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

Intégration des déficits cognitifs dans l'échelle d'invalidité de la sclérose en plaques (à propos de 215 patients)

Introduction : 40 à 70% des patients atteints de sclérose en plaques présentent des troubles cognitifs. L'actuel score fonctionnel mental (SFM) de l'EDSS est subjectif et inclut à la fois les troubles cognitifs et !a dépression. Objectif: Définir un nouveau score fonctionnel cognitif (SFC) basé sur les conclusions du bilan neuropsychologique (BN) et revaloriser sa prise en compte dans I'EDSS global. Méthodes : Cette étude transversale incluait 215 patients issus de la cohorte du LORSEP entre mars 2004 et juin 2007. Les données ont été intégrées dans la base EDMUS (European Database of Multiple Sclerosis). Le BN évaluait les fonctions cognitives (mémoire de travail, attention, fonctions exécutives, mémoire épisodique, langage, capacités visuospatiales et calcul), la fatigue grâce à I'EMIF-SEP et la dépression. Le SFC est côté de 0 (normal) à 5 (démence sévère), il exclut la dépression et inclut la fatigue. Un SFC à 1 est intégré dans I'EDSS comme tout autre score fonctionnel. Le SFC et l'EDSS intégrant le SFC sont établis à partir du BN et comparés au SFM et à I'EDSS intégrant le SFM. Résultats : L'âge moyen est de 43,5 ans (10,8), la durée de la maladie de 11,2 ans (8,6), l'EDSS moyen de 3.3 (médiane=3.0) Il y a 149 femmes (69,3%). Seulement 1,9% des patients ont un SFC à 0 contre 37,7% selon le SFM. Le SFC est plus élevé que le SFM (p=3,5. Le changement de score fonctionnel n'est ni associé à l'âge ni à l'âge de début de la maladie. Conclusion : Nous proposons un score fonctionnel cognitif basé sur le BN, excluant la dépression et incluant la fatigue. Cependant I'EDSS ne permet pas une prise en compte correcte des troubles cognitifs.NANCY1-SCD Medecine (545472101) / SudocNANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Additional Use of A beta(42)/A beta(40) Ratio with Cerebrospinal Fluid Biomarkers P-Tau and A beta(42) Increases the Level of Evidence of Alzheimer's Disease Pathophysiological Process in Routine Practice

International audienceBackground: Cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for the diagnosis of Alzheimer's disease (AD). Since interpretation of CSF profile requires the combination of three parameters, biological data are not always conclusive and isolated elevation of phosphorylated tau (P-tau) or reduction of amyloid-beta (A beta)(42) alone can be observed. In these cases, A beta(42)/A beta(40) ratio could be more relevant than A beta(42) absolute values by considering inter-individual variations in the total amyloid load. Objective: The objective of this study was to assess the use of A beta(42)/A beta(40) ratio to improve the accuracy of biological conclusions in the diagnosis of patients with ambiguous CSF A beta(42) or tau results. Methods: Among 386 lumbar punctures analyzed in the lab in 2 years, 122 showed ambiguous biological data that were completed by CSF A beta(40) quantification and A beta(42)/A beta(40) ratio calculation. A biological conclusion was then made using 0.05 as the A beta(42)/A beta(40) ratio cut-off. Results: Our results showed that one-third of the biological profiles of patients with atypical dementia were ambiguous. The addition of A beta(42)/A beta(40) ratio increased the proportion of interpretable biological profiles from 69% to 87%, without changing the conclusion when usual biomarkers (A beta(42) and P-tau) were concordant. Conclusion: Our results support the use of the A beta(42)/A beta(40) ratio in addition to the usual CSF AD biomarkers for patients with ambiguous biological profiles. This method could be specifically directed to this population in order to improve the level of certainty for clinical routine practice

Early Emotional Attention is Impacted in Alzheimer’s Disease: An Eye-Tracking Study

International audienceEmotional deficits have been repetitively reported in Alzheimer's disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning

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

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

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

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

Added value of 18F-florbetaben amyloid PET in the diagnostic workup of most complex patients with dementia in France: A naturalistic study

International audienceIntroductionAlthough some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting.MethodsThis multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early-onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172).ResultsTwo hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases.DiscussionHigh-level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases