Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort

Introduction Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension–dementia association are still poorly understood. Methods We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. Results Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. Discussion These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension–dementia association. Highlights Paths of hypertension–cognition association were assessed by structural equation models. The hypertension–cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension–cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.Stopping cognitive decline and dementia by fighting covert cerebral small vessel diseas

Diabetes Mellitus and Cognition: A Pathway Analysis in the MEMENTO Cohort

OBJECTIVE: To assess the role of biomarkers of Alzheimer's Disease (AD), neurodegeneration and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent or self-report. We used structural equation modelling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ(42)/Aβ(40) ratio and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (five neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089; -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers

The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist

Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2-diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity

NMR-based structural biology enhanced by dynamic nuclear polarization at high magnetic field

Dynamic nuclear polarization (DNP) has become a powerful method to enhance spectroscopic sensitivity in the context of magnetic resonance imaging and nuclear magnetic resonance spectroscopy. We show that, compared to DNP at lower field (400 MHz/263 GHz), high field DNP (800 MHz/527 GHz) can significantly enhance spectral resolution and allows exploitation of the paramagnetic relaxation properties of DNP polarizing agents as direct structural probes under magic angle spinning conditions. Applied to a membrane-embedded K+ channel, this approach allowed us to refine the membrane-embedded channel structure and revealed conformational substates that are present during two different stages of the channel gating cycle. High-field DNP thus offers atomic insight into the role of molecular plasticity during the course of biomolecular function in a complex cellular environment

Solid-Phase Polarization Matrixes for Dynamic Nuclear Polarization from Homogeneously Distributed Radicals in Mesostructured Hybrid Silica Materials

Mesoporous hybrid silica-organic materials containing homogeneously distributed stable mono- or dinitroxide radicals covalently bound to the silica surface were developed as polarization matrixes for solid-state dynamic nuclear polarization (DNP) NMR experiments. For TEMPO-containing materials impregnated with water or 1,1,2,2-tetrachloroethane, enhancement factors of up to 36 were obtained at similar to 100 K and 9.4 T without the need for a glass-forming additive. We show that the homogeneous radical distribution and the subtle balance between the concentration of radical in the material and the fraction of radicals at a sufficient inter-radical distance to promote the cross-effect are the main determinants for the DNP enhancements we obtain. The material, as well as an analogue containing the poorly soluble biradical bTUrea, is used as a polarizing matrix for DNP NMR experiments of solutions containing alanine and pyruvic acid. The analyte is separated from the polarization matrix by simple filtration

Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.

International audienceBACKGROUND: Blood biomarkers for Alzheimer's disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints. METHODS: The MEMENTO cohort enrolled 2323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total-tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. RESULTS: Overall, 2277 individuals had at least one baseline blood biomarker available (n=357 for CSF subsample, n=649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total-tau were mildly correlated with their equivalence in the CSF (r=0.33 to 0.46, p<0.0001) and were associated with amyloid-PET status (p<0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (AUC=0.74 [95%CI=0.69-0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index=0.73 [95%CI=0.69-0.77]); its accuracy was higher in patients with CDR=0 (c-index=0.83 [95% CI=0.69;0.97]) than in patients with CDR=0.5 (c-index=0.70 [95% CI=0.66;0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index=0.88 [95%CI=0.86-0.91] and performance increased to 0.90 [95%CI=0.88;0.92] when adding blood p181-tau+Aβ42/40. A "research" reference model (clinical model+ApoE genotype and AD-signature on MRI) had a c-index=0.91 [95%CI=0.89-0.93] increasing to 0.92 [95%CI=0.90;0.93] when adding blood p181-tau+Aβ42/40. Chronic kidney disease and vascular comorbidities did not impact predictive performances. DISCUSSION: In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors

Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort

International audienceIntroduction: Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension-dementia association are still poorly understood.Methods: We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data.Results: Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers.Discussion: These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension-dementia association.Highlights: Paths of hypertension-cognition association were assessed by structural equation models. The hypertension-cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension-cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

International audienceCausative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes

Decrease in the cortex/striatum metabolic ratio on [18F]-FDG PET: a biomarker of autoimmune encephalitis

International audienceObjective To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. Methods The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ 42 /Aβ 40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. Results There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: −0.061, 95% confidence interval: −0.089, −0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. Conclusion In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers