Differential insular cortex subregional vulnerability to alpha-synuclein pathology in Parkinson's disease and dementia with Lewy bodies

Aim: The insular cortex consists of a heterogenous cytoarchitecture and diverse connections and is thought to integrate autonomic, cognitive, emotional and interoceptive functions to guide behaviour. In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), it reveals a-synuclein pathology in advanced stages. The aim of this study is to assess the insular cortex cellular and subregional vulnerability to a-synuclein pathology in well-characterized PD and DLB subjects. Methods: We analysed postmortem insular tissue from 24 donors with incidental Lewy body disease, PD, PD with dementia (PDD), DLB and age-matched controls. The load and distribution of a-synuclein pathology and tyrosine hydroxylase (TH) cells were studied throughout the insular subregions. The selective involvement of von Economo neurons (VENs) in the anterior insula and astroglia was assessed in all groups. Results: A decreasing gradient of a-synuclein pathology load from the anterior periallocortical agranular towards the intermediate dysgranular and posterior isocortical granular insular subregions was found. Few VENs revealed a-synuclein inclusions while astroglial synucleinopathy was a predominant feature in PDD and DLB. TH neurons were predominant in the agranular and dysgranular subregions but did not reveal a-synuclein inclusions or significant reduction in density in patient groups. Conclusions: Our study highlights the vulnerability of the anterior agranular insula to a-synuclein pathology in PD, PDD and DLB. Whereas VENs and astrocytes were affected in advanced disease stages, insular TH neurons were spared. Owing to the anterior insula’s affective, cognitive and autonomic functions, its greater vulnerability to pathology indicates a potential contribution to nonmotor deficits in PD and DLB

Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy

OBJECTIVE: To investigate the histopathologic substrate of microbleeds detected on 7T postmortem MRI in autopsy cases with severe cerebral amyloid angiopathy (CAA) and Alzheimer pathology. METHODS: Five decedents (mean age at death 79.6 +/- 5.7 years) with documented severe CAA and Alzheimer pathology on standard neuropathologic examination were selected from a local database. Formalin-fixed coronal brain slices were scanned at 7T MRI, including high-resolution T2- and T2*-weighted sequences. Representative microbleeds from each case were sampled for histopathologic analysis, including the presence of blood, blood breakdown products, and markers of ischemic tissue injury. RESULTS: On MRI, we identified >300 cortical and 4 subcortical microbleeds. Two out of 15 sampled cortical microbleeds corresponded histologically to erythrocytes (suggestive of recent hemorrhages), 4 to vasculopathies (fibrinoid necrosis in 3 and a cavernoma) without substantial parenchymal tissue injury, and 9 to accumulations of iron-positive siderophages without erythrocytes (suggestive of old hemorrhages) combined with mild to moderate degrees of chronic ischemic tissue injury. CONCLUSIONS: This study provides evidence for heterogeneous pathologic substrates and possibly different pathophysiologic mechanisms underlying MRI-observed cortical microbleeds in the context of advanced CAA and Alzheimer disease

Small heat shock proteins induce a cerebral inflammatory reaction

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[Prion diseases in The Netherlands: twenty-nine years of surveillance]

Prion diseases are being monitored in The Netherlands since 29 years, the national registry is coordinated by Erasmus Medical Center. Since 2010, yearly on average 31 new patients are diagnosed with prion disease. There is a slight increase in incidence of prion diseases, probably due to better recognition and improved diagnostics. The most recent development in the diagnostic is the real-time quaking-induced conversion (RT-QuIC) test, which can detect prion proteins in cerebrospinal fluid with high sensitivity and specificity. The polymorphism of codon 129 of the prion gene (PRNP) determines the susceptibility for the different subtypes of Creutzfeldt-Jakob disease (CJD) and influences the clinical course. Awareness for atypical presentations of CJD and for CJD mimics is important, such as autoimmune encephalitis, which is often treatable and can resemble CJD

Football et relations internationales - 2002 FIFA World Cup. Korea / Japan : que la fête recommence !

Amyloid-beta (Abeta) is the most prominent protein in Alzheimer's disease (AD) senile plaques. In addition, Abeta interacts with a variety of Abeta-associated proteins (AAPs), some of which can form complexes with Abeta and influence its clearance, aggregation or toxicity. Identification of novel AAPs may shed new light on the pathophysiology of AD and the metabolic fate of Abeta. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Abeta in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential Abeta-associated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Abeta in the brain, both in diffuse and classic plaques. (ii) Dkk-3 is expressed in neurons and in blood vessel walls in the brain and (iii) is secreted by leptomeningeal smooth muscle cells in vitro. Finally, measurements using ELISA revealed that (iv) Dkk-3 protein is abundantly present in both cerebrospinal fluid and serum, but its levels are similar in non-demented controls and patients with AD, Lewy body dementia, and frontotemporal dementia. Our study demonstrates that Dkk-3 is a hitherto unidentified Abeta-associated protein which, given its relatively high cerebral concentrations and co-localization with Abeta, is potentially involved in AD pathology. In this study, we propose that Dickkopf-related protein-3 (Dkk-3) might be a novel Amyloid-beta (Abeta) associated protein. We demonstrate that Dkk-3 is expressed in the brain, especially in vessel walls, and co-localizes with Abeta in senile plaques. Furthermore, Dkk-3 levels in cerebrospinal fluid strongly correlate with Abeta40 levels, but were not suitable to discriminate non-demented controls and patients with dementia

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson's Disease.

Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson's disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and agematched controls with Braak alpha-synuclein stage ranging from 0-6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD. Copyright

A second case of Gerstmann-Str\ue4ussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient.

A rare case of Gerstmann-Str\ue4ussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Str\ue4ussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia

A second class of Gerstmann-Straussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient.

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