Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Mild behavioral impairment domains are longitudinally associated with pTAU and metabolic biomarkers in dementia-free older adults.

BACKGROUND: The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. METHODS: Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed-effects models. RESULTS: The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. DISCUSSION: Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. HIGHLIGHTS: Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p. pTau could be a pharmacological target to treat agitation and psychosis symptoms. MBI domains were linked to metabolic dysregulation involving insulin and homocysteine.

Investigating three ways of measuring the intrinsic capacity domain of vitality: nutritional status, handgrip strength and ageing biomarkers.

BACKGROUND: Vitality is conceptually considered as the underlying capacity influencing other intrinsic capacity (IC) domains and being related to nutrition, physiological reserve and biological ageing. However, there is no consensus on its operationalisation. OBJECTIVE: To investigate the structure and magnitude of the association of vitality with other IC domains and functional difficulties using three operational definitions of vitality. METHODS: We included 1,389 older adults from the Multidomain Alzheimer Preventive Trial with data on Mini Nutritional Assessment (MNA), handgrip strength and plasma biomarkers (comprising inflammatory and mitochondrial markers). Using path analysis, we examined the effects of vitality on difficulties in basic and instrumental activities of daily living (ADL and IADL) exerted directly and indirectly through the mediation of other IC domains: cognition, locomotion, psychological, vision and hearing. We further explored the longitudinal association of vitality with IC domains, ADL and IADL over 4 years using linear mixed-effect regression. RESULTS: We observed significant indirect effects of vitality on IADL, mainly through cognitive, locomotor and psychological domains, regardless of the vitality measurement. Participants with higher vitality had fewer IADL difficulties at follow-up (MNA score: ß [95% CI] = -0.020 [-0.037, -0.003]; handgrip strength: -0.011 [-0.023, 0.000]; plasma biomarker-based index: -0.015 [-0.028, -0.002]). Vitality assessed with the plasma biomarker-based index predicted improved locomotion over time. CONCLUSION: Vitality was associated with disability primarily through the mediation of other IC domains. The three indicators examined are acceptable measurements of vitality; biomarkers might be more suitable for the early detection of locomotion decline.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease.

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).

Prevalence of healthy aging among community dwelling adults age 70 and older from five European countries.

BACKGROUND: To compare the prevalence of healthy aging among adults age 70 and older from 5 European countries recruited for the DO-HEALTH clinical trial. Participants were selected for absence of prior major health events. METHODS: Cross-sectional analysis of DO-HEALTH baseline data. All 2,157 participants (mean age 74.9, SD 4.4; 61.7% women) were included and 2,123 had data for all domains of the healthy aging status (HA) definition. HA was assessed based on the Nurses` Health Study (NHS) definition requiring four domains: no major chronic diseases, no disabilities, no cognitive impairment (Montreal Cognitive Assessment, MoCA ≥25), no mental health limitation (GDS-5 <2, and no diagnosis of depression). Association between HA and age, BMI, gender, and physical function (sit-to-stand, gait speed, grip strength) was assessed by multivariate logistic regression analyses adjusting for center. RESULTS: Overall, 41.8% of DO-HEALTH participants were healthy agers with significant variability by country: Austria (Innsbruck) 58.3%, Switzerland (Zurich, Basel, Geneva) 51.2%, Germany (Berlin) 37.6%, France (Toulouse) 36.7% and Portugal (Coimbra) 8.8% (p <0.0001). Differences in prevalence by country persisted after adjustment for age. In the multivariate model, younger age (OR = 0.95, 95% CI 0.93 to 0.98), female gender (OR = 1.36, 95% CI 1.03 to 1.81), lower BMI (OR = 0.94, 95% CI 0.91 to 0.96), faster gait speed (OR = 4.70, 95% CI 2.68 to 8.25) and faster performance in sit-to-stand test (OR = 0.90, 95% CI 0.87 to 0.93) were independently and significantly associated with HA. CONCLUSIONS: Despite the same inclusion and exclusion criteria preselecting relatively healthy adults age 70 years and older, HA prevalence in DO-HEALTH varied significantly between countries and was highest in participants from Austria and Switzerland, lowest in participants from Portugal. Independent of country, younger age, female gender, lower BMI and better physical function were associated with HA. TRIAL REGISTRATION: DO-HEALTH was registered under the protocol NCT01745263 at the International Trials Registry ( clinicaltrials.gov ), and under the protocol number 2012-001249-41 at the Registration at the European Community Clinical Trial System (EudraCT).

