific amyloid fibril....

  1. Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients.

    Science.gov (United States)

    Freudenthaler, Sophie; Hegenbart, Ute; Schönland, Stefan; Behrens, Hans-Michael; Krüger, Sandra; Röcken, Christoph

    2016-05-01

    In this retrospective observational study, we investigated the histopathological and demographic characteristics of amyloid in gastrointestinal biopsies. From the Amyloid Registry Kiel, we retrieved all cases with amyloid in biopsies of the stomach, duodenum, small intestine, large intestine, and rectum submitted for tertiary referral between January 2003 and April 2013. Amyloid was identified by Congo red staining in combination with polarization microscopy and classified by immunohistochemistry. The TTR-genotype was assessed in 56 patients. Amyloid type was correlated with demographic patient characteristics. Six hundred sixty-three biopsies from 542 patients were retrieved. Amyloid was found in each biopsy as vascular and/or interstitial amyloid deposits. Biopsies were obtained from the colon [254 biopsies (38.3 %)], stomach, [153 (23.1 %)], rectum [112 (16.9 %)], duodenum [105 (15.8 %)], and jejunum/ileum [39 (5.9 %)]. ALλ amyloid was found in 286 (52.8 %), ATTR in 88 (16.2 %), ALκ in 74 (13.7 %), AA in 58 (10.7 %), and ApoAI amyloid in 4 (0.7 %) patients. The remaining 21 cases were ALys amyloid in 4 (0.7 %), AL n.o.s. in 14 (2.6 %), and mixed type amyloidosis in 3 (0.6 %). The amyloid of 11 (2.0 %) cases remained unclassified. The median age of the patients was 68 years. Men [332 (61.7 %)] were significantly more prevalent than women [206 (38.3 %); p < 0.001]. TTR mutations were found in 24 % of the patients with ATTR amyloidosis. The median age, the histoanatomical distribution (proximal to distal; mucosal to submucosal), and the deposition pattern (vascular/interstitial) varied between different amyloid types. Amyloid in gastrointestinal biopsies mainly affects male elderly patients and shows amyloid-type-specific demographic patient characteristics. PMID:26915034

  2. Plasma amyloid beta peptides and oligomers antibodies in Alzheimer's disease

    OpenAIRE

    Zhou, L.; Chu, LW; Kwan, JSC; Ho, JWM; Lam, KSL; Ho, PWL; Chan, KH

    2011-01-01

    INTRODUCTION: Various forms of amyloid beta (Aβ) including Aβ peptides, oligomers, protofibrils and fibrils are thought to be pathogenic in Alzheimer’s disease (AD). The exact pathophysiological role of endogenous Aβ autoantibodies (Ab) in healthy subjects and AD patients are uncertain. Potential protective role ...

  3. Curcumin protects against intracellular amyloid toxicity in rat primary neurons

    NARCIS (Netherlands)

    Ye, Jelina; Zhang, Yan

    2012-01-01

    To investigate whether curcumin is protective against intracellular amyloid beta (A beta) toxicity, different concentrations of curcumin were applied to with intracellular A beta in rat primary hippocampal neurons in culture. We find that at low dosages, curcumin effectively inhibits intracellular A

  4. Beta-amyloid, cholinergní neurony a Alzheimerova choroba

    Czech Academy of Sciences Publication Activity Database

    Kašparová, Jana; Doležal, Vladimír

    2002-01-01

    Roč. 51, č. 2 (2002), s. 82-94. ISSN 0009-0557 R&D Projects: GA MZd NF5183; GA ČR GA305/01/0283 Institutional research plan: CEZ:AV0Z5011922 Keywords : Alzheimer 's disease * beta-amyloid * cholinergic neurons Subject RIV: FR - Pharmacology ; Medidal Chemistry

  5. Amyloid-β positron emission tomography imaging probes

    DEFF Research Database (Denmark)

    Kepe, Vladimir; Moghbel, Mateen C; Långström, Bengt;

    2013-01-01

    number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their...

  6. Decoding vibrational states of Concanavalin A amyloid fibrils.

    Science.gov (United States)

    Piccirilli, Federica; Schirò, Giorgio; Vetri, Valeria; Lupi, Stefano; Perucchi, Andrea; Militello, Valeria

    2015-04-01

    Amyloid and amyloid-like fibrils are a general class of protein aggregates and represent a central topic in life sciences for their involvement in several neurodegenerative disorders and their unique mechanical and supramolecular morphological properties. Both their biological role and their physical properties, including their high mechanical stability and thermodynamic inertia, are related to the structural arrangement of proteins in the aggregates at molecular level. Significant variations may exist in the supramolecular organization of the commonly termed cross-β structure that constitutes the amyloid core. In this context, a fine knowledge of the structural details in fibrils may give significant information on the assembly process and on possible ways of tuning or inhibiting it. Here we propose a simple method based on the combined use of Fourier transform infrared spectroscopy and Fourier transform Raman spectroscopy to accurately reveal structural details in the fibrillar aggregates, side-chain exposure and intermolecular interactions. Interestingly, coupled analysis of mid-infrared spectra reveals antiparallel β-sheet orientation in ConA fibrils. We also report the comparison between THz absorption spectra of Concanavalin A in its native and fibrillar state at different hydration levels, allowing obtaining corroboration of peaks assignation in this range and information on the effect of amyloid supramolecular arrangement on the network dynamics of hydration water. PMID:25776525

  7. Stop-and-go kinetics in amyloid fibrillation

    DEFF Research Database (Denmark)

    Ferkinghoff-Borg, Jesper; Fonslet, Jesper; Andersen, Christian Beyschau; Krishna, Sandeep; Pigolotti, Simone; Hisashi, Yagi; Yuji, Goto; Otzen, Daniel; Jensen, Mogens Høgh

    2010-01-01

    Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermi...

  8. Amyloid/Melanin distinctive mark in invertebrate immunity

    Directory of Open Access Journals (Sweden)

    A Grimaldi

    2012-09-01

    Full Text Available Protostomes and Deuterostomes show the same nexus between melanin production, and amyloid fibril production, i.e., the presence of melanin is indissolubly linked to amyloid scaffold that, in turn, is conditioned by the redox status/cytoplasmic pH modification, pro-protein cleavage presence, adrenocorticotropin hormone (ACTH, melanocyte-stimulating hormone (α-MSH, and neutral endopeptidase (NEP overexpressions. These events represent the crucial component of immune response in invertebrates, while in vertebrates these series of occurrences could be interpreted as a modest and very restricted innate immune response. On the whole, it emerges that the mechanisms involving amyloid fibrils/pigment synthesis in phylogenetically distant metazoan (viz, cnidaria, molluscs, annelids, insects, ascidians and vertebrates are evolutionary conserved. Furthermore, our data show the relationship between immune and neuroendocrine systems in amyloid/melanin synthesis. Indeed the process is closely associated to ACTH-α-MSH production, and their role in stress responses leading to pigment production reflects and confirms again their ancient phylogeny.

  9. Mechanisms of beta-amyloid neurotoxicity : Perspectives of pharmacotherapy

    NARCIS (Netherlands)

    Harkany, T; Abraham, [No Value; Konya, C; Nyakas, C; Zarandi, M; Penke, B; Luiten, PGM

    2000-01-01

    One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta -amyloid peptides (A beta) in neuritic plaques, Experimental data indicate that different molecular forms of A beta affect a wide array of neuronal and glial functions and ther

  10. Functional amyloids as inhibitors of plasmid DNA replication.

    Science.gov (United States)

    Molina-García, Laura; Gasset-Rosa, Fátima; Moreno-Del Álamo, María; Fernández-Tresguerres, M Elena; Moreno-Díaz de la Espina, Susana; Lurz, Rudi; Giraldo, Rafael

    2016-01-01

    DNA replication is tightly regulated to constrain the genetic material within strict spatiotemporal boundaries and copy numbers. Bacterial plasmids are autonomously replicating DNA molecules of much clinical, environmental and biotechnological interest. A mechanism used by plasmids to prevent over-replication is 'handcuffing', i.e. inactivating the replication origins in two DNA molecules by holding them together through a bridge built by a plasmid-encoded initiator protein (Rep). Besides being involved in handcuffing, the WH1 domain in the RepA protein assembles as amyloid fibres upon binding to DNA in vitro. The amyloid state in proteins is linked to specific human diseases, but determines selectable and epigenetically transmissible phenotypes in microorganisms. Here we have explored the connection between handcuffing and amyloidogenesis of full-length RepA. Using a monoclonal antibody specific for an amyloidogenic conformation of RepA-WH1, we have found that the handcuffed RepA assemblies, either reconstructed in vitro or in plasmids clustering at the bacterial nucleoid, are amyloidogenic. The replication-inhibitory RepA handcuff assembly is, to our knowledge, the first protein amyloid directly dealing with DNA. Built on an amyloid scaffold, bacterial plasmid handcuffs can bring a novel molecular solution to the universal problem of keeping control on DNA replication initiation. PMID:27147472

  11. What You Should Know about Cerebral Aneurysms

    Science.gov (United States)

    ... T. Quiz 5 Things to Know About Stroke What You Should Know About Cerebral Aneurysms Updated:Jun ... Damage Treatments Click image to view an animation What is a cerebral aneurysm? An aneurysm is a ...

  12. Cerebral abscess in the recently born

    International Nuclear Information System (INIS)

    An unusual case of cerebral abscess in a newborn is reported. Emphasis is made in the paramount importance of its early diagnosis; mainly with imaging modalities like cerebral ultrasound and CT, in order to establisher the most appropriate therapy

  13. Middle cerebral artery blood velocity during rowing

    DEFF Research Database (Denmark)

    Secher, Niels Henry; Pott, F; Knudsen, L.;

    1997-01-01

    original,arterial blood pressure,central venous pressure,cerebral blood flow, exercise, transcranial Doppler......original,arterial blood pressure,central venous pressure,cerebral blood flow, exercise, transcranial Doppler...

  14. Hereditary and Sporadic Forms of Aβ-Cerebrovascular Amyloidosis and Relevant Transgenic Mouse Models

    Directory of Open Access Journals (Sweden)

    Samir Kumar-Singh

    2009-04-01

    Full Text Available Cerebral amyloid angiopathy (CAA refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer’s disease (AD and Down’s syndrome. Moreover, Aβ-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Aβ domain of the amyloid precursor protein (APP such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Aβ variants or an unaltered Aβ42/Aβ40 ratio favor vascular Aβ deposition over parenchymal plaques, but higher than critical levels of Aβ40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels.

  15. Polymorphic structures of Alzheimer's β-amyloid globulomers.

    Directory of Open Access Journals (Sweden)

    Xiang Yu

    Full Text Available BACKGROUND: Misfolding and self-assembly of Amyloid-β (Aβ peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled Aβ globulomers provide useful

  16. Primary cerebral lymphoma

    International Nuclear Information System (INIS)

    The aim of this study is to compare the survival of the patients treated with radiotherapy alone vs. patients treated with a combined schedule of radio-chemotherapy. Our results will be compared with currently published data and main prognostic factors will be briefly discussed. Patients and methods: Between 1974 and 1990, 27 cases of primary cerebral lymphoma were diagnosed at our institution. All patients had biopsy-proven disease, the pathology of which was reviewed for this study. Results: The overall median survival time was 24 months and one-, two- and three-year overall survival was 59, 46 and 29% respectively. The median radiation dose was 46 Gy, ranging from 19.5 to 60 Gy. The median dose per fraction was 2 Gy (ranging from 1.61 to 3 Gy). The median elapsed treatment time was 32 days (ranging from three to 45 days). We were not able to demonstrate any statistically significant difference between patients who received radiotherapy alone (n = 14, median survival time = 24 months) and those who received a combination of chemotherapy and radiotherapy (n = 11, median survival time = 30 months), (p = 0.4). Prognostic factors of survival were tested using a univariate analysis (Wilcoxon test). Parameters such as mass appearance (unilobular, p = 0.048), performance status at the time of the diagnosis (0 to 1, p = 0.014), and CT imaging (hypodense, p = 0.043) influenced positively survival. Centroblastic histology (Kiel) was found associated with a negative prognosis (p = 0.043). (orig./MG)

  17. Amyloid Precursor Protein Processing in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Adwait BHADBHADE

    2012-03-01

    Full Text Available How to Cite this Article: Bhadbhade A, Cheng DW. Amyloid Precursor Protein Processing in Alzheimer’s Disease. Iranian Journal of Child Neurology2012;6(1:1-5.Alzheimer’s disease (AD is a progressive neurodegenerative disorder and a leading cause of dementia. The AD is characterized by presence of intraneuronal tangles and extracellular plaques in the brain. The plaques are composed of dense and mostly insoluble deposits of amyloid beta peptide (Aβ, formed by sequential cleavage of the Amyloid Precursor Protein (APP, by two pathways amyloidogenic and non-amyloidogenic. Tangles are composed of paired helical fragments, which aggregate to form, microtubular protein tau. Although Aβ plaques are established to be the cause of the disease, there exist genetic factors and other pathological identifications in addition to these which are an integral part of the disease. This article gives an overview into the mechanism of APP action, genetic factors and other pathological identifications contributing to Alzheimer’s disease formation.References Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health 1998;88(9:1337. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population. Arch Neurol 2003;60(8:1119-22. Möller HJ, Graeber M. The case described by Alois Alzheimer in 1911. European Archives of Psychiatry and Clinical Neuroscience 1998:248(3:111-122. Selkoe D J. (2002. Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease. J Clinic Investigat 2002;110(10: 1375-82. Wolfe MS. Tau mutations in neurodegenerative diseases. J Biolog Chem 2009;284(10:6021. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiological reviews 2001;81(2:741. Selkoe DJ. The cell biology of [beta]-amyloid precursor protein and presenilin in Alzheimer

  18. Case 232: Amyloid β-related Angiitis.

    Science.gov (United States)

    Moosavi, Bardia; Torres, Carlos; Jansen, Gerard

    2016-08-01

    History A 78-year-old woman presented to a community hospital after an unwitnessed fall at her nursing home. Initial head computed tomography (CT) performed in the emergency department showed vasogenic edema in the right temporal parietal region, which prompted her transfer to our institution for additional work-up. Further history taking revealed recurrent transient motor and sensory transient ischemic attack-like symptoms over the preceding weeks. She denied having a fever or night sweats. There was no history of infection, bleeding, immunodeficiency, intravenous drug use, alcohol or tobacco abuse, malignancy, or genetic disorders. Her medical history included memory impairment and a left posterior cerebral artery territory infarction. She was not known to have any systemic inflammatory disorder. Physical examination findings at presentation were noncontributory. She was not taking any anticoagulants or immunosuppressive medication. Pertinent hematologic laboratory investigations revealed a white blood cell count of 6.7 × 10(9), a C-reactive protein level of 29 mg/L (276.2 nmol/L) (normal value, <10 mg/L [95.2 nmol/L]), and an erythrocyte sedimentation rate of 35 mm per hour (normal value, 0-10 mm per hour). Shortly after this patient was admitted to our institution, she had a generalized tonic-clonic seizure. Magnetic resonance (MR) imaging of the brain was performed the next day. PMID:27429145

  19. Cerebral edema associated with acute hepatic failure.

    OpenAIRE

    Fujiwara, Masachika; Watanabe,Akiharu; Yamauchi,Yasuhiko; Hashimoto, Makoto; Nakatsukasa, Harushige; Kobayashi, Michio; Higashi,Toshihiro; Nagashima,Hideo

    1985-01-01

    The clinicopathological findings of cerebral edema were investigated in patients with acute hepatic failure autopsied at Okayama University Hospital between 1970 and 1980 retrospectively. Nine (64%) of 14 hepatic failure cases were found to have cerebral edema during a post-mortem examination of the brain. Clinical features of the patients with cerebral edema were not significantly different from those of the patients without cerebral edema. However, general convulsions were observed more fre...

