Ignacio Illán-Gala, Spain
Institut d’Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona Sant Pau Memory Unit, Department of NeurologyAuthor Of 2 Presentations
EFFECT OF BIOLOGICAL SEX ON CLINICAL, BIOCHEMICAL AND NEUROIMAGING BIOMARKERS OF ALZHEIMER’S DISEASE IN ADULTS WITH DOWN SYNDROME: A CROSS-SECTIONAL STUDY
Abstract
Aims
Biological sex is increasingly recognized as a modifier of Alzheimer’s disease (AD) pathophysiology and disease progression. We aimed to assess the effect of sex on cognitive and biomarker measures of AD in adults with Down syndrome, who have an ultra-high risk for developing AD dementia.
Methods
Cross-sectional study of 494 adults with Down syndrome recruited from two sites. We compared clinical characteristics and AD biomarkers between men (n=268) and women (n=226). Participants had at least one biomarker assessment among plasma NfL, Aβ1-42/1-40, p-Tau-181, tau and NfL in CSF, PET with amyloid tracers or 18F-fluorodeoxyglucose and/or MRI. We compared age at symptom onset and used within-group local regression models with confidence intervals to compare the trajectory of biomarker changes with age.
Results
The mean age at which women were diagnosed with dementia was 53 years vs. 53.6 for men (p=0.46). Women with Down syndrome showed earlier decreases in CSF Aß1-42, however no differences were found when comparing the Aß1-42/Aß1-40 ratio. The biomarker trajectories of plasma NfL and CSF NfL, p-Tau-181 and tau were similar across ages between men and women. Women had smaller head sizes and hippocampal volumes, but there were no differences in hippocampal volumes when adjusted for differences in head size. There were no differences in age-associated changes in cerebral amyloid deposition (Centiloid) or glucose metabolism (FDG-PET).
Conclusions
In adults with Down syndrome, sex does not modify the age at diagnosis of dementia or the trajectories of plasma, CSF and imaging biomarkers. Reporting of negative results is important to avoid publication bias.
MICRO-RNA ALTERATIONS DETECTABLE IN CSF EXTRACELLULAR VESICLES RELATED TO DYSFUNCTION OF AUTOPHAGY PATHWAYS IN 4R-TAUOPATHIES
Abstract
Aims
Our goals were: 1) to identify microRNA alterations in cerebrospinal fluid (CSF) extracellular vesicles (EVs) from patients with frontotemporal disorders; 2) to elucidate the effect of candidate microRNAs on autophagy mechanisms and tau turnover.
Methods
EV-derived microRNA levels from 144 CSF samples (including healthy controls, patients with Alzheimer’s disease (AD) or frontotemporal disorders) were analyzed by qPCR. MicroRNA changes in patients were reproduced in two in-vitro models. Total RNA isolated from SK-N-MC cells quantified by RNA-seq. Neuro-2a cells with inducible expression of human wild-type (WT)-tau or pathogenic P301L-tau were used to measure levels of tau and autophagy-related proteins by immunoblot. Neuro-2a cells expressing fluorescent reporters were used to monitor autophagy dynamics.
Results
MicroRNA profiling in CSF-derived EVs revealed four microRNAs differentially expressed in 4R tau-related pathologies when compared to other phenotypes. Analysis of gene expression profiles upon imposing changes in miR that mimic those found in the patients’ CSF revealed 30 genes differentially expressed for three candidate microRNAs, which point to 17 significantly enriched biological pathways. Quantification of turnover of WT and mutant tau in Neuro-2a cell lines, after treatment with microRNA modulators, suggests that autophagic degradation of tau is impaired when reproducing certain microRNA alterations observed in patients. Autophagy reporter studies also indicate that microRNA changes observed in the patients are inhibitory in some autophagy pathways.
Conclusions
Our results indicate the presence of a characteristic microRNA signature seemingly specific for 4R-tauopathies. Functional studies of these microRNAs in cultured cells showed inhibitory effects on some autophagy pathways and impairment of tau turnover.