Extracellular Vesicle-Enriched miRNA-Biomarkers Show Improved Utility for Detecting Alzheimer's Disease Dementia and Medial Temporal Atrophy.

Background: Emerging diagnostic modalities suggest that miRNA profiles within extracellular vesicles (EVs) isolated from peripheral blood specimens may provide a non-invasive diagnostic alternative for dementia and neurodegenerative disorders. Given that EVs confer a protective environment against miRNA enzymatic degradation, the miRNAs enriched in the EV fraction of blood samples could serve as more stable and clinically relevant biomarkers compared to those obtained from serum. Objective: To compare miRNAs isolated from EVs versus serum in blood taken from Alzheimer's disease (AD) dementia patients and control cohorts. Methods: We compared 25 AD patients to 34 individuals who exhibited no cognitive impairments (NCI). Subjects were Singapore residents with Chinese heritage. miRNAs purified from serum versus blood-derived EVs were analyzed for associations with AD dementia and medial temporal atrophy detected by magnetic resonance imaging. Results: Compared to serum-miRNAs, we identified almost twice as many EV-miRNAs associated with AD dementia, and they also correlated more significantly with medial temporal atrophy, a neuroimaging marker of AD-brain pathology. We further developed combination panels of serum-miRNAs and EV-miRNAs with improved performance in identifying AD dementia. Dominant in both panels was miRNA-1290. Conclusions: This data indicates that miRNA profiling from EVs offers diagnostic superiority. This underscores the role of EVs as vectors harboring prognostic biomarkers for neurodegenerative disorders and suggests their potential in yielding novel biomarkers for AD diagnosis.

Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics.

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.

Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia.

Ergothioneine (ET) is a dietary amino-thione with strong antioxidant and cytoprotective properties and has possible therapeutic potential for neurodegenerative and vascular diseases. Decreased blood concentrations of ET have been found in patients with mild cognitive impairment, but its status in neurodegenerative and vascular dementias is currently unclear. To address this, a cross-sectional study was conducted on 496 participants, consisting of 88 with no cognitive impairment (NCI), 201 with cognitive impairment, no dementia (CIND) as well as 207 with dementia, of whom 160 have Alzheimer's Disease (AD) and 47 have vascular dementia. All subjects underwent blood-draw, neuropsychological assessments, as well as neuroimaging assessments of cerebrovascular diseases (CeVD) and brain atrophy. Plasma ET as well as its metabolite l-hercynine were measured using high sensitivity liquid chromatography tandem-mass spectrometry (LC-MS/MS). Plasma ET concentrations were lowest in dementia (p < 0.001 vs. NCI and CIND), with intermediate levels in CIND (p < 0.001 vs. NCI). A significant increase in l-hercynine to ET ratio was also observed in dementia (p < 0.01 vs. NCI). In multivariate models adjusted for demographic and vascular risk factors, lower levels of ET were significantly associated with dementia both with or without CeVD, while ET associations with CIND were significant only in the presence of CeVD. Furthermore, lower ET levels were also associated with white matter hyperintensities and brain atrophy markers (reduced global cortical thickness and hippocampal volumes). The incremental decreases in ET levels along the CIND-dementia clinical continuum suggest that low levels of ET are associated with disease severity and could be a potential biomarker for cognitive impairment. Deficiency of ET may contribute towards neurodegeneration- and CeVD-associated cognitive impairments, possibly via the exacerbation of oxidative stress in these conditions.

APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms.

OBJECTIVE: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. METHODS: We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). RESULTS: Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.