Search

Background and Objectives: Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period., Methods: We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline., Results: A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: β MMSE = -0.055, 95% CI -0.067 to -0.043, β FCSRT = -0.034, 95% CI -0.043 to -0.025, β fluency = -0.029, 95% CI -0.038 to -0.020, β SPPB = -0.040, 95% CI -0.057 to -0.022, and β 4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: β MMSE = -0.039, 95% CI -0.053 to -0.025, β FCSRT = -0.022, 95% CI -0.032 to -0.012, β fluency = -0.014, 95% CI -0.024 to -0.004, and β 4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002-0.020, and β = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level., Discussion: In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Background and Objectives: Patients' comorbidities can affect Alzheimer disease (AD) blood biomarker concentrations. Because a limited number of factors have been explored to date, our aim was to assess the proportion of the variance in fluid biomarker levels explained by the clinical features of AD and by a large number of non-AD-related factors., Methods: MEMENTO enrolled 2,323 individuals with cognitive complaints or mild cognitive impairment in 26 French memory clinics. Baseline evaluation included clinical and neuropsychological assessments, brain MRI, amyloid-PET, CSF (optional), and blood sampling. Blood biomarker levels were determined using the Simoa-HDX analyzer. We performed linear regression analysis of the clinical features of AD (cognition, AD genetic risk score, and brain atrophy) to model biomarker concentrations. Next, we added covariates among routine biological tests, inflammatory markers, demographic and behavioral determinants, treatments, comorbidities, and preanalytical sample handling in final models using both stepwise selection processes and least absolute shrinkage and selection operator (LASSO)., Results: In total, 2,257 participants were included in the analysis (median age 71.7, 61.8% women, 55.2% with high educational levels). For blood biomarkers, the proportion of variance explained by clinical features of AD was 13.7% for neurofilaments (NfL), 11.4% for p181-tau, 3.0% for Aβ-42/40, and 1.4% for total-tau. In final models accounting for non-AD-related factors, the variance was mainly explained by age, routine biological tests, inflammatory markers, and preanalytical sample handling. In CSF, the proportion of variance explained by clinical features of AD was 24.8% for NfL, 22.3% for Aβ-42/40, 19.8% for total-tau, and 17.2% for p181-tau. In contrast to blood biomarkers, the largest proportion of variance was explained by cognition after adjustment for covariates. The covariates that explained the largest proportion of variance were also the most frequently selected with LASSO. The performance of blood biomarkers for predicting A+ and T+ status (PET or CSF) remained unchanged after controlling for drivers of variance., Discussion: This comprehensive analysis demonstrated that the variance in AD blood biomarker concentrations was mainly explained by age, with minor contributions from cognition, brain atrophy, and genetics, conversely to CSF measures. These results challenge the use of blood biomarkers as isolated stand-alone biomarkers for AD.

Background and Objectives: Global amyloid-PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid-PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments., Methods: The French MEMENTO cohort (a cohort of outpatients from French research memory centers to improve knowledge on Alzheimer disease and related disorders) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid-PET) for a subset of participants; semiannual cognitive testing was subsequently performed. We predicted mini-mental state examination (MMSE) scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of amyloid burden as a predictor in these models was evaluated with percent reduction of the mean squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared with a continuous amyloid-standardized uptake-value ratio., Results: Our analytic sample comprised 510 individuals who underwent amyloid-PET scans with at least 4 MMSE assessments. The mean age at the PET scan was 71.6 (standard deviation 7.4) years; 60.7% were female. The median follow-up was 4.6 years (interquartile range: 0.9 years). Adding amyloid burden when adjusting for only demographic characteristics reduced the MSE of predictions by 5.08% (95% CI 0.97%-10.86%) and 12.64% (95% CI 3.35%-25.28%) for binary and continuous amyloid, respectively. If the model included 1 past MMSE measure, the MSE improvement was 3.51% (95% CI 1.01%-7.28%) when adding binary amyloid and 8.83% (95% CI 2.63%-16.37%) when adding continuous amyloid. Improvements in model fit were smaller with the addition of amyloid burden when more than 1 past cognitive assessment was included. For all models incorporating past cognitive assessments, differences in predictions amounted to a fraction of 1 MMSE point on average., Discussion: In a clinical setting, global amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available., Trial Registration Information: ClinicalTrials.gov Identifier: NCT02164643.

Background and Objective: Blood biomarkers for Alzheimer 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 2,323 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, 2,277 individuals had at least 1 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 (area under the curve = 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 clinical dementia rating (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 + apolipoprotein E 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 affect 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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997-1999 and followed up to 2009., Design: Prospective study of 1046 patients at 47 French clinical sites., Methods: Potential determinants of diabetes occurrence, defined by confirmed increased glycemia and/or initiation of antidiabetic treatment, were assessed by a proportional hazards model, including time-updated metabolic parameters and ART exposure., Results: Among the cohort, representing 7846 person-years of follow-up (PYFU), 54% received indinavir, 75% stavudine and 52% didanosine. Overall, 111 patients developed diabetes, with an incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women). Incidence peaked in 1999-2000 (23.2/1000 PYFU) and decreased thereafter. The incidence of diabetes was associated [adjusted hazard ratio (aHR), all P<0.02] with older age (hazard ratio = 2.13 when 40-49 years, hazard ratio = 3.63 when ≥50 years), overweight (hazard ratio = 1.91 for a BMI 25-29 kg/m(2), hazard ratio = 2.85 >30 kg/m(2)), waist-to-hip ratio (hazard ratio = 3.87 for ≥0.97 male/0.92 female), time-updated lipoatrophy (hazard ratio = 2.14) and short-term exposure to indinavir (0-1 year: hazard ratio = 2.53), stavudine (0-1 year: hazard ratio = 2.56, 1-2 years: hazard ratio = 2.65) or didanosine (2-3 years: hazard ratio = 3.16). Occurrence of diabetes was not associated with HIV-related markers, hepatitis C, hypertension or family history of diabetes. Insulin resistance was predictive for incident diabetes., Conclusions: In this nationwide cohort, followed for 10 years after cART initiation, diabetes incidence peaked in 1990-2000, was markedly higher than that reported for European uninfected or other HIV-infected populations (4-6/1000 PYFU) and linked with age and adiposity. Adiposity and glycemic markers should be monitored in aging HIV-infected patients.

Objectives: To evaluate the efficacy of adding interleukin-2 (IL-2) to an optimized background treatment in HIV-1 patients with advanced failure., Design: Randomized, open-label, multicentre controlled trial., Methods: Patients with CD4 T-cell count of less than 200 cells/microl, plasma HIV-1 RNA of more than 10 000 copies/ml and a genotypic sensitivity score showing two or less active drugs were randomized to either eight IL-2 cycles with optimized background treatment or optimized background treatment alone. Optimization was made according to genotypic sensitivity score. Enfuvirtide was added in enfuvirtide-naive patients. Evaluation was performed at week 52 on the proportions of patients with CD4 cell count of at least 200 cells/microl (primary outcome), of patients with a CD4 cell count increase of at least 50 cells/microl from week 0, on plasma HIV-1 RNA and HIV-related events., Results: Fifty-six patients were analysed. Median age was 43 years, 61% were at Center for Disease Control and Prevention stage C, 43% had a genotypic sensitivity score of 0, median baseline CD4 cell count and plasma HIV-1 RNA values were 64 cells/microl and 4.9 log10 copies/ml, respectively. Treatment could be optimized in 23 patients. At week 52, in the IL-2 and control groups, the proportion of patients with CD4 cell count of at least 200 cells/microl (14 and 18%) or a CD4 cell count increase of at least 50 cells/microl (25 and 32%) and median plasma HIV-1 RNA were not significantly different. In multivariate analysis, optimization with enfuvirtide and baseline CD4 cell count were statistically associated with CD4 cell count of at least 200 cells/microl at week 52 (P = 0.003 and P = 0.01). Optimization with enfuvirtide was the only factor associated with a CD4 cell count gain of at least 50 cells/microl (P < 0.001). There was no difference in the rate of AIDS events between groups., Conclusion: IL-2 failed to increase CD4 cell count in immunocompromised patients with multiple therapeutic failures. Enfuvirtide use was highly associated with success.