Prevalence and incidence of iron deficiency in European community-dwelling older adults: an observational analysis of the DO-HEALTH trial.

BACKGROUND AND AIM: Iron deficiency is associated with increased morbidity and mortality in older adults. However, data on its prevalence and incidence among older adults is limited. The aim of this study was to investigate the prevalence and incidence of iron deficiency in European community-dwelling older adults aged ≥ 70 years. METHODS: Secondary analysis of the DO-HEALTH trial, a 3-year clinical trial including 2157 community-dwelling adults aged ≥ 70 years from Austria, France, Germany, Portugal and Switzerland. Iron deficiency was defined as soluble transferrin receptor (sTfR) > 28.1 nmol/L. Prevalence and incidence rate (IR) of iron deficiency per 100 person-years were examined overall and stratified by sex, age group, and country. Sensitivity analysis for three commonly used definitions of iron deficiency (ferritin < 45 µg/L, ferritin < 30 µg/L, and sTfR-ferritin index > 1.5) were also performed. RESULTS: Out of 2157 participants, 2141 had sTfR measured at baseline (mean age 74.9 years; 61.5% women). The prevalence of iron deficiency at baseline was 26.8%, and did not differ by sex, but by age (35.6% in age group ≥ 80, 29.3% in age group 75-79, 23.2% in age group 70-74); P < 0.0001) and country (P = 0.02), with the highest prevalence in Portugal (34.5%) and the lowest in France (24.4%). As for the other definitions of iron deficiency, the prevalence ranged from 4.2% for ferritin < 30 µg/L to 35.3% for sTfR-ferritin index > 1.5. Occurrences of iron deficiency were observed with IR per 100 person-years of 9.2 (95% CI 8.3-10.1) and did not significantly differ by sex or age group. The highest IR per 100 person-years was observed in Austria (20.8, 95% CI 16.1-26.9), the lowest in Germany (6.1, 95% CI 4.7-8.0). Regarding the other definitions of iron deficiency, the IR per 100 person-years was 4.5 (95% CI 4.0-4.9) for ferritin < 45 µg/L, 2.4 (95% CI 2.2-2.7) for ferritin < 30 µg/L, and 12.2 (95% CI 11.0-13.5) for sTfR-ferritin index > 1.5. CONCLUSIONS: Iron deficiency is frequent among relatively healthy European older adults, with people aged ≥ 80 years and residence in Austria and Portugal associated with the highest risk.

Neuroimaging correlates of persistent fatigue in older adults: A secondary analysis from the Multidomain Alzheimer Preventive Trial (MAPT) trial.

OBJECTIVES: Fatigue has been suggested as a marker of biological aging. It seems plausible that this symptom might be associated with changes in brain health. The objective of this study was to examine the associations between persistent fatigue and neuroimaging correlates in a non-disease-specific population of community-dwelling older adults. METHODS: We performed a cross-sectional analysis using data from The Multidomain Alzheimer Preventive Trial (MAPT). We included 458 subjects. Persistent fatigue was defined as meeting exhaustion criterion of Fried frailty phenotype in two consecutive clinical visits six months apart between study baseline and one year. Brain imaging correlates, assessed by magnetic resonance imaging (MRI), were the outcomes. The associations between persistent fatigue and brain correlates were explored using mixed model linear regressions with random effect at the center level. RESULTS: The mean age of the participants was 74.8 ± 4 years old, and 63% of the subjects were women. Forty-seven participants (10%) exhibited a persistent fatigue profile. People with persistent fatigue were older compared to subjects without persistent fatigue (76.2 years ± 4.3 vs.74.7 ± 3.9 p = 0.009). Persistent fatigue was associated with higher white matter hyperintensity volume in the fully adjusted analysis. We did not find any cross-sectional association between persistent fatigue and sub-cortical volumes and global and regional cortical thickness. CONCLUSION: Persistent fatigue was cross-sectionnally associated with higher white matter hyperintensity volume in older adults. Further longitudinal studies, using an assessment tool specifically designed and validated for measuring fatigue, are needed to confirm our findings.

Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia.

BACKGROUND: Little is known regarding the dose-response function in multidomain interventions for dementia prevention. METHOD: The Multidomain Alzheimer Preventive Trial is a 3-year randomized controlled trial comprising cognitive training, physical activity, nutrition, and omega-3 polyunsaturated fatty acids for at-risk older adults. The dose delivered (number of sessions attended) was modeled against global cognition, memory, and fluency in 749 participants. Interaction effects were assessed for age, sex, education, dementia score (CAIDE), frailty score, and apolipoprotein E (APOE) ε4 status. RESULTS: The dose-response models were non-linear functions indicating benefits up to about 12 to 14 training hours or 15 to 20 multidomain sessions followed by a plateau. Participants who benefited from a higher dose included women, younger participants, frail individuals, and those with lower education or lower risk of dementia. DISCUSSION: The non-linear function indicates that a higher dose is not necessarily better in multidomain interventions. The optimal dose was about half of the potentially available sessions.

Cognitive decline as an outcome and marker of progression toward dementia, in early preventive trials.

INTRODUCTION: Recent Food and Drug Administration guidance endorses cognitive assessment as a possible primary endpoint for early trials for Alzheimer's disease but emphasizes the need for certainty regarding the relationship with progression to dementia. METHODS: We compared the validity of the 2-year change (Y0-Y2) of 11 markers of neuropsychological and functional abilities for the prediction of incident dementia over the following 3 years (Y2-Y5), in 860 subjects aged 70 years or older, who consulted for memory loss and were included in the "GuidAge" prevention trial. RESULTS: The Free and Cued Selective Reminding Test-Free Recall (FCSRT-FR) score showed the most predictive 2-year change (area under the curve = 0.72 95% confidence interval = 0.64;0.81). Changes in other subscores of the FCSRT, verbal fluencies tasks, and composite cognitive score were also significantly predictive. Conversely, 2-year change of Mini-Mental State Examination, Trail Making test (TMT)-A, TMT-B, Clinical Dementia Rating Sum of Boxes, and Instrumental Activities of Daily Living scores did not significantly predict occurrence of dementia. CONCLUSION: The FCSRT, the Fluency Task, and the composite cognitive score appear to be good cognitive markers of progression toward dementia in early prevention trials.

Plasma amyloid beta predicts conversion to dementia in subjects with mild cognitive impairment: The BALTAZAR study.

INTRODUCTION: Blood-based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. METHODS: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large-scale longitudinal multicenter cohort, were followed-up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aß)1-42 , Aß1-40 , Aß1-42 /Aß1-40 ratio were analyzed with logistic and Cox models. RESULTS: Converters to dementia had lower level of plasma Aß1-42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value = .03) and lower Aß1-42 /Aß1-40 ratio than non-converters (0.148 [0.125] vs. 0.154 [0.076], P value = .02). MCI participants in the highest quartile of Aß1-42 /Aß1-40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31-0.86], P value = .01). DISCUSSION: In this large cohort of MCI subjects we identified a threshold for plasma Aß1-42 /Aß1-40 ratio that may detect patients with a low risk of conversion to dementia within 3 years.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aß1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS: A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

What day is today? Cognitive capacity and the risk of incident dementia in the context of integrated care for older people (ICOPE Step 1).

Based on clinical observations, our objective was to test if the older adults who failed to recall the name of the weekday, or had a higher number of mistakes in the word recall were at higher risk of mild cognitive impairment (MCI) or dementia. Longitudinal data of the Multidomain Alzheimer Preventive Trial (MAPT) was used to retrospectively measure the cognitive capacity according to the ICOPE Step 1 tool. Incident dementia was assessed by two multidisciplinary committees independent from each other. MCI was defined as Clinical Dementia Rating scale CDR = 0.5. Failure to recall the name of the weekday had a three-fold risk of incident dementia in the next 5 years (HRa = 3.11, 95%CI: 1.18-8.17). Having two or three mistakes in the word recall carried a higher risk of incident dementia, (HRa for two mistakes = 3.50, 95% CI: 1.49-8.26; HRa for three mistakes = 4.28, 95% CI: 1.60-11.46), but not MCI. People with impaired cognitive capacity according to the ICOPE Step 1 tool deserve further assessment and a closer follow-up.

Neuroimaging markers of chronic fatigue in older people: a narrative review.

BACKGROUND: Chronic fatigue is a common symptom in older adults. Although some studies have attempted to identify the neuronal correlates of fatigue associated with chronic diseases, the scientific evidence is scarce regarding fatigue in older people not suffering from a specific disease. AIMS: To gather available evidence of neuroimaging studies investigating the associations between fatigue and brain health in older adults out of the context of a specific disease, and to identify potential brain structures associated with this symptom. METHODS: Studies considering exclusively patients with a specific disease and/or studies focusing on physiological mechanisms of acute fatigue induced by the realization of cognitive and physical tasks were excluded. RESULTS: Very few studies on the associations of fatigue with neuroimaging markers are currently available. Fatigue was associated with reduced hippocampus volumes and with hippocampal amyloid deposition. Regarding the association between fatigue and the circuit of basal ganglia, putamen and thalamus were associated with physical fatigability, whereas amygdala and thalamus with mental fatigability. Very limited evidence about white matter integrity found that healthy individuals with high levels of fatigue had a greater total volume of leukoaraiosis. CONCLUSION: This review suggests that hippocampus damage and potentially loss of function in basal ganglia networks could play a role on chronic fatigue during aging. Further studies are needed to assess the associations of fatigue with white matter alterations.

Update on the ESCEO recommendation for the conduct of clinical trials for drugs aiming at the treatment of sarcopenia in older adults.

BACKGROUND: In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia. AIMS: The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations. METHODS: This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations. RESULTS: The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure. CONCLUSION: The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria.

INTRODUCTION: The 2017 European Union-North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician-rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria. METHODS: In a modified Delphi process, Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory-Clinician (NPI-C) items were mapped to IPA agitation domains generating novel instruments, CMAI-IPA and NPI-C-IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity. RESULTS: MCID was -17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8-32.6) for CMAI; -5 (OR = 9.3, 95% CI = 4.0-21.2) for CMAI-IPA; -3 (OR = 11.9, 95% CI = 4.1-34.8) for NPI-C-A+A; and -5 (OR = 7.8, 95% CI = 3.4-17.9) for NPI-C-IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high. CONCLUSION: Internal consistency and reliability analyses demonstrated better accuracy for the NPI-C-IPA than for the CMAI-IPA and can be used for agitation clinical trial inclusion, and for response to intervention.

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease.

INTRODUCTION: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. METHODS: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. RESULTS: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-ß (Aß42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aß measures in CU individuals. DISCUSSION: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.

[The digital tool for the prevention of dependency in the elderly]. / L'outil numérique au service de la prévention de la dépendance des sujets âgés.

Dependency care is a real public health issue. The lengthening of life expectancy and the increase in polypathologies require health policies that are as close as possible to the needs of the elderly. The World Health Organisation has set up a program to encourage healthy ageing. Based on this program, the Toulouse gerontopôle has developed digital tools for the prevention, evaluation, monitoring and management of ageing in order to detect and monitor 200,000 elderly people in Occitania within five years.