  20. Cerebritis: an unusual complication of Klebsiella pneumoniae.

    Science.gov (United States)

    Majumdar, Mainak; Simes, David C; Prabha, Ramesh D

    2009-01-01

    Cerebritis is part of a continuum of brain infection and is difficult to diagnose. Cerebritis caused by Klebsiella in immunocompetent adults without predisposing factors such as neurosurgery or penetrating brain injury has not been reported before. We report a case of Klebsiella cerebritis in an adult patient with a proven extracranial focus of infection. We suggest considering cerebritis as a differential diagnosis for altered level of consciousness in patients of severe sepsis, even if an extracranial source of infection is proven. PMID:19881180

  1. Cerebritis: An unusual complication of Klebsiella pneumoniae

    OpenAIRE

    Majumdar, Mainak; Simes1, David C.; Prabha1, Ramesh D.

    2009-01-01

    Cerebritis is part of a continuum of brain infection and is difficult to diagnose. Cerebritis caused by Klebsiella in immunocompetent adults without predisposing factors such as neurosurgery or penetrating brain injury has not been reported before. We report a case of Klebsiella cerebritis in an adult patient with a proven extracranial focus of infection. We suggest considering cerebritis as a differential diagnosis for altered level of consciousness in patients of severe sepsis, even if an e...

  2. Cerebritis: An unusual complication of Klebsiella pneumoniae

    Science.gov (United States)

    Majumdar, Mainak; Simes1, David C.; Prabha1, Ramesh D.

    2009-01-01

    Cerebritis is part of a continuum of brain infection and is difficult to diagnose. Cerebritis caused by Klebsiella in immunocompetent adults without predisposing factors such as neurosurgery or penetrating brain injury has not been reported before. We report a case of Klebsiella cerebritis in an adult patient with a proven extracranial focus of infection. We suggest considering cerebritis as a differential diagnosis for altered level of consciousness in patients of severe sepsis, even if an extracranial source of infection is proven. PMID:19881180

  3. Amyloid-plaque imaging in diagnosis of dementia

    International Nuclear Information System (INIS)

    The increasing life-expectancy of our society results in a continuously growing number of patients suffering from dementing disorders, particularly Alzheimer's disease (AD). Apart from the deleterious consequences for the patients and their relatives, this has also alarming effects on our social systems. These facts have justified increased scientific efforts regarding the identification of basic pathomechanisms of dementia and the development of new treatment options. Increased production of specific proteins and their pathologic aggregation in the brain appears to be a pathomechanism which occurs early in the course of many different neurodegenerative disorders. Among the most well-known of these protein aggregations are the amyloid-plaques, which arise from the aggregation of the β-amyloid protein. Currently, this amyloid-aggregation pathology is regarded as a key pathology, playing a causal role in the development of AD. Consequently, modern therapy approaches are directed towards this target. Limited access to brain tissue has so far restricted the definite diagnosis of AD to post mortem histopathological assessment of brain tissue. For the same reason, a clear association between extent of amyloid deposition pathology and clinical course of AD has not been established so far. However, particularly with regard to new therapeutic options a reliable in vivo diagnosis is required. Modern molecular imaging tracers such as [11C]PIB do now open the possibility to visualize amyloid-depositions in vivo, using Positron Emission Tomography (PET). These techniques allow the characterization of dementing disorders on the basis of the underlying pathology rather than on their symptomatic appearance. This type of ''in vivo histopathology''-approach may offer improved options for early and differential diagnosis, as well as for patient selection for therapy trials and for objective therapy monitoring. (orig.)

  4. Surface Mediated Self-Assembly of Amyloid Peptides

    Science.gov (United States)

    Fakhraai, Zahra

    2015-03-01

    Amyloid fibrils have been considered as causative agents in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes and amyloidosis. Amyloid fibrils form when proteins or peptides misfold into one dimensional crystals of stacked beta-sheets. In solution, amyloid fibrils form through a nucleation and growth mechanism. The rate limiting nucleation step requires a critical concentration much larger than those measured in physiological conditions. As such the exact origins of the seeds or oligomers that result in the formation of fully mature fibrils in the body remain topic intense studies. It has been suggested that surfaces and interfaces can enhance the fibrillization rate. However, studies of the mechanism and kinetics of the surface-mediated fibrillization are technologically challenging due to the small size of the oligomer and protofibril species. Using smart sample preparation technique to dry the samples after various incubation times we are able to study the kinetics of fibril formation both in solution and in the vicinity of various surfaces using high-resolution atomic force microscopy. These studies elucidate the role of surfaces in catalyzing amyloid peptide formation through a nucleation-free process. The nucleation free self-assembly is rapid and requires much smaller concentrations of peptides or proteins. We show that this process resembles diffusion limited aggregation and is governed by the peptide adhesion rate, two -dimensional diffusion of the peptides on the surface, and preferential interactions between the peptides. These studies suggest an alternative pathway for amyloid formation may exist, which could lead to new criteria for disease prevention and alternative therapies. Research was partially supported by a seed grant from the National Institute of Aging of the National Institutes of Health (NIH) under Award Number P30AG010124 (PI: John Trojanowski) and the University of Pennsylvania.

  5. Mechanisms of cerebral radiation syndrome

    International Nuclear Information System (INIS)

    Ability of exogenous succinate to prevent the postradiation violations in neuronal respiration and to correct the manifestations of cerebral radiation syndrome is studied. Rats-males were used for experiments. RUM-17 X-ray therapeutic apparatus was applied for irradiation at the dose rate of 25 Gy/min. It is established that the neurological violations in rats following X-ray exposure at 150 Gy dose depend on cerebral energy deficiency connected with NAD neuronal pool depletion. Efficiency is demonstrated of two approaches to the prevention of cerebral radiation syndrome providing: a) retroinhibition of adenosine diphosphoribosyltransferase, b) administration of NAD - independently oxidated bioenergetic substrate. It is marked that the application of sodium succinate may be of special interest in the cases when the dose for forthcoming irradiation is unknown

  6. Cerebral venous thrombosis in childhood

    Energy Technology Data Exchange (ETDEWEB)

    Huisman, T.A.G.M.; Martin, E.; Willi, U.V. [Dept. of Diagnostic Imaging and Radiology, University Children' s Hospital Zurich (Switzerland); Holzmann, D. [Dept. of Otorhinolaryngology, University Children' s Hospital Zurich, Zurich (Switzerland)

    2001-09-01

    This was a retrospective study to determine different etiologies of cerebral venous thrombosis (CVT) in childhood and to correlate extent and location of thrombosis with the etiology and the age of the child as well as the final outcome. In addition, the radiologic approach is discussed. This was a retrospective analysis of 19 children with CVT. The children were examined by contrast-enhanced dynamic CT. Radiologic findings were correlated with the etiology of CVT. Cerebral venous thrombosis is not as infrequent in children as has been thought. Cerebral venous thrombosis in children can occur due to trauma (n=9), infections (n=7), or coagulation disorders (n=3). Extent and location of thrombosis, as well as complications, final outcome, and therapy, depend on the etiology. Computed tomography remains a valuable primary imaging modality in the diagnosis of CVT in the acutely injured or diseased child. (orig.)

  7. Cerebral venous thrombosis in childhood

    International Nuclear Information System (INIS)

    This was a retrospective study to determine different etiologies of cerebral venous thrombosis (CVT) in childhood and to correlate extent and location of thrombosis with the etiology and the age of the child as well as the final outcome. In addition, the radiologic approach is discussed. This was a retrospective analysis of 19 children with CVT. The children were examined by contrast-enhanced dynamic CT. Radiologic findings were correlated with the etiology of CVT. Cerebral venous thrombosis is not as infrequent in children as has been thought. Cerebral venous thrombosis in children can occur due to trauma (n=9), infections (n=7), or coagulation disorders (n=3). Extent and location of thrombosis, as well as complications, final outcome, and therapy, depend on the etiology. Computed tomography remains a valuable primary imaging modality in the diagnosis of CVT in the acutely injured or diseased child. (orig.)

  8. Calcium-dependent and -independent binding of the pentraxin serum amyloid P component to glycosaminoglycans and amyloid proteins

    DEFF Research Database (Denmark)

    Danielsen, B; Sørensen, I J; Nybo, Mads; Nielsen, E H; Kaplan, B; Svehag, S E

    1997-01-01

    beta2M) by ELISA. An increase in the dose-dependent binding of SAP to heparan sulfate, AA-protein and beta2M was observed as the pH decreased from 8.0 to 5.0. Furthermore, a lower, but significant Ca2(+)-independent binding of SAP to heparan sulfate, dermatan sulfate, AA protein and the amyloid...

  9. Early identification of amyloid heart disease by technetium-99m-pyrophosphate scintigraphy: a study with familial amyloid polyneuropathy

    International Nuclear Information System (INIS)

    To determine whether technetium-99m-pyrophosphate (Tc-99m-PYP) scanning or two-dimensional echocardiography can detect amyloid heart disease in an earlier stage of familial amyloid polyneuropathy, 15 patients were examined. Although 10 of the 15 patients had no clinical evidence of congestive heart failure, as well as normal ventricular wall thickness and normal values for left ventricular systolic function, five (50%) of them showed mild or moderate myocardial uptake. On the other hand, none had characteristic highly refractile myocardial echoes on the two-dimensional echocardiographic images (p less than 0.01), and values for diastolic function were reduced in four of the five and normal in the remaining one. In 85 control subjects, diffuse positive pyrophosphate scans of the heart were found in four (5%) of them (three with dilated cardiomyopathy and one with sarcoidosis), and highly refractile granular sparkling echoes were observed in nine (11%) (five with hypertrophic cardiomyopathy, three with aortic stenosis, and one with hypereosinophilic syndrome). We conclude that Tc-99m-PYP scanning is a more sensitive and specific method and may have the potential ability to detect amyloid heart disease in the earlier stage of familial amyloid polyneuropathy than two-dimensional echocardiography

  10. Early identification of amyloid heart disease by technetium-99m-pyrophosphate scintigraphy: a study with familial amyloid polyneuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Hongo, M.; Hirayama, J.; Fujii, T.; Yamada, H.; Okubo, S.; Kusama, S.; Ikeda, S.

    1987-03-01

    To determine whether technetium-99m-pyrophosphate (Tc-99m-PYP) scanning or two-dimensional echocardiography can detect amyloid heart disease in an earlier stage of familial amyloid polyneuropathy, 15 patients were examined. Although 10 of the 15 patients had no clinical evidence of congestive heart failure, as well as normal ventricular wall thickness and normal values for left ventricular systolic function, five (50%) of them showed mild or moderate myocardial uptake. On the other hand, none had characteristic highly refractile myocardial echoes on the two-dimensional echocardiographic images (p less than 0.01), and values for diastolic function were reduced in four of the five and normal in the remaining one. In 85 control subjects, diffuse positive pyrophosphate scans of the heart were found in four (5%) of them (three with dilated cardiomyopathy and one with sarcoidosis), and highly refractile granular sparkling echoes were observed in nine (11%) (five with hypertrophic cardiomyopathy, three with aortic stenosis, and one with hypereosinophilic syndrome). We conclude that Tc-99m-PYP scanning is a more sensitive and specific method and may have the potential ability to detect amyloid heart disease in the earlier stage of familial amyloid polyneuropathy than two-dimensional echocardiography.

  11. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.

    Science.gov (United States)

    Castellani, Rudy J; Lee, Hyoung-gon; Siedlak, Sandra L; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. PMID:19584435

  12. Neuroevolutional Approach to Cerebral Palsy and Speech.

    Science.gov (United States)

    Mysak, Edward D.

