(1/353) Role of cytochrome c as a stimulator of alpha-synuclein aggregation in Lewy body disease.

alpha-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which alpha-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in alpha-synuclein aggregation. When recombinant alpha-synuclein was coincubated with cytochrome c/hydrogen peroxide, alpha-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/hydrogen peroxide similarly induced aggregation of alpha-synuclein, and both cytochrome c/hydrogen peroxide- and hemin/hydrogen peroxide-induced aggregation of alpha-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that iron-catalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting alpha-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/alpha-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease. Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stress-induced aggregation of alpha-synuclein in Parkinson's disease and related disorders.  (+info)

(2/353) Inverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia.

The most common neuropathological substrates of dementia are Alzheimer's disease, cerebrovascular disease, and dementia with Lewy bodies. A preliminary, retrospective postmortem analysis was performed of the relative burden of each pathology in 25 patients with predominantly Alzheimer's disease-type dementia. Log linear modelling was used to assess the relations between ApoE genotype, Alzheimer's disease, and cerebrovascular disease pathology scores. Sixteen of 18 cases (89%) with a Braak neuritic pathology score +info)

(3/353) Diagnostic impact of cerebral transit time in the identification of microangiopathy in dementia: A transcranial ultrasound study.

BACKGROUND AND PURPOSE: The diagnosis and quantification of microangiopathy in dementia is difficult. The assessment of small-vessel disease requires expensive and sophisticated nuclear medicine techniques. This study was performed to identify microangiopathy related to the integrity of cerebral microcirculation by sonographic measurements (arteriovenous cerebral transit time [cTT]). METHODS: We performed transcranial color-coded duplex sonography in 40 patients with vascular dementia, 20 patients with Alzheimer's disease or Lewy body disease, and 25 age-matched controls. The clinical diagnosis was established by history of dementia and neuroimaging findings. Cognitive impairment was assessed by the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. cTT is defined as the time required by an ultrasound contrast agent to pass from a cerebral artery to a vein. This was measured by recording the power-Doppler intensity curves in the P2 segment of the posterior cerebral artery and the vein of Galen. Previous studies have shown a prolongation of cTT in patients with cerebral microangiopathy. RESULTS: cTT was substantially prolonged in patients with vascular dementia (5.8 seconds; 25th percentile 4.5; 75th percentile 7.5; U test, P<0.001) compared with controls (3.1 seconds; 2.3; 3.4) but not in patients with degenerative dementia (3.7 seconds; 3.7; 4.2). In patients with vascular dementia, cTT was significantly correlated with cognitive impairment. CONCLUSIONS: cTT may be useful tool to disclose small-vessel disease in demented patients. Examination is noninvasive and quickly performed. It may be also useful in follow-up examinations in patients undergoing therapy.  (+info)

(4/353) Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein.

Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to gammaS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in addition to alphaS, in the onset/progression of PD and DLB.  (+info)

(5/353) An autopsy-verified study of the effect of education on degenerative dementia.

A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.  (+info)

(6/353) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.  (+info)

(7/353) Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity.

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.  (+info)

(8/353) Accumulation of NACP/alpha-synuclein in lewy body disease and multiple system atrophy.

OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in sporadic Parkinson's disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/alpha-synuclein antibodies. METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntington's disease, two with progressive supranuclear palsy (PSP), one with Pick's disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS: In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/alpha-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinson's disease/DLBD. NACP/alpha-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION: Completely different types of NACP/alpha-synuclein accumulation in Parkinson's disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies.  (+info)