Hippocampal Sclerosis in the Oldest Old : A Finnish Population-Based Study

Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85(+) study includes all inhabitants of the city of Vantaa, who were > 85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE-staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p <0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p <0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.Peer reviewe

Re-examining tau-immunoreactive pathology in the population: granulovacuolar degeneration and neurofibrillary tangles.

INTRODUCTION: Alzheimer's disease (AD) is associated with neurofibrillary pathology, including neurofibrillary tangles (NFT), neuritic plaques (NP) and neuropil threads containing aggregated microtubule associated protein tau. Aggregated tau is also associated with granulovacuolar degeneration (GVD). The relationships between tau, GVD, NFT and dementia are unclear. METHODS: We assessed hippocampal (CA1) tau-immunoreactive GVD and NFT pathology in brain donations from the population-representative Cambridge City over 75s Cohort (CC75C) using the CERAD protocol and a modified protocol that included a morphological characterisation of tau-immunoreactive deposits within neurons as NFTs or as GVD. Associations between GVD, NFT and dementia were investigated. RESULTS: Hippocampal pyramidal neurons affected with either NFT or GVD are common in the older population. Some tau-immunoreactive deposits resemble ghost GVD neurons. Tau immunoreactivity identified GVD in 95% cases rated as none with haematoxylin and eosin staining. Both severe NFT (odds ratio (OR) 7.33, 95% confidence interval (CI) 2.01; 26.80, p = 0.003) and severe GVD (OR 7.48, 95% (CI) 1.54; 36.24, p = 0.012) were associated with dementia status. Increasing NFT (OR 2.47 95% (CI) 1.45; 4.22, p = 0.001) and GVD (OR 2.12 95% (CI) 1.23; 3.64, p = 0.007) severities are associated with increasing dementia severity. However, when the analyses were controlled for other neuropathologies (NFT, NP, Tar-DNA binding Protein-43 and amyloid deposits), the associations between GVD and dementia lost significance. CONCLUSIONS: Current neuropathological assessments do not adequately evaluate the presence and severity of the GVD pathology and its contribution to dementia remains unclear. We recommend that protocols to assess GVD should be developed for routine use and that tau, in a non-PHF associated conformation, is reliably associated with GVD.CC75C is a member study of the Cambridgeshire and Peterborough Collaboration for Leadership in Applied Health Research and Care (CLAHRC). The Cambridge Brain Bank Laboratory (which processed all CC75C cases) is supported by the National Institute for Health Research, Cambridge BioMedical Research Centre. EM-L is supported by Alzheimer’s Society (London, UK).This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13195-015-0141-

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan–Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the ‘MUC4/MMP9/EGFR axis’ may play a vital role in glioblastoma diagnostics

Neuropathologic Findings of Dementia with Lewy Bodies (DLB) in a Population-based Vantaa 85+Study

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Population-based analysis of pathological correlates of dementia in the oldest old

Objective: The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population. Methods: All 601 persons aged >= 85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 + study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 +/- 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Ab]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size ( 15 mm) and by location. Brain hemorrhages were classified as microscopic ( 2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly. Interpretation: These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.Peer reviewe

Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment

Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers 4 of the gene's 5 exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing Mini-Mental State Examination (MMSE) scores and diagnoses of dementia, we did not find any significant differences between TYROBP deletion carriers and noncarriers (all p-values >0.5). Neuropathological analysis of 2 deletion carriers (aged 89 and 94 years) demonstrated only minimal beta amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+cohort exhibit two divergent patterns : a population-based study

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