    Intended for cerebral palsy specialists, the book emphasizes the contribution that a neuroevolutional approach to therapy can make to habilitation goals of the child with cerebral palsy and applies the basic principles of the Bobath approach to therapy. The first section discusses cerebral palsy as a reflection of disturbed neuro-ontogenisis and…

  13. Cerebral toksoplasmose primaert diagnosticeret som tumor

    DEFF Research Database (Denmark)

    Cortsen, M E; Skøt, J; Skriver, E B

    1992-01-01

    Three cases of cerebral toxoplasmosis as the presenting manifestation of AIDS are reported. The initial diagnoses were brain tumors because of the cerebral mass lesions which resembled glioblastoma. In the light of the increasing occurrence of AIDS, attention is drawn to cerebral toxoplasmosis...

  14. Cerebral vasculitis associated with cocaine abuse

    International Nuclear Information System (INIS)

    A case of cerebral vasculitis in a previously healthy 22-year-old man with a history of cocaine abuse is described. Cerebral angiograms showed evidence of vasculitis. A search for possible causes other than cocaine produced no results. The authors include cocaine with methamphetamines, heroin, and ephedrine as illicit drugs that can cause cerebral vasculitis

  15. Lifetime costs of cerebral palsy

    DEFF Research Database (Denmark)

    Kruse, Marie; Michelsen, Susan Ishøy; Flachs, Esben Meulengracht;

    2009-01-01

    This study quantified the lifetime costs of cerebral palsy (CP) in a register-based setting. It was the first study outside the US to assess the lifetime costs of CP. The lifetime costs attributable to CP were divided into three categories: health care costs, productivity costs, and social costs....... The population analyzed was retrieved from the Danish Cerebral Palsy Register, which covers the eastern part of the country and has registered about half of the Danish population of individuals with CP since 1950. For this study we analyzed 2367 individuals with CP, who were born in 1930 to 2000 and...

  16. Features to validate cerebral toxoplasmosis

    Directory of Open Access Journals (Sweden)

    Carolina da Cunha Correia

    2013-06-01

    Full Text Available Introduction Neurotoxoplasmosis (NT sometimes manifests unusual characteristics. Methods We analyzed 85 patients with NT and AIDS according to clinical, cerebrospinal fluid, cranial magnetic resonance, and polymerase chain reaction (PCR characteristics. Results In 8.5%, focal neurological deficits were absent and 16.4% had single cerebral lesions. Increased sensitivity of PCR for Toxoplasma gondii DNA in the central nervous system was associated with pleocytosis and presence of >4 encephalic lesions. Conclusions Patients with NT may present without focal neurological deficit and NT may occur with presence of a single cerebral lesion. Greater numbers of lesions and greater cellularity in cerebrospinal fluid improve the sensitivity of PCR to T gondii.

  17. Vortex Dynamics in Cerebral Aneurysms

    CERN Document Server

    Byrne, Greg

    2013-01-01

    We use an autonomous three-dimensional dynamical system to study embedded vortex structures that are observed to form in computational fluid dynamic simulations of patient-specific cerebral aneurysm geometries. These structures, described by a vortex which is enclosed within a larger vortex flowing in the opposite direction, are created and destroyed in phase space as fixed points undergo saddle-node bifurcations along vortex core lines. We illustrate how saddle-node bifurcations along vortex core lines also govern the formation and evolution of embedded vortices in cerebral aneurysms under variable inflow rates during the cardiac cycle.

  18. Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta

    DEFF Research Database (Denmark)

    Holton, J.L; Lashley, T.; Ghiso, J.;

    2002-01-01

    -fibrillary) lesions was found. A[beta] was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive...

  19. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.

    Science.gov (United States)

    Sipe, Jean D; Benson, Merrill D; Buxbaum, Joel N; Ikeda, Shu-ichi; Merlini, Giampaolo; Saraiva, Maria J M; Westermark, Per

    2012-12-01

    The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 6-10, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils. PMID:23113696

  20. Radiosurgery for cerebral cavernomas.

    Science.gov (United States)

    Nagy, G; Kemeny, A A

    2015-09-01

    The role of stereotactic radiosurgery (SRS) in the management of cerebral cavernomas (CCMs) remains controversial. However, during the last decade the increasing knowledge on natural history and numerous publications from SRS centers using modern treatment protocols has been changing the initial resistance of the neurosurgical community. Unfortunately, the quality of publications on CCM SRS remains heterogeneous. Controversies arise from the lack of control groups, the different definition of hemorrhage, heterogeneous patient populations, and poor definition of treatment protocols. The key for proper interpretation of results is the understanding of the natural history of CCMs, which is varied both according to anatomical location and the presence or absence of previous hemorrhage. Hemispheric lesions appear to be more benign with lower annual bleed rate and risk of persisting disability, whereas those found in the thalamus, basal ganglia and brainstem typically have higher rebleed risk resulting in higher cumulative morbidity following subsequent hemorrhages. However, we are still unable at presentation to predict the future behavior of an individual lesion. In the present paper we critically review and analyze the modern SRS literature on CCMs. The expanding number of available data with current treatment protocols strongly supports the initial intuition that SRS is an effective treatment alternative for deep-seated CCMs with multiple hemorrhages reducing pretreatment annual rebleed rates from 32% pre-treatment to 1.5% within 2 years after treatment (N.=197). Moreover, it appears to stabilize lesions with no more than one bleed, and it is also effective for CCMs causing therapy resistant epilepsy especially if applied within 3 years after presentation. In modern SRS series the rate of persisting adverse radiation effects is low, resulting only in mild morbidity even in deep-seated lesions (4.16%, N.=376), and morbidity caused by post-treatment hemorrhages is also

  1. What is cerebral small vessel disease?

    International Nuclear Information System (INIS)

    An accumulating amount of evidence suggests that the white matter hyperintensities on T2 weighted brain magnetic resonance imaging predict an increased risk of dementia and gait disturbance. This state has been proposed as cerebral small vessel disease, including leukoaraiosis, Binswanger's disease, lacunar stroke and cerebral microbleeds. However, the concept of cerebral small vessel disease is still obscure. To understand the cerebral small vessel disease, the precise structure and function of cerebral small vessels must be clarified. Cerebral small vessels include several different arteries which have different anatomical structures and functions. Important functions of the cerebral small vessels are blood-brain barrier and perivasucular drainage of interstitial fluid from the brain parenchyma. Cerebral capillaries and glial endfeet, take an important role for these functions. However, the previous pathological investigations on cerebral small vessels have focused on larger arteries than capillaries. Therefore little is known about the pathology of capillaries in small vessel disease. The recent discoveries of genes which cause the cerebral small vessel disease indicate that the cerebral small vessel diseases are caused by a distinct molecular mechanism. One of the pathological findings in hereditary cerebral small vessel disease is the loss of smooth muscle cells, which is an also well-recognized finding in sporadic cerebral small vessel disease. Since pericytes have similar character with the smooth muscle cells, the pericytes should be investigated in these disorders. In addition, the loss of smooth muscle cells may result in dysfunction of drainage of interstitial fluid from capillaries. The precise correlation between the loss of smooth muscle cells and white matter disease is still unknown. However, the function that is specific to cerebral small vessel may be associated with the pathogenesis of cerebral small vessel disease. (author)

  2. Caffeine induced changes in cerebral circulation

    International Nuclear Information System (INIS)

    While the caffeine induced cerebral vasoconstriction is well documented, the effects of oral ingestion of the drug in a dose range comparable to the quantities in which it is usually consumed and the intensity and duration of the associated reduction in cerebral circulation are unknown. Cerebral blood flow was measured via the 133Xenon inhalation technique before and thirty and ninety minutes after the oral administration of 250 mg of caffeine or a placebo, under double-blind conditions. Caffeine ingestion was found to be associated with significant reductions in cerebral perfusion thirty and ninety minutes later. The placebo group showed no differences between the three sets of cerebral blood flow values

  3. Contraceptives and cerebral thrombosis: a five-year national case-control study

    DEFF Research Database (Denmark)

    Lidegaard, Øjvind; Kreiner, Svend

    2002-01-01

    Oral contraceptives; Cerebral thrombosis; Thrombotic stroke; Transitory cerebral ischemic attack; Thrombosis......Oral contraceptives; Cerebral thrombosis; Thrombotic stroke; Transitory cerebral ischemic attack; Thrombosis...

  4. Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism

    Directory of Open Access Journals (Sweden)

    Wieland Felix T

    2007-02-01

    Full Text Available Abstract Background Alzheimer's disease (AD is characterized by cerebral deposition of β-amyloid (Aβ peptides. Aβ is released from ectodomain cleaved amyloid precursor protein (APP via intramembranous proteolysis by γ-secretase, a complex consisting of presenilin and a few other proteins. p23/TMP21, a member of the p24 family type I transmembrane proteins, was recently identified as a presenilin complex component capable of modulating γ-secretase cleavage. The p24 family proteins form oligomeric complexes and regulate vesicular trafficking in the early secretory pathway, but their role in APP trafficking has not been investigated. Results Here, we report that siRNA-mediated depletion of p23 in N2a neuroblastoma and HeLa cells produces concomitant knockdown of additional p24 family proteins and increases secretion of sAPP. Furthermore, intact cell and cell-free Aβ production increases following p23 knockdown, similar to data reported earlier using HEK293 cells. However, we find that p23 is not present in mature γ-secretase complexes isolated using an active-site γ-secretase inhibitor. Depletion of p23 and expression of a familial AD-linked PS1 mutant have additive effects on Aβ42 production. Knockdown of p23 expression confers biosynthetic stability to nascent APP, allowing its efficient maturation and surface accumulation. Moreover, immunoisolation analyses show decrease in co-residence of APP and the APP adaptor Mint3. Thus, multiple lines of evidence indicate that p23 function influences APP trafficking and sAPP release independent of its reported role in γ-secretase modulation. Conclusion These data assign significance to p24 family proteins in regulating APP trafficking in the continuum of bidirectional transport between the ER and Golgi, and ascribe new relevance to the regulation of early trafficking in AD pathogenesis.

  5. Bilateral posterior cerebral artery infarction

    OpenAIRE

    Ryan, Davinia; Murphy, Sinead M; Hennessey, Michael J

    2010-01-01

    We report the case of a 70-year-old man who presented with short-term memory impairment and a homonymous left inferior quadrantanopia secondary to simultaneous bilateral posterior cerebral artery (PCA) territory infarction. As in more than a quarter of cases of PCA

  6. Investigating cerebral oedema using poroelasticity.

    Science.gov (United States)

    Vardakis, John C; Chou, Dean; Tully, Brett J; Hung, Chang C; Lee, Tsong H; Tsui, Po-Hsiang; Ventikos, Yiannis

    2016-01-01

    Cerebral oedema can be classified as the tangible swelling produced by expansion of the interstitial fluid volume. Hydrocephalus can be succinctly described as the abnormal accumulation of cerebrospinal fluid (CSF) within the brain which ultimately leads to oedema within specific sites of parenchymal tissue. Using hydrocephalus as a test bed, one is able to account for the necessary mechanisms involved in the interaction between oedema formation and cerebral fluid production, transport and drainage. The current state of knowledge about integrative cerebral dynamics and transport phenomena indicates that poroelastic theory may provide a suitable framework to better understand various diseases. In this work, Multiple-Network Poroelastic Theory (MPET) is used to develop a novel spatio-temporal model of fluid regulation and tissue displacement within the various scales of the cerebral environment. The model is applied through two formats, a one-dimensional finite difference - Computational Fluid Dynamics (CFD) coupling framework, as well as a two-dimensional Finite Element Method (FEM) formulation. These are used to investigate the role of endoscopic fourth ventriculostomy in alleviating oedema formation due to fourth ventricle outlet obstruction (1D coupled model) in addition to observing the capability of the FEM template in capturing important characteristics allied to oedema formation, like for instance in the periventricular region (2D model). PMID:26749338

  7. MR imaging of cerebral palsy

    Energy Technology Data Exchange (ETDEWEB)

    Saginoya, Toshiyuki [Urasoe General Hospital, Okinawa (Japan); Yamaguchi, Keiichiro; Kuniyoshi, Kazuhide [and others

    1996-06-01

    We evaluated 35 patients with cerebral palsy on the basis of MR imaging findings in the brain. The types of palsy were spastic quadriplegia (n=11), spastic diplegia (n=9), spastic hemiplegia (n=2), double hemiplegia (n=1), athetosis (n=10) and mixed (n=2). Of all patients, 28 (80%) generated abnormal findings. In spastic quadriplegia, although eight cases revealed severe brain damage, two cases showed no abnormal findings in the brain. One of the three had cervical cord compression caused by atlanto-axial subluxation. In spastic diplegia, the findings were divided according to whether the patient was born at term or preterm. If the patient had been born prematurely, the findings showed periventricular leukomalacia and abnormally high intensity in the posterior limbs of the internal capsule on T2-weighted images. MR imaging in spastic hemiplegia revealed cerebral infarction. In the athetoid type, half of all cases showed either no abnormal findings or slight widening of the lateral ventricle. Three cases showed abnormal signals of the basal ganglia. The reason why athetoid-type palsy did not show severe abnormality is unknown. We believe that MR imaging is a useful diagnostic modality to detect damage in the brain in cerebral palsy and plays an important role in the differentiation of cerebral palsy from the spastic palsy disease. (author)

  8. Cerebral imaging revealing Alzheimer's disease

    International Nuclear Information System (INIS)

    Cerebral imaging is the only non-invasive means of examining the brain and is essential in studying Alzheimer's disease. As a tool for early diagnosis, evaluation and treatment monitoring, this technology is at the heart of the research being done to further improve its reliability and sensitivity. (authors)

  9. Cerebral Palsy and Neonatal Encephalopathy

    OpenAIRE

    J Gordon Millichap

    2005-01-01

    The type and severity of cerebral palsy (CP) and pattern of associated disability in children with or without preceding neonatal encephalopathy (NE) were compared in a population-based case-control study of patients followed for 6 years at the Children’s Hospital, Westmead, Sydney, Australia.

