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Keywords: atrophy, dementia with Lewy bodies, magnetic resonance imaging, sex differences
Published in DiRROS: 03.06.2026; Views: 254; Downloads: 245
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Abstract: Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
Keywords: Alzheimer’s disease, dementia, extracellular vesicles, neuroprotection, prions, proteolytic processing
Published in DiRROS: 03.06.2026; Views: 179; Downloads: 178
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Abstract: Background: Evidence suggests statins may influence cognition in Alzheimer's disease (AD), but specific use patterns in AD patients remain unclear. Objective: To identify factors influencing statin use in AD and explore associations between statins, cholesterol, and cognition, evaluated with Mini-Mental State Examination (MMSE) at dementia diagnosis. Methods: A cross-sectional study using data from the Swedish Registry for Dementia and Cognitive Disorders (SveDem) and Stockholm Creatinine Measurements (SCREAM) from 2007 to 2018. Multivariable logistic regression examined associations between baseline characteristics and statin use, while linear regression analyzed relationships between statins, cholesterol levels, and MMSE scores. Results: We included 3074 AD patients (mean age 78.1 years; 59.4% women), of whom 1028 used statins (79.6% simvastatin, 20.4% atorvastatin). Patients with diabetes mellitus, ischemic heart disease, or stroke had greater odds of receiving statins. Older patients had slightly lower odds of receiving any statin at baseline (simvastatin use OR 0.98, 95% CI 0.97–0.99). Simvastatin users had 0.53 points higher MMSE on average at baseline compared to non-users of statins (se 0.23, p = 0.021). Higher low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were associated with higher MMSE in non-users of statins, but not in statin users. Conclusions: Younger AD patients and those with cardiovascular disease were more likely to use statins. Simvastatin use was linked to higher cognitive scores at diagnosis. In non-users, higher LDL-C, TC, and HDL-C levels correlated with better baseline cognitive scores. Longitudinal studies are needed to investigate the effects of statins on cognitive decline in AD.
Keywords: Alzheimer's disease, cholesterol, dementia, drug repurposing, mini-mental state examination
Published in DiRROS: 15.04.2026; Views: 297; Downloads: 138
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Abstract: Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages. Methods: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements. Results: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB. Conclusions: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.
Keywords: Alzheimer's disease, Lewy body dementia, FDG PET, functional imaging, mild cognitive impairment
Published in DiRROS: 19.03.2026; Views: 393; Downloads: 272
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