Home About us Contact
|
Home About us Contact | ||
|
|
||
Amyloid Deposition (amyloid + deposition)
Selected AbstractsCognition, reserve, and amyloid deposition in normal agingANNALS OF NEUROLOGY, Issue 3 2010Dorene M. Rentz PsyD Objective To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association. Methods In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies. Results We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test. Interpretation Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment. ANN NEUROL 2010;67:353,364 [source] ,-cell preservation: a potential role for thiazolidinediones to improve clinical care in Type 2 diabetesDIABETIC MEDICINE, Issue 8 2005L. A. Leiter Abstract Type 2 diabetes is caused by progressively increasing insulin resistance coupled with deteriorating ,-cell function, and there is a growing body of evidence to suggest that both of these defects precede hyperglycaemia by many years. Several studies have demonstrated the importance of maintaining ,-cell function in patients with Type 2 diabetes. This review explores parameters used to indicate ,-cell dysfunction, in Type 2 diabetes and in individuals with a predisposition to the disease. A genetic element undoubtedly underlies ,-cell dysfunction; however, a number of modifiable components are also associated with ,-cell deterioration, such as chronic hyperglycaemia and elevated free fatty acids. There is also evidence for a link between pro-inflammatory cytokines and impairment of insulin-signalling pathways in the ,-cell, and the potential role of islet amyloid deposition in ,-cell deterioration continues to be a subject for debate. The thiazolidinediones are a class of agents that have demonstrated clinical improvements in indices of ,-cell dysfunction and have the potential to improve ,-cell function. Data are accumulating to show that this therapeutic group offers a number of advantages over traditionally employed oral agents, and these data demonstrate the growing importance of thiazolidinediones in Type 2 diabetes management. [source] Age-dependent cognitive decline in the APP23 model precedes amyloid depositionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2003Debby Van Dam Abstract Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6,8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-,1,42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-,1,42 peptides, but probe trial performance did correlate negatively with soluble amyloid-, brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model. [source] Classical and alternative pathway complement activation are not required for reactive systemic AA amyloid deposition in miceIMMUNOLOGY, Issue 2 2004Winston L. Hutchinson Summary During induction of reactive systemic amyloid A protein (AA) amyloidosis in mice, either by chronic inflammation or by severe acute inflammation following injection of amyloid enhancing factor, the earliest deposits form in a perifollicular distribution in the spleen. Because the splenic follicular localization of immune complexes and of the scrapie agent are both complement dependent in mice, we investigated the possible complement dependence of AA amyloid deposition. In preliminary experiments, substantial depletion of circulating C3 by cobra venom factor had little effect on experimental amyloid deposition. More importantly, mice with targeted deletion of the genes for C1q or for both factor B and C2, and therefore unable to sustain activation, respectively, of either the classical complement pathway or both the classical and alternative pathways, showed amyloid deposition similar to wild type controls. Complement activation by either the classical or alternative pathways is thus not apparently necessary for the experimental induction of systemic AA amyloid in mice. [source] Potential implications of endogenous aldehydes in ,-amyloid misfolding, oligomerization and fibrillogenesisJOURNAL OF NEUROCHEMISTRY, Issue 5 2006Kun Chen Abstract Aldehydes are capable of inducing protein cross-linkage. An increase in aldehydes has been found in Alzheimer's disease. Formaldehyde and methylglyoxal are produced via deamination of, respectively, methylamine and aminoacetone catalyzed by semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6. The enzyme is located on the outer surface of the vasculature, where amyloidosis is often initiated. A high SSAO level has been identified as a risk factor for vascular disorders. Serum SSAO activity has been found to be increased in Alzheimer's patients. Malondialdehyde and 4-hydroxynonenal are derived from lipid peroxidation under oxidative stress, which is also associated with Alzheimer's disease. Aldehydes may potentially play roles in ,-amyloid aggregation related to the pathology of Alzheimer's disease. In the present study, thioflavin-T fluorometry, dynamic light scattering, circular dichroism spectroscopy and atomic force microscopy were employed to reveal the effect of endogenous aldehydes on ,-amyloid at different stages, i.e. ,-sheet formation, oligomerization and fibrillogenesis. Formaldehyde, methylglyoxal and malondialdehyde and, to a lesser extent, 4-hydroxynonenal are not only capable of enhancing the rate of formation of ,-amyloid ,-sheets, oligomers and protofibrils but also of increasing the size of the aggregates. The possible relevance to Alzheimer's disease of the effects of these aldehydes on ,-amyloid deposition is discussed. [source] Advanced glycation endproducts and pro-inflammatory cytokines in transgenic Tg2576 mice with amyloid plaque pathologyJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Gerald Münch Abstract Increased expression and altered processing of the amyloid precursor protein (APP) and generation of ,-amyloid peptides is important in the pathogenesis of amyloid plaques in Alzheimer's disease (AD). Transgenic Tg2576 mice overexpressing the Swedish mutation of human APP exhibit ,-amyloid deposition in the neocortex and limbic areas, accompanied by gliosis and dystrophic neurites. However, murine plaques appear to be less cross-linked and the mice show a lower degree of inflammation and neurodegeneration than AD patients. ,Advanced glycation endproducts (AGEs)', formed by reaction of proteins with reactive sugars or dicarbonyl compounds, are able to cross-link proteins and to activate glial cells, and are thus contributing to plaque stability and plaque-induced inflammation in AD. In this study, we analyze the tissue distribution of AGEs and the pro-inflammatory cytokines IL-1, and TNF-, in 24-month-old Tg2576 mice, and compare the AGE distribution in these mice with a younger age group (13 months old) and a typical Alzheimer's disease patient. Around 70% of the amyloid plaque cores in the 24-month-old mice are devoid of AGEs, which might explain their solubility in physiological buffers. Plaque associated glia, which express IL-1, and TNF-,, contain a significant amount of AGEs, suggesting that plaques, i.e. A, as its major component, can induce intracellular AGE formation and the expression of the cytokines on its own. In the 13-month-old transgenic mice, AGEs staining can neither be detected in plaques nor in glial cells. In contrast, AGEs are present in high amounts in both plaques and glia in the human AD patient. The data obtained in this show interesting differences between the transgenic mouse model and AD patients, which should be considered using the transgenic approach to test therapeutical strategies to eliminate plaques or to attenuate the inflammatory response in AD. [source] Marginal zone B-cell lymphoma of minor salivary gland representing tumor-forming amyloidosis of the oral cavity.JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 5 2006A case report We report here a case of mucosa-associated lymphoid tissue (MALT)-type lymphoma arising from the minor salivary gland of the oral cavity exhibiting tumor-forming amyloidosis. The patient was a 64-year-old Japanese woman who presented with 4-year history of a left soft palate mass. Despite multiple and multifocal recurrences including the lip, soft palate, tongue, oral base and vocal code and soft palate, the tumor remained localized in the upper aerodigestive tract, and the patient did not develop multiple myeloma during the course of disease. Histologically, the majority of the lesion was occupied by amyloid deposition. Only the periphery of the lesion contained numerous plasmacytoid cells, along with occasional centrocyte-like cells. In addition, lymphoepithelial lesion and follicular colonization were noted. The present case indicates that primary minor salivary gland MALT-type lymphoma appears to be the cause of tumor-forming amyloidosis of the upper aerodigestive tract including the larynx. [source] Transthyretin-derived amyloid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liverLIVER TRANSPLANTATION, Issue 2 2007Yo-ichi Takei Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required. Liver Transpl, 2006. © 2006 AASLD. [source] Cerebral amyloid angiopathy: An overviewNEUROPATHOLOGY, Issue 1 2000Masahito Yamada Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid ,-protein (A,), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of A, type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives. [source] Genetic,morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathyNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2005M. Christoforidis Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in ,-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5, polymorphism (LRP5,) is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with, the, severity, of, CAAlep., and, CAAcort.,, implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5,87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition. [source] Familial British