  10. Ocular defects in cerebral palsy

    OpenAIRE

    Katoch Sabita; Devi Anjana; Kulkarni Prajakta

    2007-01-01

    There is a high prevalence of ocular defects in children with developmental disabilities. This study evaluated visual disability in a group of 200 cerebral palsy (CP) patients and found that 68% of the children had significant visual morbidity. These findings emphasize the need for an early ocular examination in patients with CP.

  11. [Cerebral ischemia in young adults].

    Science.gov (United States)

    Berlit, P; Endemann, B; Vetter, P

    1991-08-01

    An overview is given over etiology and prognosis of cerebral ischemias until the age of 40. In a time period of 19 years, 168 patients were diagnosed with cerebral ischemia until the age of 40 (91 females, 77 males). The most frequent etiology is premature atherosclerosis in patients with vascular risk factors (up to 50%). Cardiogenic embolism is responsible for 1 to 34% of the cases: cardiac valve diseases and endocarditis being the most frequent sources. In 2 to 19% a vasculitis is diagnosed. While infectious arteritis is especially frequent in countries of the third world, immunovasculitides are common in Europe and the USA. Noninflammatory vasculopathies include spontaneous or traumatic dissection, fibromuscular dysplasia and vascular malformations. A migrainous stroke is especially frequent in female smokers with intake of oral contraceptives. During pregnancy both sinus thrombosis and arterial ischemia occur. Hematologic causes for ischemia are polycythemia, thrombocytosis and genetic diseases (sickle cell anemia, AT3-deficiency). Cerebral ischemia may occur in connection with the ingestion of ergot-derivates. The prognosis of cerebral ischemia in young adults is better than in older stroke-patients. PMID:1937340

  12. CT of cerebral hydatid disease

    International Nuclear Information System (INIS)

    Six cases of cerebral hydatid disease (CHD) were seen in Kuwait over a period of 8 years. The typical CT appearance of a large well-defined spherical nonenhanced unilocular cyst was seen in four cases. Two unusual but characteristic types of calcification were seen, one in each of the remaining two cases. (orig.)

  13. MR imaging of cerebral palsy

    International Nuclear Information System (INIS)

    We evaluated 35 patients with cerebral palsy on the basis of MR imaging findings in the brain. The types of palsy were spastic quadriplegia (n=11), spastic diplegia (n=9), spastic hemiplegia (n=2), double hemiplegia (n=1), athetosis (n=10) and mixed (n=2). Of all patients, 28 (80%) generated abnormal findings. In spastic quadriplegia, although eight cases revealed severe brain damage, two cases showed no abnormal findings in the brain. One of the three had cervical cord compression caused by atlanto-axial subluxation. In spastic diplegia, the findings were divided according to whether the patient was born at term or preterm. If the patient had been born prematurely, the findings showed periventricular leukomalacia and abnormally high intensity in the posterior limbs of the internal capsule on T2-weighted images. MR imaging in spastic hemiplegia revealed cerebral infarction. In the athetoid type, half of all cases showed either no abnormal findings or slight widening of the lateral ventricle. Three cases showed abnormal signals of the basal ganglia. The reason why athetoid-type palsy did not show severe abnormality is unknown. We believe that MR imaging is a useful diagnostic modality to detect damage in the brain in cerebral palsy and plays an important role in the differentiation of cerebral palsy from the spastic palsy disease. (author)

  14. [Should cerebral autoregulation be reassessed?

    DEFF Research Database (Denmark)

    Secher, Niels H.

    2009-01-01

    Maintained cardiac output (CO) and cerebral oxygenation (ScO2) are of importance for a reduction in perioperative complications. Normovolaemia is defined as a central blood volume that does not limit CO for the supine patient and is maintained by individualized goal directed fluid therapy. Thereby...

  15. Cerebral edema in drug addicts

    Directory of Open Access Journals (Sweden)

    Daruši Dragana J.

    2014-01-01

    Full Text Available Background/Aim. The effect of drugs leaves permanent consequences on the brain, organic in type, followed by numerous manifestations, and it significantly affects the development of mental dysfunctions. The clinicians are often given a task to estimate a patient’s personality during treatment or during experts estimate of a drug addict. The aim of this research was to determine the differences, if any, in characteristics of addicts experience and personality traits in drug addicts with or without cerebral edema. Methods. The research was conducted on a sample of 252 male drug addicts, the average age of 23.3 (SD = 4.3 years. Cerebral edema was confirmed on magnetic resonance (MR images of the brain performed during the treatment of the addicts. The participants were tested by the psychologists using Minnesota Multiphasic Personality Inventory (MMPI-201 test, and the data were processed using canonical discriminate analysis within the SPSS program. The dependent variable in the study was cerebral edema. A block of independent variables, designed for the requirements of this study, consisted of two subgroups. The first one consisted of 12 variables describing the relevant characteristics of drug abuse. The second subgroup consisted of 8 psychopathological tendencies in the personality defined by the mentioned test. Results. Cerebral edema was confirmed in 52 (20.63% of the drug addicts. The differences between the groups of drug addicts with and without cerebral edema were determined in the following: the time span of taking drugs (0.301, use of alcohol parallel with drugs (0.466, and treatment for addiction (0.603. In the drug addicts with a cerebral edema, MMPI-201 confirmed the increase in the scales for hypochondria, psychopathic deviations and psychastenia, and the decrease in the scales for schizophrenia and depression. Conclusion. Our study confirmed a possible connection between cerebral edema and personality traits in a number of the

  16. Late cerebral ischaemia after subarachnoid haemorrhage

    DEFF Research Database (Denmark)

    Edvinsson, L; Povlsen, G K

    2011-01-01

    Late cerebral ischaemia after subarachnoid haemorrhage (SAH) carries high morbidity and mortality because of reduced cerebral blood flow (CBF) and subsequent cerebral ischaemia. This is associated with upregulation of contractile receptors in cerebral artery smooth muscles via the activation of...... intracellular signalling. In addition, delayed cerebral ischaemia after SAH is associated with inflammation and disruption of the blood-brain barrier (BBB). This article reviews recent evidence concerning the roles of vasoconstrictor receptor upregulation, inflammation and BBB breakdown in delayed cerebral...... ischaemia after SAH. In addition, recent studies investigating the role of various intracellular signalling pathways in these processes and the possibilities of targeting signalling components in SAH treatment are discussed. Studies using a rat SAH model have demonstrated that cerebral arteries increase...

  17. Anestesia e paralisia cerebral Anestesia y parálisis cerebral Anesthesia and cerebral palsy

    Directory of Open Access Journals (Sweden)

    Március Vinícius M Maranhão

    2005-12-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: A paralisia cerebral (PC é uma doença não progressiva decorrente de lesão no sistema nervoso central, levando a um comprometimento motor do paciente. O portador de PC freqüentemente é submetido a procedimentos cirúrgicos devido a doenças usuais e situações particulares decorrentes da paralisia cerebral. Foi objetivo deste artigo revisar aspectos da paralisia cerebral de interesse para o anestesiologista, permitindo um adequado manuseio pré, intra e pós-operatório neste tipo de paciente. CONTEÚDO: O artigo aborda aspectos da paralisia cerebral como etiologia, classificação, fatores de risco, fisiopatologia, quadro clínico, diagnóstico, terapêuticas utilizadas bem como avaliação pré-operatória, medicação pré-anestésica, manuseio intra e pós-operatório, analgesia pós-operatória e dor crônica. CONCLUSÕES: O anestesiologista desempenha um papel importante na diminuição da morbidade e mortalidade anestésico-cirúrgica em pacientes portadores de paralisia cerebral. O conhecimento da fisiopatologia dos diferentes tipos de paralisia cerebral bem como das doenças associadas e suas terapêuticas é imprescindível, pois permite ao anestesiologista antecipar e prevenir complicações intra e pós-operatórias neste tipo de paciente.JUSTIFICATIVA Y OBJETIVOS: La parálisis cerebral (PC es una enfermedad no progresiva consecuente de una lesión en el sistema nervioso central, llevando a un comprometimiento motor del paciente. El portador de PC, frecuentemente es sometido a procedimientos quirúrgicos debido a enfermedades usuales y situaciones particulares consecuentes de la parálisis cerebral. El objetivo de este artículo, fue revisar aspectos de la parálisis cerebral de interés para el anestesista, permitiendo un adecuado manoseo pre, intra y posoperatorio en este tipo de paciente. CONTENIDO: El artículo aborda aspectos de la parálisis cerebral como etiología, clasificación, factores de

  18. Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations.

    Science.gov (United States)

    Witte, Michael M; Foster, Norman L; Fleisher, Adam S; Williams, Monique M; Quaid, Kimberly; Wasserman, Michael; Hunt, Gail; Roberts, J Scott; Rabinovici, Gil D; Levenson, James L; Hake, Ann Marie; Hunter, Craig A; Van Campen, Luann E; Pontecorvo, Michael J; Hochstetler, Helen M; Tabas, Linda B; Trzepacz, Paula T

    2015-09-01

    Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID:27239516

  19. Oligomer Formation of Toxic and Functional Amyloid Peptides Studied with Atomistic Simulations.

    Science.gov (United States)

    Carballo-Pacheco, Martín; Ismail, Ahmed E; Strodel, Birgit

    2015-07-30

    Amyloids are associated with diseases, including Alzheimer's, as well as functional roles such as storage of peptide hormones. It is still unclear what differences exist between aberrant and functional amyloids. However, it is known that soluble oligomers formed during amyloid aggregation are more toxic than the final fibrils. Here, we perform molecular dynamics simulations to study the aggregation of the amyloid-β peptide Aβ25-35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Although the three peptides have similar primary sequences, tachykinin peptides, in contrast to Aβ25-35, form nontoxic amyloids. Our simulations reveal that the charge of the C-terminus is essential to controlling the aggregation process. In particular, when the kassinin C-terminus is not amidated, the aggregation kinetics decreases considerably. In addition, we observe that the monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. PMID:26130191

  20. T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

    Directory of Open Access Journals (Sweden)

    de Calignon Alix

    2011-03-01

    Full Text Available Abstract Background Immunization against amyloid-β (Aβ, the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD, causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization. Results To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas. Conclusions Our results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.

  1. Digital subtraction angiography in cerebral infarction

    International Nuclear Information System (INIS)

    The usefulness and radiographic findings of the angiography in cerebral infarction are well known. We attempted to evaluate the angiographic causes, findings, and the usefulness of DSA in cerebral infarction. The authors reviewed retrospectively DSA images of 51 patients who were diagnosed as having cerebral infarction by brain CT and/or MRI and clinical settings. DSA was performed in all 51 patients, and in 3 patients, conventional angiogram was also done. Both carotid DSA images were obtained in AP, lateral, oblique projections, and one or both vertebral DSA images in AP and lateral. The authors reviewed the patient's charts for symptoms, operative findings and final diagnosis, and analysed DSA findings of cerebral atherosclerosis with focus on 6 major cerebral arteries. Among the 51 patients of cerebral infarction 43 patients (84.3%) had cerebral atherosclerosis, 1 dissecting aneurysm, 1 moyamoya disease and 6 negative in angiogram. DSA findings of cerebral atherosclerosis were multiple narrowing in 42 patients (97.7%), tortuosity in 22 (51.2%), dilatation in 14, occlusion in 12, avascular region in 8, collaterals in 7, ulcer in 6, and delayed washout of contrast media in 3. In cerebral atherosclerosis, internal carotid artery was involved in 37 patients (86.0%), middle cerebral artery in 29 (67.4%) posterior cerebral artery in 28, anterior cerebral artery in 26, vertebral artery in 22, and basilar artery in 15. Intracranial involvement of cerebral atherosclerosis (64.9%) was more common than extracranial involvement (16.2%). In cerebral infarction MRA may be the screening test, but for more precise evaluation of vascular abnormality and its extent, DSA should be considered

  2. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N‑truncated Abeta in sporadic Alzheimer disease cases and mouse models.

    Science.gov (United States)

    Bouter, Yvonne; Lopez Noguerola, Jose Socrates; Tucholla, Petra; Crespi, Gabriela A N; Parker, Michael W; Wiltfang, Jens; Miles, Luke A; Bayer, Thomas A

    2015-11-01

    Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-β (Aβ) which are currently tested in multiple clinical trials for the prevention of Alzheimer's disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal Aβ in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified Aβ, while Solanezumab and Crenezumab do detect N-terminally modified Aβ peptides Aβ4-42 and pyroglutamate Aβ3-42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically Aβ4-42 and pyroglutamate Aβ3-42, but not full-length Aβ1-42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal Aβ and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of

  3. Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

    OpenAIRE

    Tomita, Tatsuo

    2012-01-01

    Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to...

  4. A peptide study of the relationship between the collagen triple-helix and amyloid

    OpenAIRE

    Parmar, Avanish S.; Nunes, Ana Monica; Baum, Jean; Brodsky, Barbara

    2012-01-01

    Type XXV collagen, or Collagen-Like Amyloidogenic Component (CLAC), is a component of amyloid plaques, and recent studies suggest this collagen affects amyloid fibril elongation and has a genetic association with Alzheimer’s disease. The relationship between the collagen triple helix and amyloid fibrils was investigated by studying peptide models, including a very stable triple helical peptide (Pro-Hyp-Gly)10; an amyloidogenic peptide GNNQQNY; and a hybrid peptide where the GNNQQNY sequence w...

  5. Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim-Habibi, Azadeh; Navidpour, Latifeh;

    2011-01-01

    amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds. In this...... study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin-T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the...

  6. Dimensionality of carbon nanomaterial impacting on the modulation of amyloid peptide assembly

    Science.gov (United States)

    Wang, J.; Zhu, Z.; Bortolini, C.; Hoffmann, S. V.; Amari, A.; Zhang, H. X.; Liu, L.; Dong, M. D.

    2016-07-01

    A wide variety of inorganic nanomaterials have been exploited so far for their great potential for biological applications. Some of these materials could be valid candidates to modulate the assembly of amyloid peptides, which is relevant to amyloid-related diseases. In this work, we reveal that a carbon nanomaterial can indeed modulate the assembly of amyloid peptides and, additionally, we show that this modulating effect is closely related to the dimensionality of the nanomaterials.

  7. Classification of amyloid status using machine learning with histograms of oriented 3D gradients

    OpenAIRE

    Cattell, Liam; Platsch, Günther; Pfeiffer, Richie; Declerck, Jérôme; Schnabel, Julia A.; Hutton, Chloe

    2016-01-01

    Brain amyloid burden may be quantitatively assessed from positron emission tomography imaging using standardised uptake value ratios. Using these ratios as an adjunct to visual image assessment has been shown to improve inter-reader reliability, however, the amyloid positivity threshold is dependent on the tracer and specific image regions used to calculate the uptake ratio. To address this problem, we propose a machine learning approach to amyloid status classification, which is independent ...

  8. Experimentally Derived Structural Constraints for Amyloid Fibrils of Wild-Type Transthyretin

    OpenAIRE

    Bateman, David A.; Tycko, Robert; Wickner, Reed B.

    2011-01-01

    Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region e...

  9. Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population.

    Directory of Open Access Journals (Sweden)

    Yian Gu

    Full Text Available We aimed to whether the abnormally high amyloid-β (Aβ level in the brain among apparently healthy elders is related with subtle cognitive deficits and/or accelerated cognitive decline.A total of 116 dementia-free participants (mean age 84.5 years of the Washington Heights Inwood Columbia Aging Project completed 18F-Florbetaben PET imaging. Positive or negative cerebral Aβ deposition was assessed visually. Quantitative cerebral Aβ burden was calculated as the standardized uptake value ratio in pre-established regions of interest using cerebellar cortex as the reference region. Cognition was determined using a neuropsychological battery and selected tests scores were combined into four composite scores (memory, language, executive/speed, and visuospatial using exploratory factor analysis. We examined the relationship between cerebral Aβ level and longitudinal cognition change up to 20 years before the PET scan using latent growth curve models, controlling for age, education, ethnicity, and Apolipoprotein E (APOE genotype.Positive reading of Aβ was found in 41 of 116 (35% individuals. Cognitive scores at scan time was not related with Aβ. All cognitive scores declined over time. Aβ positive reading (B = -0.034, p = 0.02 and higher Aβ burden in temporal region (B = -0.080, p = 0.02 were associated with faster decline in executive/speed. Stratified analyses showed that higher Aβ deposition was associated with faster longitudinal declines in mean cognition, language, and executive/speed in African-Americans or in APOE ε4 carriers, and with faster memory decline in APOE ε4 carriers. The associations remained significant after excluding mild cognitive impairment participants.High Aβ deposition in healthy elders was associated with decline in executive/speed in the decade before neuroimaging, and the association was observed primarily in African-Americans and APOE ε4 carriers. Our results suggest that measuring cerebral Aβ may give us

  10. Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Voss, S.D.; Hall, F.M. [Dept. of Radiology, Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Murphey, M.D. [Dept. of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (United States); Dept. of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD (United States); Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland (United States)

    2001-09-01

    A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. (orig.)

  11. Amyloid-like fibril elongation follows michaelis-menten kinetics.

    Directory of Open Access Journals (Sweden)

    Katazyna Milto

    Full Text Available A number of proteins can aggregate into amyloid-like fibrils. It was noted that fibril elongation has similarities to an enzymatic reaction, where monomers or oligomers would play a role of substrate and nuclei/fibrils would play a role of enzyme. The question is how similar these processes really are. We obtained experimental data on insulin amyloid-like fibril elongation at the conditions where other processes which may impact kinetics of fibril formation are minor and fitted it using Michaelis-Menten equation. The correlation of the fit is very good and repeatable. It speaks in favour of enzyme-like model of fibril elongation. In addition, obtained [Formula: see text] and [Formula: see text] values at different conditions may help in better understanding influence of environmental factors on the process of fibril elongation.

  12. Melatonin attenuates β-amyloid-induced inhibition of neurofilament expression

    Institute of Scientific and Technical Information of China (English)

    Ying-chun ZHANG; Ze-fen WANG; Qun WANG; Yi-peng WANG; Jian-zhi WANG

    2004-01-01

    AIM: To explore the effect of β-amyloid (Aβ) on metabolism of cytoskeletal protein neurofilament, and search for effective cure to the lesion. METHODS: Wild type murine neuroblastoma N2a (N2awt) and N2a stably transfected with wild type amyloid precursor protein (N2aAPP) were cultured. Sandwich ELISA, immunocytochemistry, and Western blot were used respectively to measure the level of Aβ, the expression and phosphorylation of neurofilament proteins. RESULTS: The immunoreactivity of neurofilament protein was almost abolished in N2aAPP, which beard a significantly higher level of Aβ. Melatonin effectively decreased the level of Aβ, and restored partially the level of phosphorylated and non-phosphorylated neurofilament in N2aAPP. CONCLUSION: Overproduction of Aβ inhibits neurofilament expression, and melatonin attenuates the Aβ-induced lesion in cytoskeletal protein.

  13. New Cyclolignans from Origanumglandulosum Active Against b -amyloid Aggregation

    Directory of Open Access Journals (Sweden)

    Abdelkader Basli

    2014-05-01

    Full Text Available Origanum glandulosum Desf is an endemic flavoring herb widely distributed in North Africa that is commonly used in traditional medicine. This oregano species is rich in essential oils but little is known about its phenolic composition. In the present study, a crude extract of O. glandulosum was prepared in order to isolate and investigate its neuroprotective potential to inhibit β-amyloid peptide (Aβ aggregation. The three major compounds of the extract were isolated: rosmarinic acid and two cyclolignans in Origanum genus, globoidnan A and a new derivative named globoidnan B. Rosmarinic acid and globoidnan A showed significant anti-aggregative activity against β amyloid aggregation (IC50 7.0 and 12.0 µM, respectively. In contrast, globoidnan B was found to be less active.

  14. Thermodynamics of amyloid formation and the role of intersheet interactions

    International Nuclear Information System (INIS)

    The self-assembly of proteins into β-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical (NVT) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional

  15. Thermodynamics of amyloid formation and the role of intersheet interactions

    CERN Document Server

    Irbäck, Anders

    2016-01-01

    The self-assembly of proteins into $\\beta$-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical ($NVT$) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional.

  16. Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

    Directory of Open Access Journals (Sweden)

    Bastus Neus

    2008-01-01

    Full Text Available Abstract Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

  17. Localization microscopy for the study of amyloid fibril formation

    Science.gov (United States)

    Pinotsi, Dorothea; Kaminski Schierle, Gabriele S.; Rees, Eric; Kaminski, Clemens F.

    2013-09-01

    Super-resolution microscopy has emerged as a powerful and non-invasive tool for the study of molecular processes both in vitro, but also as they occur in live cells. Here we present the application of direct stochastic optical reconstruction microscopy (dSTORM), a super-resolution technique based on single molecule localization, to determine the morphology of protein aggregates and of small extra- and intracellular structures. The technique reveals details down to 20 nm providing information on scales much smaller than the wavelength of the probing light. We use dSTORM in the study of amyloid fibril self-assembly processes associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We show that the aggregation process can be followed kinetically and observe the emergence of amyloid structures in time as they occur in vitro. As an all optical technique, there is translation potential from studies in vitro to in vivo applications.

  18. Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

    Science.gov (United States)

    Araya, Eyleen; Olmedo, Ivonne; Bastus, Neus G.; Guerrero, Simón; Puntes, Víctor F.; Giralt, Ernest; Kogan, Marcelo J.

    2008-11-01

    Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ) amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

  19. Effects of Yizhi Capsule (益智胶囊) on Learning and Memory Disorder and β-amyloid Peptide Induced Neurotoxicity in Rats

    Institute of Scientific and Technical Information of China (English)

    WU Hang-yu; XU Jiang-ping; LI Lin; ZHU Bai-hua

    2006-01-01

    Objective: To explore the effects of Yizhi Capsule (益智胶囊, YZC) on learning and memory disorder and β-amyloid peptide induced neurotoxicity in rats. Methods: Various doses of YZC were administered to Sprague-Dawley (SD) rats for 8 consecutive days, twice a day. On the 8th day of the experiment,scopolamine hydrobromide was intraperitoneally injected to every rat and Morris water maze test and shuttle dark avoidance test were carried out respectively to explore the changes of learning and memory capacities in the rats. Besides, after the cerebral cortical neurons of newborn SD rats aged within 3 days were cultured in vitro for 7 days, drug serum containing YZC was added to the cultured neurons before or after β amyloid peptide25-35 (Aβ25-35) intoxication to observe the protective effect of YZC on neurotoxicity by MTT assay and to determine the LDH content in the supernatant. Results: Compared with those untreated with YZC, the rats having received YZC treatment got superiority in shorter time of platform seeking in Morris water maze test,as well as elongated latent period and less times of error in shuttle dark avoidance test. On the cultured neurons, YZC drug serum could effectively increase the survival rate of Aβ25-35 intoxicated neurons and reduce the LDH contents in cultured supernatant. Conclusion: YZC has an action of improving learning and memory disorder, and good protective effect on Aβ25-35 induced neurotoxicity in SD rats.

  20. β-Amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues

    International Nuclear Information System (INIS)

    Progressive cerebral deposition of extracellular filaments composed of the β-amyloid protein (βAP) is a constant feature of Alzheimer disease (AD). Since the gene on chromosome 21 encoding the βAP precursor (βAPP) is not known to be altered in AD, transcriptional or posttranslational changes may underlie accelerated βAP deposition. Using two antibodies to the predicted carboxyl terminus of βAPP, the authors have identified the native βAPP in brain and nonneural human tissues as a 110- to 135-kDa protein complex that is insoluble in buffer and found in various membrane-rich subcellular fractions. These proteins are relatively uniformly distributed in adult brain, abundant in fetal brain, and detected in nonneural tissues that contain βAPP mRNA. Similarly sized proteins occur in rat, cow, and monkey brain and in cultured human HL-60 and HeLa cells; the precise patterns in the 110- to 135-kDa range are heterogeneous among various tissues and cell lines. They conclude that the highly conserved βAPP molecule occurs in mammalian tissues as a heterogeneous group of membrane-associated proteins of ∼ 120 kDa. Detection of the nonamyloidogenic carboxyl terminus within plaques suggests that proteolytic processing of the βAPP into insoluble filaments occurs locally in cortical regions that develop β-amyloid deposits with age

  1. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology.

    Directory of Open Access Journals (Sweden)

    Panayiota Papadopoulos

    Full Text Available Animal models of Alzheimer's disease (AD are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months and aged (>18 months bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind and a constitutively active form of transforming growth factor-β1 (TGF-β1. A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

  2. White matter changes in stroke patients. Relationship with stroke subtype and outcome

    DEFF Research Database (Denmark)

    Leys, D; Englund, E; Del Ser, T;

    1999-01-01

    vascular dementia. WMC are more frequent in patients with lacunar infarcts, deep intracerebral hemorrhages, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cerebral amyloid angiopathy. After an acute ischemic stroke, WMC are associated with a higher risk of...... death or dependency, recurrent stroke of any type, cerebral bleeding under anticoagulation, myocardial infarction, and poststroke dementia. WMC in stroke patients are often associated with small-vessel disease and lead to a higher risk of death, and poor cardiac and neurological outcome. However......White matter changes (WMC), detected by imaging techniques, are frequent in stroke patients. The aim of the study was to determine how WMC relate to stroke subtypes and to stroke outcome. We made a systematic Medline search for articles appearing with two of the following key words: either 'WMC or...

  3. Curcumin protects against intracellular amyloid toxicity in rat primary neurons

    OpenAIRE

    Ye, Jelina; Zhang, Yan

    2012-01-01

    To investigate whether curcumin is protective against intracellular amyloid β (Aβ) toxicity, different concentrations of curcumin were applied to with intracellular Aβ in rat primary hippocampal neurons in culture. We find that at low dosages, curcumin effectively inhibits intracellular Aβ toxicity. Reactive oxidative species (ROS) is involved in mediating intracellular Aβ toxicity and possibly curcumin protection. Our results indicate that oxidative stress may mediate cell death induced by i...

  4. The contrasting effect of macromolecular crowding on amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available BACKGROUND: Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1 have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins. METHODOLOGY/PRINCIPAL FINDINGS: As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l. CONCLUSIONS/SIGNIFICANCE: We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of

  5. Amyloid polyneuropathy caused by wild-type transthyretin

    OpenAIRE

    Lam, L.; Margeta, M; Layzer, R

    2015-01-01

    © 2015 Wiley Periodicals, Inc. Introduction: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. Methods: We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. Results: The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elde...

  6. NNanomechanical characteristics of proteins and peptides in amyloid

    OpenAIRE

    Boayue, Nya Mehnwolo

    2012-01-01

    ......The understanding of the aggregation of amyloid fibrils is essential as they are linked to a number of diseases such as Alzheimer and Parkston’s disease. Amy- loids from different proteins or peptides have common characteristics such as core β-sheet structure, green birefringence upon binding to Congo red, and fibrillar mor- phology. In this thesis, I report single molecule analysis of TTR105−115 a fragment of transthyretin, a serum and cerebrospinal fluid carrier of ...

  7. Designed amyloid fibers as materials for selective carbon dioxide capture

    OpenAIRE

    Li, Dan; Furukawa, Hiroyasu; Deng, Hexiang; Liu, Cong; Yaghi, Omar M.; Eisenberg, David S.

    2013-01-01

    New and improved materials capable of binding carbon dioxide are essential to addressing the global threat of accelerating climate change. The presently used industrial methods for carbon dioxide capture have severe drawbacks, including toxicity and energy inefficiency. Newer porous materials are so far less effective in water, invariably a component of combustion gases. Here, we present a material for carbon dioxide capture. This material, amyloid fibers in powdered form, selectively capture...

  8. Modeling an Anti-Amyloid Combination Therapy for Alzheimer's Disease

    OpenAIRE

    Chow, Vivian W.; Savonenko, Alena V; Melnikova, Tatiana; Kim, Hyunsu; Price, Donald L.; Li, Tong; Wong, Philip C.

    2010-01-01

    As only symptomatic treatments are now available for Alzheimer's disease (AD), safe and effective mechanism-based therapies remain a great unmet need for patients with this neurodegenerative disease. Although γ-secretase and BACE1 [β-site β-amyloid (Aβ) precursor protein (APP) cleaving enzyme 1] are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition or reductions in amounts of these aspartyl proteases have raised concerns regarding their therap...

  9. "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy.

    Science.gov (United States)

    Conceição, Isabel; González-Duarte, Alejandra; Obici, Laura; Schmidt, Hartmut H-J; Simoneau, Damien; Ong, Moh-Lim; Amass, Leslie

    2016-03-01

    Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed. PMID:26663427

  10. MetAmyl: a METa-predictor for AMYLoid proteins.

    Directory of Open Access Journals (Sweden)

    Mathieu Emily

    Full Text Available The aggregation of proteins or peptides in amyloid fibrils is associated with a number of clinical disorders, including Alzheimer's, Huntington's and prion diseases, medullary thyroid cancer, renal and cardiac amyloidosis. Despite extensive studies, the molecular mechanisms underlying the initiation of fibril formation remain largely unknown. Several lines of evidence revealed that short amino-acid segments (hot spots, located in amyloid precursor proteins act as seeds for fibril elongation. Therefore, hot spots are potential targets for diagnostic/therapeutic applications, and a current challenge in bioinformatics is the development of methods to accurately predict hot spots from protein sequences. In this paper, we combined existing methods into a meta-predictor for hot spots prediction, called MetAmyl for METapredictor for AMYLoid proteins. MetAmyl is based on a logistic regression model that aims at weighting predictions from a set of popular algorithms, statistically selected as being the most informative and complementary predictors. We evaluated the performances of MetAmyl through a large scale comparative study based on three independent datasets and thus demonstrated its ability to differentiate between amyloidogenic and non-amyloidogenic polypeptides. Compared to 9 other methods, MetAmyl provides significant improvement in prediction on studied datasets. We further show that MetAmyl is efficient to highlight the effect of point mutations involved in human amyloidosis, so we suggest this program should be a useful complementary tool for the diagnosis of these diseases.

  11. Designing peptidic inhibitors of serum amyloid A aggregation process.

    Science.gov (United States)

    Sosnowska, Marta; Skibiszewska, Sandra; Kamińska, Emilia; Wieczerzak, Ewa; Jankowska, Elżbieta

    2016-04-01

    Amyloid A amyloidosis is a life-threatening complication of a wide range of chronic inflammatory, infectious and neoplastic diseases, and the most common form of systemic amyloidosis worldwide. It is characterized by extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A protein (SAA), a major acute-phase reactant protein, produced predominantly by hepatocytes. Currently, there are no approved therapeutic agents directed against the formation of fibrillar SAA assemblies. We attempted to develop peptidic inhibitors based on their similarity and complementarity to the regions critical for SAA self-association, which they should interact with and block their assembly into amyloid fibrils. Inh1 and inh4 which are comprised of the residues from the amyloidogenic region of SAA1.1 protein and Aβ peptide, respectively, were found by us as capable to significantly suppress aggregation of the SAA1-12 peptide. It was chosen as an aggregation model that mimicks the amyloidogenic nucleus of SAA protein. We suppose that aromatic interactions may be responsible for inhibitory activity of both compounds. We also recognized that aromatic residues are involved in self-association of SAA1-12. PMID:26759015

  12. Cerebral aterial spasm. I. Adrenergic mechanism in experimental cerebral vasospasm.

    Directory of Open Access Journals (Sweden)

    Morooka,Hiroshi

    1978-04-01

    Full Text Available This study demonstrates that an adrenergic mechanism plays an important role in producing the delayed cerebral vasospasm which follows subarachnoid hemorrhage. Results were as follows: 1. Experimental subarachnoid hemorrhage (SAH was produced by injection of fresh arterial blood into the cisterna magna in cats. The cerebral vasospasm was shown angiographically to be biphasic in nature: immediate constriction lasting 1 h and marked prolonged spasm occurring between the 3rd and 5th day after SAH. The amount of noradrenaline (NA and dopamine-beta-hydroxylase (DBH activity decreased over a period of 24 h both within the wall of the basilar artery and in the locus ceruleus and then gradually increased, reaching a maximum on the 3rd day after SAH. 2. Topical application of spasmogenic substances (NA and blood produced a marked constriction of the hypersensitive basilar artery on the 3rd day after SAH. 3. 6-Hydroxydopamine (6-OHDA injection into the cisterna magna produced prolonged vasocilatation. The dilated vessel responded with mild transient constriction after the topical application of NA or fresh blood. DBH activity and NA concentration in the vessels, locus ceruleus and medial hypothalamus decreased markedly on the 3rd day after the cisternal injection of 6-OHDA. 4. Various spasmogenic substances (i.e. serotonin, NA, prostaglandins and methemoglobin were measured in a mixture of equal volume of CSF and blood in cats. ONly the serotonin in the mixed fluid produced vasoconstriction. Spasmogenic substances decreased markedly in the mixed fluid incubated for 3 days at 37 degrees C, and none of these substances apart from methemoglobin was present in a concentration sufficient to produce constriction of vessels. 5. These results suggest that early spasm is induced by serotonin around the arteries of the cranial base, and delayed spasm might be caused by hyperreaction of cerebral vessels to spasmogenic substances such as methemoglobin, during the

  13. What's new in cerebral palsy.

    Science.gov (United States)

    JONES, M H

    1953-11-01

    Among new researches bearing on cerebral palsy are the growth of brain cells in tissue cultures for experimentation; the use of polysaccharides to prevent the formation of a glial barrier to nerve growth after injury; observation of changes in reactions of neurons at various stages of development; the finding of hypernatremia and hyperchloremia in lesions of the frontal lobe and the thalamus; stimulation of cerebral blood flow by injection of sodium bicarbonate and retardation with ammonium chloride; and studies of serial sections of brains of palsied children who died. Study of development in the early months of life has made possible the detection of significant abnormalities in behavior early in life. Loss of hearing may be tested in very young children by measuring minute variations in electrical resistance of the skin upon auditory stimulation of the sympathetic nervous system. Conditions which have been described as having been confused with cerebral palsy are dislocation of a cervical vertebra, hereditary spastic paraplegia, transverse myelopathy, injury to the spinal cord or cauda equina by anomalous growths of the spine, and also encephalitis and meningitis. Sedation has proved a valuable adjunct to electroencephalographic study of cerebral palsy. Better criteria for abnormality in the young child should be determined and the application of them more clearly standardized. Simple exercises are useful for early training of palsied children to stimulate development. "Crossed laterality"-the dominant eye being contralateral to the preferred hand-has been counteracted by special training with great success in eliminating emotional and behavior problems and accelerating development.Recent studies indicate that only 50 per cent of cerebral palsy patients have normal or better intelligence. Subluxation of the hip joint, a common deformity associated with cerebral palsy, can sometimes be corrected by operation if detected at an early stage. Radical ablation of

  14. Clinical application of cerebral dynamic perfusion studies

    International Nuclear Information System (INIS)

    Radionuclide cerebral perfusion studies are assuming a far greater importance in the detection and differential diagnosis of cerebral lesions. Perfusion studies not only contribute to the differential diagnosis of lesions but in certain cases are the preferred methods by which more accurate clinical interpretations can be made. The characteristic blood flow of arterio-venous malformations readily differentiates this lesion from neoplasms. The decreased perfusion or absent perfusion observed in cerebral infarctions is diagnostic without concurrent evidence from static images. Changes in rates and direction of blood flow contribute fundamental information to the status of stenosis and vascular occlusion and, in addition, offer valuable information on the competency and routes of collateral circulation. The degree of cerebral perfusion after cerebral vascular accidents appears to be directly related to patient recovery, particularly muscular function. Cerebral perfusion adds a new parameter in the diagnosis of subdural haematomas and concussion and in the differentiation of obscuring radioactivity from superficial trauma. Although pictorial displays of perfusion blood flow will offer information in most cerebral vascular problems, the addition of computer analysis better defines temporal relationships of regional blood flow, quantitative changes in flow and the detection of the more subtle increases or decreases in cerebral blood flow. The status of radionuclide cerebral perfusion studies has taken on an importance making it the primary modality for the diagnosis of cerebral lesions. (author)

  15. CEREBRAL PALSY. PRENTICE-HALL FOUNDATIONS OF SPEECH PATHOLOGY SERIES.

    Science.gov (United States)

    CHANCE, BURTON, JR.; MCDONALD, EUGENE T.

    THIS INTRODUCTORY TEXT ON CEREBRAL PALSY IS DIVIDED INTO TWO SECTIONS. THE FIRST SECTION OF THE BOOK CONTAINS INFORMATION ABOUT UNDERSTANDING THE MEANING OF CEREBRAL PALSY, PROGRAMS FOR THOSE WITH CEREBRAL PALSY, THE NEUROLOGICAL BASES, ETIOLOGY, AND DIAGNOSIS, AND THE CLASSIFICATION OF CEREBRAL PALSY. PROBLEMS OFTEN ASSOCIATED WITH CEREBRAL PALSY…

  16. In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Mathieu D. Santin

    2016-03-01

    Full Text Available Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here we have used in vivo gadolinium-stained high resolution (29*29*117µm3 MRI to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952 directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-month-old animals, but not in 5.5-month animals compared to mice treated with a control antibody (DM4. Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-month SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

  17. The Synthesis of 1,4,7-Triazacyclononane Conjugated Amyloid-phillic Compound and Its Binding Affinity to the β-Amyloid Fibril

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Jong Min; Jo, Jee Hye [Sejong University, Seoul (Korea, Republic of)

    2003-09-15

    The development of new compounds which have affinity for the β-amyloid fibril would lead to the new compounds that could have therapeutic effects on AD. Previously, we generated new amyloid-phillic amide derivative of Chrysamine G and found that this compound protect human astrocyte cells against Aβ-induced toxicity. As conjugation of amyloid-philic molecules with suitable metal chelating ligands could lead to new diagnostic molecules for in vivo quantification of amyloid deposition and new probes for amyloid structure, we designed the compound, which was conjugate of 1,4,7-triazacyclo-nonane and the amyloid-philic compound 1. Here, we would like to report the synthesis of compound 2 and its binding property of β-amyloid fibril. The synthesis of compound was achieved by combining three fragments the biphenyl amine, isophthalic acid 5 and 1,4,7-triazacyclononane. The synthesis of isophthalic acid part 5 commenced with esterfication of isophthalic acid in methanol with HCl to produce the monoester 4 in 38% yield. Treatment of the monoester 4 with oxalyl chloride afforded the acyl chloride 5 in 95% yield.

  18. Clues for divergent, polymorphic amyloidogenesis through dissection of amyloid forming steps of bovine carbonic anhydrase and its critical amyloid forming stretch.

    Science.gov (United States)

    Garg, Dushyant Kumar; Kundu, Bishwajit

    2016-07-01

    Certain amino acid stretches are considered 'critical' to trigger amyloidogenesis in a protein. Synthetic peptides corresponding to these stretches are often used as experimental mimics for studying the amyloidogenesis of their parent protein. Here we provide evidence that such simple extrapolation is misleading. We scrutinized each step of amyloid progression of full length bovine carbonic anhydrase (BCA) and compared it with the amyloidogenic process of its critical peptide stretch 201-227 (PepB). We found that under similar solution conditions amyloidogenesis of BCA followed surface-catalyzed secondary nucleation, whereas, that of PepB followed classical nucleation-dependent pathway. AFM images showed that while BCA formed short, thick and branched fibrils, PepB formed thin, long and unbranched fibrils. Structural information obtained by ATR-FTIR spectroscopy suggested parallel arrangement of intermolecular β-sheet in BCA amyloids in contrast to PepB amyloids which arranged into antiparallel β sheets. Amyloids formed by BCA were unable to seed the fibrillation of PepB and vice versa. Even the intermediates formed during lag phase revealed contrasting FTIR and far UV CD signature, hydrophobicity, morphology and cell cytotoxicity. Thus, we propose that sequences other than critical amyloidogenic stretches may significantly influence the initiation, polymerization and final fibrillar morphology of amyloid forming protein. The results have been discussed in light of primary sequence mediated amyloid polymorphism and its importance in the rational design of amyloid nanomaterials possessing desired physico-chemical properties. PMID:27045222

  19. First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

    Science.gov (United States)

    Cummings, Damian M; Liu, Wenfei; Portelius, Erik; Bayram, Sevinç; Yasvoina, Marina; Ho, Sui-Hin; Smits, Hélène; Ali, Shabinah S; Steinberg, Rivka; Pegasiou, Chrysia-Maria; James, Owain T; Matarin, Mar; Richardson, Jill C; Zetterberg, Henrik; Blennow, Kaj; Hardy, John A; Salih, Dervis A; Edwards, Frances A

    2015-07-01

    Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly

  20. Animal models of cerebral ischemia

    Science.gov (United States)

    Khodanovich, M. Yu.; Kisel, A. A.

    2015-11-01

    Cerebral ischemia remains one of the most frequent causes of death and disability worldwide. Animal models are necessary to understand complex molecular mechanisms of brain damage as well as for the development of new therapies for stroke. This review considers a certain range of animal models of cerebral ischemia, including several types of focal and global ischemia. Since animal models vary in specificity for the human disease which they reproduce, the complexity of surgery, infarct size, reliability of reproduction for statistical analysis, and adequate models need to be chosen according to the aim of a study. The reproduction of a particular animal model needs to be evaluated using appropriate tools, including the behavioral assessment of injury and non-invasive and post-mortem control of brain damage. These problems also have been summarized in the review.