dementia (FBD): a cerebral amyloidosis with systemic amyloid depositionNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2002J. L. Holton Introduction:, FBD is an autosomal dominant disease with neuropathological similarities to Alzheimer's disease (AD) as it is characterized by amyloid angiopathy, parenchymal amyloid plaque deposition and neurofibrillary degeneration. FBD is associated with a stop codon mutation in the BRI2 gene encoding a type II transmembrane protein, BriPP. Mutation results in an extended precursor protein, ABriPP, from which a C-terminal 34 amino acid peptide (ABri) is generated by furin-like proteolytic cleavage and deposited as amyloid and preamyloid in the central nervous system. Despite the morphological parallels with AD the sequences of the amyloidogenic peptides, ABri in FBD and A, in AD, are completely different. We examined systemic tissues in FBD for ABri deposition. Materials and methods:, Immunohistochemistry using an ABri-specific antibody, Ab338, counterstained with Thioflavin S and Ab338 immuno-electron microscopy identified ABri deposits and determined whether these were amyloid or preamyloid in nature. Results:, Amyloid bearing blood vessels stained positively for ABri in myocardium, uterus, bladder, spleen, pancreas, lung and skeletal muscle. ABri was also identified in either amyloid or preamyloid conformation in the parenchyma of myocardium, adrenal, pancreas and skeletal muscle. Conclusion:, This study demonstrates that FBD is the first described cerebral amyloidosis with neurofibrillary pathology and dementia to be accompanied by systemic amyloid deposition. [source] Quantitative MRI reveals aging-associated T2 changes in mouse models of Alzheimer's diseaseNMR IN BIOMEDICINE, Issue 3 2007M. F. Falangola Abstract In this study, we used MRI to analyze quantitative parametric maps of transverse (T2) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive , -amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before , -amyloid deposition, only PS/APP mice show a reduced T2 in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T2 values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T2 values compared with NTg controls. Thus, T2 changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit , -amyloid (PS mice), but are intensified in the presence of amyloid deposition. Copyright © 2007 John Wiley & Sons, Ltd. [source] Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhagePATHOLOGY INTERNATIONAL, Issue 6 2001Naomi Sakashita We report an autopsy case of familial amyloidotic polyneuropathy (FAP) with cerebral hemorrhage. A 38-year-old woman with a typical FAP pedigree started developing severe diarrhea and sensori-motor polyneuropathy at the age of 28 years; autonomic nervous system, heart and renal dysfunction manifested themselves in the following years. Genetic analysis revealed a single amino acid substitution at codon 30 of transthyretin (ATTR Val30Met). Ten years after her initial symptoms, the patient died of a sudden convulsive attack and respiratory failure. Autopsy revealed lethal cerebral hemorrhages and uremic lungs. Histochemical and immunohistochemical analyses revealed TTR-derived amyloid protein in every tissue examined, particularly in glomeruli and peripheral vessels. Severe meningo-cerebrovascular amyloidosis was also detected. Because uremia causes oxidative damage to the vascular system and amyloid formation is closely associated with oxidative stress, it is possible that uremic endothelial damage facilitated an unusual cerebral amyloid deposition. In typical FAP (ATTR Val30Met), cerebral amyloid angiopathy does not usually have clinical manifestations. However, cerebral amyloid angiopathy should be considered to explain FAP symptoms when some risk factors such as uremic vascular damage are accompanying features. [source] Centella asiatica extract selectively decreases amyloid , levels in hippocampus of Alzheimer's disease animal modelPHYTOTHERAPY RESEARCH, Issue 1 2009Muralikrishnan Dhanasekaran Abstract PSAPP mice expressing the ,Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid , plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid , 1,40 and 1,42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid , pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease. Copyright © 2008 John Wiley & Sons, Ltd. [source] DE-loop mutations affect ,2 microglobulin stability, oligomerization, and the low-pH unfolded formPROTEIN SCIENCE, Issue 7 2010Carlo Santambrogio Abstract ,2 microglobulin (,2m) is the light chain of class-I major histocompatibility complex (MHC-I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of ,2m aggregation, several ,2m mutants have been previously studied. Among these, three single-residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect ,2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild-type (w.t.) ,2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray-ionization mass spectrometry (ESI-MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE-loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, ,2m DE-loop mutations display long-range effects, affecting stability and structural properties of the native protein and its low-pH intermediate. The evidence presented here hints to a crucial role played by the DE-loop in determining the overall properties of native and partially folded ,2m. [source] Primary lung involvement with amyloid deposition in Waldenström's macroglobulinemia: Observations from over 20 yearsRESPIROLOGY, Issue 3 2004Miyuki OKUDA Abstract: Primary lung involvement in Waldenström's macroglobulinemia (WM) is rare. The present case had lymphoplasmacytic lymphoma, secreting monoclonal IgM, localized to the lung. WM is also of great interest with regard to the pathogenesis of amyloidosis. The nodular, parenchymal amyloid lesions of the lung are presented with CXR observations of more than 20 years. [source] A molecular correlate of clinicopathology in transthyretin amyloidosis,THE JOURNAL OF PATHOLOGY, Issue 1 2009Mark B Pepys Abstract The mechanisms responsible for amyloid deposition at different times and in different organs, even in individuals with the same amyloidogenic mutation, are not known. The demonstration, in hereditary systemic transthyretin Val30Met amyloidosis, that such differences are consistently associated with amyloid fibrils composed of different length transthyretin fragments sheds new light on this question and will open the way to further informative studies. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Successful Long-Term Outcome of the First Combined Heart and Kidney Transplant in a Patient with Systemic AL AmyloidosisAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009V. Audard Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. During the follow-up period (36 months), plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission. [source] Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen A,-Chain GeneAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2006C. Mousson Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen A,-chain. Four mutations in the fibrinogen A,-chain that are able to induce amyloidosis have been identified so far, the most common being the Glu526Val mutation. We have observed a family in which the father and his son reached end-stage renal failure because of renal amyloidosis induced by a frame-shift mutation in the fibrinogen A,-chain gene producing a novel amyloid protein. Two kidney transplantations in the father and one in the son resulted in fast graft loss caused by recurrence of amyloid deposition. We then performed hepatorenal transplantation in the son. Three years later, liver and kidney functions are normal without recurrence of amyloid deposition. This case, together with three others with the Glu526Val mutation in the extensive literature, suggests that liver transplantation can cure hereditary fibrinogen amyloidosis, whatever the mutation may be. [source] Relationship between atrophy and ,-amyloid deposition in Alzheimer diseaseANNALS OF NEUROLOGY, Issue 3 2010Gaël Chételat PhD Objective Elucidating the role of aggregated ,-amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship. Methods Brain magnetic resonance imaging and [11C]Pittsburgh compound B (PiB)-positron emission tomography scans were obtained from 94 healthy elderly subjects (49 with subjective cognitive impairment), 34 patients with mild cognitive impairment, and 35 patients with Alzheimer disease. The correlations between global and regional neocortical PiB retention and atrophy were analyzed in each clinical group. Results Global and regional atrophy were strongly related to ,-amyloid load in participants with subjective cognitive impairment but not in patients with mild cognitive impairment or Alzheimer disease. Global neocortical ,-amyloid deposition correlated to atrophy in a large brain network including the hippocampus, medial frontal and parietal areas, and lateral temporoparietal cortex, whereas regional ,-amyloid load was related to local atrophy in the areas of highest ,-amyloid load only, that is, medial orbitofrontal and anterior and posterior cingulate/precuneus areas. Interpretation There is a strong relationship between ,-amyloid deposition and atrophy very early in the disease process. As the disease progresses to mild cognitive impairment and Alzheimer disease clinical stages, pathological events other than, and probably downstream from, aggregated ,-amyloid deposition might be responsible for the ongoing atrophic process. These findings suggest that antiamyloid therapy should be administered very early in the disease evolution to minimize synaptic and neuronal loss. ANN NEUROL 2010;67:317,324 [source] Cognition, reserve, and amyloid deposition in normal agingANNALS OF NEUROLOGY, Issue 3 2010Dorene M. Rentz PsyD Objective To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association. Methods In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies. Results We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test. Interpretation Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment. ANN NEUROL 2010;67:353,364 [source] Imaging of amyloid burden and distribution in cerebral amyloid angiopathyANNALS OF NEUROLOGY, Issue 3 2007Keith A. Johnson MD Objective Cerebrovascular deposition of ,-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the ,-amyloid,binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. Methods We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). Results All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 ± 0.06) relative to healthy control subjects (1.04 ± 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 ± 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 ± 0.07 vs 0.86 ± 0.05; p = 0.003). Interpretation We conclude that PiB-positron emission tomography can detect cerebrovascular ,-amyloid and may serve as a method for identifying the extent of CAA in living subjects. Ann Neurol 2007 [source] X-ray crystallographic studies of two transthyretin variants: further insights into amyloidogenesisACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2005Ricardo M. Neto-Silva Transthyretin (TTR) is a homotetrameric plasma protein that, as a result of a set of not yet fully characterized conformational changes, forms fibrillar aggregates that are the major protein component of amyloid deposits. More than 80 mutations associated with TTR amyloid deposition have been described in the literature. X-ray crystallography was used to elucidate the three-dimensional structure of two important TTR variants: TTR Y78F, an amyloidogenic protein, and TTR R104H, which is associated with a protective effect over the amyloidogenic V30M mutation. The structures of those two TTR variants have been determined in space group P21212 to 1.55 and 1.60,Å resolution, respectively, using molecular-replacement techniques. Detailed analysis of the protein model for TTR Y78F indicates a destabilization of the contacts between the ,-helix and AB loop and the body of the molecule, intimately related to the amyloidogenic nature; contrastingly, in the TTR R104H variant new contacts involving the N-terminal region and His104 are clearly antagonists of amyloid formation. [source] Greasing the wheels of A, clearance in Alzheimer's Disease: The role of lipids and apolipoprotein EBIOFACTORS, Issue 3 2009Jianjia Fan Abstract Although apolipoprotein E (apoE) is the most common genetic risk factor for Alzheimer's Disease (AD), how apoE participates in AD pathogenesis remains incompletely understood. ApoE is also the major carrier of lipids in the brain. Here, we review studies showing that the lipidation status of apoE influences the metabolism of A, peptides, which accumulate as amyloid deposits in the neural parenchyma and cerebrovasculature. One effect of apoE is to inhibit the transport of A, across the blood-brain-barrier (BBB), particularly when apoE is lipidated. A second effect is to facilitate the proteolytic degradation of A, by neprilysin and insulin degrading enzyme (IDE), which is enhanced when apoE is lipidated. We also describe how apoE becomes lipidated and how this impacts A, metabolism. Specifically, genetic loss of the cholesterol transporter ABCA1 impairs apoE lipidation and promotes amyloid deposition in AD mouse models. ABCA1 catalyses the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoproteins including apoE. Conversely, selective overexpression of ABCA1 increases apoE lipidation in the central nervous system (CNS) and eliminates the formation of amyloid plaques in vivo. Deficiency of Liver-X-Receptors (LXRs), transcription factors that stimulate ABCA1 and apoE expression, exacerbates AD pathogenesis in vivo, whereas treatment of AD mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance. These studies provide new insights into the mechanisms by which apoE affects A, metabolism, and offer opportunities to develop novel therapeutic approaches to reduce the leading cause of dementia in the elderly. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Heparan Sulfate Accumulation with A, Deposits in Alzheimer's Disease and Tg2576 Mice is Contributed by Glial CellsBRAIN PATHOLOGY, Issue 4 2008Paul O'Callaghan Abstract Amyloid ,-peptide (A,) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in A, deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with A, plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the A,40 dense cores of neuritic plaques, but was largely absent from diffuse A,42 plaques, suggesting that A,42 deposition may occur independently of HS. A codeposition pattern of HS with A, deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with A, deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following A, stimulation. These results suggest that HS codeposits with A,40 in neuritic plaques and is mainly derived from glial cells. [source] The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal ModelsBRAIN PATHOLOGY, Issue 1 2006Efrat Levy A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa-i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes. [source] Neuropathology and Pathogenesis of Encephalitis following Amyloid , Immunization in Alzheimer's DiseaseBRAIN PATHOLOGY, Issue 1 2004Isidre Ferrer Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop ,-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im-munization with amyloid , peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid-, peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation- with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense A,42and A,40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1:SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and ,-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28,/, inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro-teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from ,-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-, peptide immunization [source] Anosacral cutaneous amyloidosis: a study of 10 Chinese casesBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2000W-J. Wang Background,Primary cutaneous amyloidoses are rare in Western countries, but are relatively common in Taiwan. Anosacral cutaneous amyloidosis is a rare type of primary cutaneous amyloidoses, first reported in Japanese patients. Patients/methods,In the present study, we investigated the age of onset, sites of involvement, associated systemic diseases, and histopathological findings in 10 cases of anosacral cutaneous amyloidosis seen during the past 27 years. Results,In previous reports the aetiology of anosacral cutaneous amyloidosis was thought to be a senile change, but half of our patients developed the disease before the age of 60 years. Based on our histopathological findings, apoptosis may be the initial event causing amyloid deposition, although the precise mechanism causing apoptosis needs further investigation. Three patients were found to have diabetes mellitus, but any relationship to anosacral cutaneous amyloidosis is unclear. Conclusions,No cases of this cutaneous disorder have been reported in the Western literature; there seems to be a racial difference accounting for the disease, although the precise factor is not clarified yet. The disease could easily be misdiagnosed as lichen simplex chronicus, postinflammatory hyperpigmentation or tinea cruris; therefore, a thorough history, a careful physical examination and a skin biopsy is needed to establish a firm diagnosis. [source] Ocular manifestations in liver transplant recipients with familial amyloid polyneuropathyACTA OPHTHALMOLOGICA, Issue 5 2008Ola Sandgren Abstract. Purpose:, To evaluate postoperative ocular involvement in Swedish liver transplant (LT) recipients with familial amyloid polyneuropathy (FAP). Methods:, Routine ophthalmological examinations were performed in 48 LT recipients, with particular attention given to amyloid deposition in the anterior segment and the vitreous body. Medical records were scrutinized for information regarding neurological impairment at the time of the LT. The diagnosis was secured in all cases by examining for amyloid deposits in biopsy specimens and positive genetic testing for amyloidogenic transthyretin (ATTR) Val30Met mutation. Results:, Six patients (12.5%) developed vitreous opacities within the post-LT observation period. The first opacities were seen 40 months after transplantation, 8 years after the onset of systemic disease. Four patients (8%) developed secondary glaucoma, the first of which was observed 18 months after the procedure and 6.5 years after the onset of disease. Sixteen patients (33%) developed deposits on the anterior surface of the lens. Scalloped pupillary margins were noted in 10 patients (21%). Conclusion:, The prevalence of eye complications increases with time after LT and regular follow-up is necessary, especially to disclose the development of glaucoma , a complication with insidious symptoms of which patients are normally unaware. [source] Hypopigmented macular amyloidosis with or without hyperpigmentationCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 8 2009M. S. L. Ho Summary Primary cutaneous amyloidosis (PCA) is a chronic pruritic skin disorder with characteristic amyloid deposits in the papillary dermis. We report three cases of PCA, which shared common features of hypopigmentation as a predominant feature with or without reticular hyperpigmentation, no itching, adult onset and dermal papillary amyloid deposition. These cases did not conform to the usual features of PCA. [source] | ||||||||||||||||||||||||||||||||||