  1. Chinese semantic processing cerebral areas

    Institute of Scientific and Technical Information of China (English)

    SHAN Baoci; ZHANG Wutian; MA Lin; LI Dejun; CAO Bingli; TANG Yiyuan; WU Yigen; TANG Xiaowei

    2003-01-01

    This study has identified the active cerebral areas of normal Chinese that are associated with Chinese semantic processing using functional brain imaging. According to the traditional cognitive theory, semantic processing is not particularly associated with or affected by input modality. The functional brain imaging experiments were conducted to identify the common active areas of two modalities when subjects perform Chinese semantic tasks through reading and listening respectively. The result has shown that the common active areas include left inferior frontal gyrus (BA 44/45), left posterior inferior temporal gyrus (BA37); the joint area of inferior parietal lobules (BA40) and superior temporal gyrus, the ventral occipital areas and cerebella of both hemispheres. It gives important clue to further discerning the roles of different cerebral areas in Chinese semantic processing.

  2. Cerebral calcifications and schizophreniform disorder

    Directory of Open Access Journals (Sweden)

    Leonardo Fernandez Meyer

    2013-01-01

    Full Text Available OBJECTIVES: Discuss pathophysiological aspects of cerebral calcifications (CC and highlight its importance related to the occurrence of neuropsychiatric syndromes. METHOD: Single case report. RESULT: Man 52 years old, 20 years after going through a total thyroidectomy, starts showing behavioral disturbance (psychotic syndrome. He was diagnosed as schizophrenic (paranoid subtype and submitted to outpatient psychiatric treatment. During a psychiatric admission to evaluate his progressive cognitive and motor deterioration, we identified a dementia syndrome and extensive cerebral calcifications, derived from iatrogenic hypoparathyroidism. CONCLUSION: The calcium and phosphorus disturbances, including hypoparathyroidism, are common causes of CC. Its symptoms can imitate psychiatric disorders and produce serious and permanent cognitive sequelae. The exclusion of organicity is mandatory in any psychiatric investigative diagnosis in order to avoid unfavorable outcomes, such as in the present case report.

  3. Complete Genome Sequence of Pseudomonas sp. UK4, a Model Organism for Studies of Functional Amyloids in Pseudomonas

    OpenAIRE

    Dueholm, Morten Simonsen; Danielsen, Heidi Nolsøe; Nielsen, Per Halkjær

    2014-01-01

    Here, we present the complete genome of Pseudomonas sp. UK4. This bacterium was the first Pseudomonas strain shown to produce functional amyloids, and it represents a model organism for studies of functional amyloids in Pseudomonas (Fap).

  4. Bilateral posterior cerebral artery infarction.

    Science.gov (United States)

    Ryan, Davinia; Murphy, Sinead M; Hennessey, Michael J

    2010-01-01

    We report the case of a 70-year-old man who presented with short-term memory impairment and a homonymous left inferior quadrantanopia secondary to simultaneous bilateral posterior cerebral artery (PCA) territory infarction. As in more than a quarter of cases of PCA infarction, no aetiological cause was identified. Unlike the transient nature of symptoms in some cases following unilateral infarction, his deficits persisted on 2-month follow-up. PMID:22798298

  5. Clinical studies on cerebral infarction

    International Nuclear Information System (INIS)

    Hemorrhagic infarction (HI) is termed as the infarction in which a large part of the necrotic tissue is stippled with small hemorrhage. The pathogenetic mechanism of this disease still remains controversial. Cerebral infarction has long been divided into two subtypes-thrombosis and embolism-according to the pathogenetic mechanisms. Clinical studies were carried out in 31 cases of HI with cerebral thrombosis. CT findings of these cases were classified into five groups according to both size of low density area which indicates regions of infarction and distribution of arterial supply. The low density area of Type I-Type III were observed in the area of the middle cerebral artery. That of Type IV was observed in the area of the internal capsule and basal ganglia. That of Type V was observed in the area of the posterior cerebral artery. CT reveals two patterns of HI -pattern A and pattern B-. The CT finding of pattern A is appearance of high density area in the low density area. The CT finding of pattern B is appearance of iso density area in the low density area. rCBF was measured by 133Xe inhalation technique in 21 patients with CT type I, II and III. Thereafter, with regard to the various findings in CT, the clinical findings and CBF findings, a comparative study was carried out on these ten groups. From the results of present studies, it is concluded that sequential changes of CBF in cases with pattern A are different from those with pattern B, and that CBF measurement does not permit an estimation of a patient's chance for functionary recovery after a stroke in acute and subacute stage but permits estimation of functional outcome in chronic stage. (J.P.N.)

  6. Cerebral palsy and neonatal encephalopathy.

    OpenAIRE

    Gaffney, G; Flavell, V; Johnson, A; Squier, M.; Sellers, S

    1994-01-01

    A retrospective cohort study was carried out to test the hypothesis that children born at term with cerebral palsy with signs of neurological dysfunction preceded by depression at birth (termed neonatal encephalopathy) differ from those without such signs in the frequency of antenatal and perinatal factors, and in the severity and characteristics of their impairment and disability. The study was carried out in the area covered by Oxford Regional Health Authority. Antenatal, intrapartum, neona...

  7. Visual disorders in cerebral palsy

    OpenAIRE

    Govind Amita; Lamba P

    1988-01-01

    Seventy children with cere-bral palsy were examined for aetiological factors responsible, type of disorder and ocular abnormalities. The overall inci-dence of ocular abnormalities was 68.69%, the highest frequency being of squint (35.7%). Other anomalies detected inclu-ded refractive errors (28.5%), optic atrophy (10%) and coloboma (2.9%). Most children were spastic quadriplegics with asphyxia as the major aetiological factor. The study created an awareness ...

  8. Primary cerebral lymphoma: radiological findings

    International Nuclear Information System (INIS)

    We present four cases of primary cerebral lymphoma in non-immunodepressed adult patients. All cases were dsemonstrated with pathological study. CAT study showed solitary or multiple isodense lesions, which incorporated avidly and homoneneously the contrast. Arteriography performed in three patients and magnetic resonance, performed in one did not help for diagnosis. We also review the radiological findings obtained with different imaging methods, and suggest the criteria which could be useful for early diagnosis (Author)

  9. Baclofen in Spastic Cerebral Palsy

    OpenAIRE

    J Akhundian

    2002-01-01

    To evaluate the effect of oral baclofen in spastic cerebral palsy (cp), we studied 40 children with different clinical types of spastic cp. Half of these children served as control group and the others received oral baclofen. All of them were treated with physiotherapy under equal conditions for 6 weeks. We used two methods, modified Ashworth scale and range of motion for evaluation. At the end of therapy we found a significant improvement in the baclofen group compared to control group. As a...

  10. Cerebral palsy in preterm infants

    OpenAIRE

    Demeši-Drljan Čila; Mikov Aleksandra; Filipović Karmela; Tomašević-Todorović Snežana; Knežević Aleksandar; Krasnik Rastislava

    2016-01-01

    Background/Aim. Cerebral palsy (CP) is one of the leading causes of neurological impairment in childhood. Preterm birth is a significant risk factor in the occurrence of CP. Clinical outcomes may include impairment of gross motor function and intellectual abilities, visual impairment and epilepsy. The aim of this study was to examine the relationships among gestational age, type of CP, functional ability and associated conditions. Methods. The sample size w...

  11. Cerebral Palsy: A Dental Update

    OpenAIRE

    Sehrawat, Nidhi; Marwaha, Mohita; Bansal, Kalpana; Chopra, Radhika

    2014-01-01

    ABSTRACT Special and medically compromised patients present a unique population that challenges the dentist’s skill and knowledge. Providing oral care to people with cerebral palsy (CP) requires adaptation of the skills we use everyday. In fact, most people with mild or moderate forms of CP can be treated successfully in the general practice setting. This article is to review various dental considerations and management of a CP patient. How to cite this article: Sehrawat N, Marwaha M, Bansal ...

  12. Acute hypoxia increases the cerebral metabolic rate

    DEFF Research Database (Denmark)

    Vestergaard, Mark Bitsch; Lindberg, Ulrich; Aachmann-Andersen, Niels Jacob;

    2016-01-01

    imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N......-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.......058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% ([Formula: see text]), glutamate increased by 4.7% ([Formula: see text]) and creatine and phosphocreatine decreased by 15.2% (p[Formula: see text]). The N-acetylaspartate concentration...

  13. Behcet's disease with cerebral vasculitis

    International Nuclear Information System (INIS)

    The case presented illustrates the diagnostic dilemma off neurological involvement in Behcet's disease and other inflammatory diseases. 'Psychiatric' symptoms were present for 2 years without abnormalities on SPECT or MRI and without CSF pleocytosis. Even at the time of fitting, no CSF abnormalities were observed. The preceding psychiatric presentations may have been due to cerebral vasculitis that was exacerbated by withdrawal of steroids. Magnetic resonance imaging is currently the most sensitive imaging modality. Lesions are usually in the brainstem, cerebellum, basal ganglia region or periventricular white matter, and the pons and the mesencephalon are commonly affected. In our patient there was no diencephalic or brainstem involvement. The inflammatory process can appear as a very large lesion, with gadolinium enhancement and significant mass effect, as in our patient. Brain magnetic resonance imaging. Postgadolinium-diethylenetriamine pentaacetic acid, axial image shows two large lesions in the right frontal lobe, with the larger, posterior lesion demonstrating vivid ring enhancement. A central nodule is isodense, with the cerebral white matter within the larger lesion. Surrounding low T1 signal involves the hemispheric white matter without cortical extension and is consistent with vasogenic oedema. Minor mass effect is demonstrated with bowing of the anterior falx cerebri to the left. Biopsy shows prominent fibrinoid necrosis in small calibre postcapillary venules and cerebral white matter. There are surrounding acute and chronic inflammatory cells and nuclear debris, consistent with vasculitis

  14. MR findings of cerebral palsy

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Sang Hum; Chang, Seung Kuk; Cho, Mee Young; Park, Dong Woo; Kim, Jong Deok; Eun, Choong Ki [Pusan Paik Hospital, Pusan (Korea, Republic of)

    1994-11-15

    To evaluate the MR findings of brain damage in cerebral palised patients and to correlate it with gestational age and the time of damage. A retrospective analysis was performed in 40 patients who underwent MR scanning for evaluation of brain lesion in clinically diagnosed cerebral palsy. Authors classified the patients into two groups as premature and full-term and compared MR findings of the two groups. Abnormal MR findings were noted in 28 cases (70%). Five out of 6 patients who had been born prematurely showed isolate periventricular white matter lesions. Twenty-three out of 34 patients who had been born at full-term showed abnormal MR findings. Of these 23 patients, migration anomalies in 7 patients, isolate periventricular white matter lesions in 3 patients, and other combined periventricular subcortical white matter and deep gray matter lesions in 14 patients were seen. At least, 10 patients(43%) of full term group showed abnormal MRI findings reflecting intrauterine brain damage and all 5 patients of premature group showed isolate periventricular white matter lesions suggesting immaturity of brain. MRI is thought to be very useful in the assessment of brain damage for the patients with cerebral palsy by recognizing the location of the lesion and estimating the time of damage.

  15. MR findings of cerebral palsy

    International Nuclear Information System (INIS)

    To evaluate the MR findings of brain damage in cerebral palised patients and to correlate it with gestational age and the time of damage. A retrospective analysis was performed in 40 patients who underwent MR scanning for evaluation of brain lesion in clinically diagnosed cerebral palsy. Authors classified the patients into two groups as premature and full-term and compared MR findings of the two groups. Abnormal MR findings were noted in 28 cases (70%). Five out of 6 patients who had been born prematurely showed isolate periventricular white matter lesions. Twenty-three out of 34 patients who had been born at full-term showed abnormal MR findings. Of these 23 patients, migration anomalies in 7 patients, isolate periventricular white matter lesions in 3 patients, and other combined periventricular subcortical white matter and deep gray matter lesions in 14 patients were seen. At least, 10 patients(43%) of full term group showed abnormal MRI findings reflecting intrauterine brain damage and all 5 patients of premature group showed isolate periventricular white matter lesions suggesting immaturity of brain. MRI is thought to be very useful in the assessment of brain damage for the patients with cerebral palsy by recognizing the location of the lesion and estimating the time of damage

  16. Parental age, genetic mutation, and cerebral palsy.

    OpenAIRE

    Fletcher, N A; Foley, J

    1993-01-01

    Parental age and birth order were studied in 251 patients with cerebral palsy. No parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia. These observations indicate that some cases of athetoid/dystonic or hemiplegic cerebral palsy might arise by fresh dominant genetic mutation.

  17. Cerebral palsy in very low birthweight infants.

    OpenAIRE

    Cooke, R W

    1990-01-01

    Eighty one very low birthweight survivors with cerebral palsy were matched with controls by sex, gestational age, and place of birth. Using discriminant analysis, the perinatal profiles for infants with cerebral palsy and their controls were shown to differ significantly. When infants with various types of cerebral palsy were analysed with their controls the discriminating variables differed. Diplegic infants could be differentiated from controls on antenatal variables alone, but significant ...

  18. Evaluation measures for children with cerebral palsy

    OpenAIRE

    Sršen, Katja Groleger

    2013-01-01

    Abstract. Cerebral palsy is a well-recognized neurodevelopmental condition. The most recentdefinition describes cerebral palsy as a group of disorders of movement andposture, causing activity limitation. An important step in the process of(re)habilitation is evaluation of functional abilities of an individual. To beas accurate as possible in the evaluation of functioning, proper measurementinstruments have to be used. There are many different measurement tools forchildren with cerebral palsy,...

  19. Dental characteristics of children with cerebral palsy

    OpenAIRE

    Stevanović Radoje; Jovičić Olivera

    2004-01-01

    Cerebral palsy is one of the commonest children's physical handicaps with frequency of 1.5-3/1000. Beside many other disturbances, these children may have serious disorders caused by dental diseases. Concerning this fact, the objective of our study was to examine children with cerebral palsy in our country and determine condition of dental health and suggest adequate protective measures. A total of 116 children, 3-18 years old, with cerebral palsy were examined and the results were compared t...

  20. Epilepsy in children with cerebral palsy

    OpenAIRE

    J Akhundian

    2013-01-01

    Epilepsy occurs in 15-60% of children with cerebral palsy (CP). However, its clinical course is not well defined. This retrospective study reviews the prevalence, nature and prognosis of epilepsy in cerebral palsy. 53 of 133 children with cerebral palsy seen in the neuropediatric clinic in Mashhad emam Reza hospital between 1999 and 2001 had epilepsy. A control group of 70 epileptic children with normal neurodevelopment status was seen during the same period. Epilepsy most commonly affected p...

  1. Epilepsy in children with cerebral palsy

    OpenAIRE

    Bruck Isac; Antoniuk Sérgio Antônio; Spessatto Adriane; Bem Ricardo Schmitt de; Hausberger Romeu; Pacheco Carlos Gustavo

    2001-01-01

    OBJECTIVE: To describe the prevalence and characteristics of epilepsy in patients with cerebral palsy in a tertiary center. METHODS: a total of 100 consecutive patients with cerebral palsy were retrospectively studied. Criteria for inclusion were follow-up period for at least 2 years. Types and incidence of epilepsy were correlated with the different forms of cerebral palsy. Other factors associated with epilepsy such as age of first seizure, neonatal seizures and family history of epilepsy w...

  2. Cerebral energy metabolism during induced mitochondrial dysfunction

    DEFF Research Database (Denmark)

    Nielsen, T H; Bindslev, TT; Pedersen, S M;

    2013-01-01

    In patients with traumatic brain injury as well as stroke, impaired cerebral oxidative energy metabolism may be an important factor contributing to the ultimate degree of tissue damage. We hypothesize that mitochondrial dysfunction can be diagnosed bedside by comparing the simultaneous changes in...... brain tissue oxygen tension (PbtO(2)) and cerebral cytoplasmatic redox state. The study describes cerebral energy metabolism during mitochondrial dysfunction induced by sevoflurane in piglets....

  3. Assessment of the hand in cerebral palsy

    OpenAIRE

    Praveen Bhardwaj; S Raja Sabapathy

    2011-01-01

    Cerebral palsy is the musculoskeletal manifestation of a nonprogressive central nervous system lesion that usually occurs due to a perinatal insult to the brain. Though the cerebral insult is static the musculoskeletal pathology is progressive. Some patients with cerebral palsy whose hands are affected can be made better by surgery. The surgical procedures as such are not very technically demanding but the assessment, decision-making, and selecting the procedures for the given patient make th...

  4. Prevalence of amyloid deposition in mature healthy chickens in the flock that previously had outbreaks of vaccine-associated amyloidosis

    OpenAIRE

    IBI, Kanata; MURAKAMI, Tomoaki; GODA, Wael Mohamed; Kobayashi, Naoki; ISHIGURO, Naotaka; Yanai, Tokuma

    2015-01-01

    Avian amyloid A (AA) amyloidosis is commonly observed in adult birds with chronic inflammation, such as that caused by bacterial infection. We previously described vaccine-associated AA amyloidosis in juvenile chickens. In this study, the prevalence of amyloid deposition was measured in mature healthy chickens that survived a previous outbreak of avian AA amyloidosis while they were juveniles. Herein, we analyzed the amyloid deposition in mature chickens and compared the prevalence of amyloid...

  5. Cerebral Palsy. Fact Sheet = La Paralisis Cerebral. Hojas Informativas Sobre Discapacidades.

    Science.gov (United States)

    National Information Center for Children and Youth with Disabilities, Washington, DC.

    This fact sheet on cerebral palsy is written in both English and Spanish. First, it provides a definition of cerebral palsy and considers various causes (e.g., an insufficient amount of oxygen reaching the fetal or newborn brain). The fact sheet then offers incidence figures and explains characteristics of the three main types of cerebral palsy:…

  6. A study on the pathogenesis of human cerebral malaria and cerebral babesiosis

    Directory of Open Access Journals (Sweden)

    Masamichi Aikawa

    1992-01-01

    Full Text Available Cerebral complications are important, but poorly understood pathological features of infections caused by some species of Plasmodium and Babesia. Patients dying from P. falciparum were classified as cerebral or non-cerebral cases according to the cerebral malaria coma scale. Light microscopy revealed that cerebral microvessels of cerebral malaria patients were field with a mixture of parazited and unparazited erythrocytes, with 94% of the vessels showing parasitized red blood cell (PRBC sequestration. Some degree of PRBC sequestration was also found in non-cerebral malaria patients, but the percentage of microvessls with sequestered PRBC was only 13% Electron microscopy demonstrated knobs on the membrane of PRBC that formed focal junctions with the capillary endothelium. A number of host cell molecules such as CD36, thrombospondim (TSP and intracellular adhesion molecule I (ICAM-1 may function as endothelial cell surfacereports for P. falciparum-infected erythrocytes. Affinity labeling of CD36 and TSP to the PRBC surface showed these molecules specifically bind to the knobs. Babesia bovis infected erythrocytes procedure projections of the erythrocyte membrane that are similar to knobs. When brain tissue from B. bovis-infected cattle was examined, cerebral capillaries were packed with PRBC. Infected erythrocytes formed focal attachments with cerebral endothelial cells at the site of these knob-like projections. These findings indicate that cerebral pathology caused by B. bovis is similar to human cerebral malaria. A search for cytoadherence proteins in the endothelial cells may lead to a better understanding of the pathogenisis of cerebral babesiosis.

  7. Magnetic resonance imaging (MRI) of cerebral infarction

    International Nuclear Information System (INIS)

    Fifty-five patients with cerebral infarction were studied with magnetic resonance imaging (MRI) and correlative CT scans. MRI was more sensitive than CT for detecting cerebral infarction, and T2-weighted spin-echo (SE) pulse sequence was most sensitive for detecting cerebral infarction except for some subcortical infarction. The size of infarcted areas on MRI was larger than that on CT in 29 of 51 infarcted areas, equal in 22. The pulse sequence using long repetition time (TR) and double echo delay time (TE), such as SE (2000/30, 90), improved the detectability of cerebral infarction. (author)

  8. Acute cerebral vascular accident associated with hyperperfusion

    International Nuclear Information System (INIS)

    Cerebral radionuclide angiography can demonstrate decreased or normal radioactivity in the affected region during the arterial phase in patients who have sustained a cerebral vascular accident and thus enhances the diagnostic specificity of the static brain image. In an occasional patient, however, a seemingly paradoxical pattern of regional hyperperfusion with a return to normal or subnormal perfusion following the acute phase has been observed. This phenomenon, called luxury perfusion, has been defined using intra-arterial 133Xe for semiquantitative cerebral blood flow measurements and should be kept in mind as a potentially misleading cerebral imaging pattern

  9. Cerebritis: An unusual complication of Klebsiella pneumoniae

    Directory of Open Access Journals (Sweden)

    Majumdar Mainak

    2009-01-01

    Full Text Available Cerebritis is part of a continuum of brain infection and is difficult to diagnose. Cerebritis caused by Klebsiella in immunocompetent adults without predisposing factors such as neurosurgery or penetrating brain injury has not been reported before. We report a case of Klebsiella cerebritis in an adult patient with a proven extracranial focus of infection. We suggest considering cerebritis as a differential diagnosis for altered level of consciousness in patients of severe sepsis, even if an extracranial source of infection is proven.

  10. Depletion of spleen macrophages delays AA amyloid development: a study performed in the rapid mouse model of AA amyloidosis.

    Directory of Open Access Journals (Sweden)

    Katarzyna Lundmark

    Full Text Available AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM, marginal zone macrophages (MZM, metallophilic marginal zone macrophages (MMZM. MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.

  11. Curcumin as an Amyloid-indicator Dye in E. coli †

    OpenAIRE

    McCrate, Oscar A.; Zhou, Xiaoxue; Cegelski, Lynette

    2013-01-01

    We have demonstrated that curcumin is an amyloid-specific dye in E. coli. Curcumin binds to curliated whole cells and to isolated curli amyloid fibers. Similar to Congo red, curcumin exhibits a red-shift in absorbance and a significant increase in fluorescence upon binding to isolated curli.

  12. A new prealbumin variant in familial amyloid cardiomyopathy of Danish origin.

    Science.gov (United States)

    Nordlie, M; Sletten, K; Husby, G; Ranløv, P J

    1988-01-01

    A C-terminal fragment of a prealbumin variant was isolated from amyloid material obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin. The prealbumin variant fragment was shown to have a methionine for leucine substitution in position 111. PMID:3340821

  13. Experimentally derived structural constraints for amyloid fibrils of wild-type transthyretin.

    Science.gov (United States)

    Bateman, David A; Tycko, Robert; Wickner, Reed B

    2011-11-16

    Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region exposing the two main β-sheets of the protein for fibril elongation. However, we find that the wild-type TTR sequence forms amyloid fibrils that are considerably different from the previously suggested amyloid structure. Using protease digestion with mass spectrometry, we observe the amyloid core to be primarily composed of the C-terminal region, starting around residue 50. Solid-state NMR measurements prove that TTR differs from other pathological amyloids in not having an in-register parallel β-sheet architecture. We also find that the TTR amyloid is incapable of binding thyroxine as monitored by either isothermal calorimetry or 1,8-anilinonaphthalene sulfonate competition. Taken together, our experiments are consistent with a significantly different configuration of the β-sheets compared to the previously suggested structure. PMID:22098747

  14. Protein Folding and Aggregation into Amyloid: The Interference by Natural Phenolic Compounds

    Directory of Open Access Journals (Sweden)

    Massimo Stefani

    2013-06-01

    Full Text Available Amyloid aggregation is a hallmark of several degenerative diseases affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils and final mature fibrils display different toxicity. Consequently, compounds counteracting amyloid aggregation have been investigated for their ability (i to stabilize toxic amyloid precursors; (ii to prevent the growth of toxic oligomers or speed that of fibrils; (iii to inhibit fibril growth and deposition; (iv to disassemble preformed fibrils; and (v to favor amyloid clearance. Natural phenols, a wide panel of plant molecules, are one of the most actively investigated categories of potential amyloid inhibitors. They are considered responsible for the beneficial effects of several traditional diets being present in green tea, extra virgin olive oil, red wine, spices, berries and aromatic herbs. Accordingly, it has been proposed that some natural phenols could be exploited to prevent and to treat amyloid diseases, and recent studies have provided significant information on their ability to inhibit peptide/protein aggregation in various ways and to stimulate cell defenses, leading to identify shared or specific mechanisms. In the first part of this review, we will overview the significance and mechanisms of amyloid aggregation and aggregate toxicity; then, we will summarize the recent achievements on protection against amyloid diseases by many natural phenols.

  15. Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity : Relevance to Alzheimer's disease

    NARCIS (Netherlands)

    Harkany, T; Hortobagyi, T; Sasvari, M; Konya, C; Penke, B; Luiten, PGM; Nyakas, C

    1999-01-01

    1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition arid processing, and memory formation. A beta fragments are producedin a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor prot

  16. Neuroprotective Approaches in Experimental Models of β-Amyloid Neurotoxicity : Relevance to Alzheimer's Disease

    NARCIS (Netherlands)

    Harkany, Tibor; Hortobágyi, Tibor; Sasvári, Maria; Kónya, Csaba; Penke, Botond; Luiten, Paul G.M.; Nyakas, Csaba

    1999-01-01

    1. β-Amyloid peptides (Aβs) accumulate abundantly in the Alzheimer’s disease (AD) brain in areas subserving information acquisition and processing, and memory formation. Aβ fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). W

  17. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

    NARCIS (Netherlands)

    Lee, Jiyeon; Retamal, Claudio; Cuitino, Loreto; Caruano-Yzermans, Amy; Shin, Jung-Eun; van Kerkhof, Peter; Marzolo, Maria-Paz; Bu, Guojun

    2008-01-01

    Accumulation of extracellular amyloid beta peptide (A beta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of A beta from APP is greatly affected by the subcellular loca

  18. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that dena

  19. Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer's Disease Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Christina Rose Kyrtsos

    Full Text Available Alzheimer's disease (AD is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ deposition and the presence of neurofibrillary tangles (NFTs within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain.

  20. Solanezumab for the treatment of mild-to-moderate Alzheimer's disease.

    Science.gov (United States)

    Imbimbo, Bruno P; Ottonello, Simone; Frisardi, Vincenza; Solfrizzi, Vincenzo; Greco, Antonio; Seripa, Davide; Pilotto, Alberto; Panza, Francesco

    2012-02-01

    Solanezumab (LY2062430) is a humanized monoclonal antibody that binds to the central region of β-amyloid, a peptide believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Eli Lilly & Co is developing an intravenous formulation of solanezumab for the treatment of mild-to-moderate AD. Acute and subchronic treatment with solanezumab of transgenic mice attenuated or reversed memory deficits with no effects on incidence or severity of cerebral amyloid angiopathy-associated microhemorrhages, a severe side effect associated with bapineuzumab, another monoclonal antibody. Phase II studies in AD patients have shown a good safety profile with encouraging indications on cerebrospinal and plasma biomarkers. The drug is currently being investigated in Phase III trials. While there is a strong hope that solanezumab may represent the first effective passive vaccine for AD treatment, skepticism still exists on the ability of the drug to slow the rate of deterioration in patients with fully established disease. PMID:22288451