Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial

International audienceIntroductionNeuroinflammation is thought to be important in Alzheimer's disease pathogenesis. Mast cells are a key component of the inflammatory network and participate in the regulation of the blood-brain barrier's permeability. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. As the brain is rich in mast cells, the therapeutic potential of masitinib as an adjunct therapy to standard care was investigated.MethodsA randomised, placebo-controlled, phase 2 study was performed in patients with mild-to-moderate Alzheimer's disease, receiving masitinib as an adjunct to cholinesterase inhibitor and/or memantine. Patients were randomly assigned to receive masitinib (n = 26) (starting dose of 3 or 6 mg/kg/day) or placebo (n = 8), administered twice daily for 24 weeks. The primary endpoint was change from baseline in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog) to assess cognitive function and the related patient response rate.ResultsThe rate of clinically relevant cognitive decline according to the ADAS-Cog response (increase >4 points) after 12 and 24 weeks was significantly lower with masitinib adjunctive treatment compared with placebo (6% vs. 50% for both time points; P = 0.040 and P = 0.046, respectively). Moreover, whilst the placebo treatment arm showed worsening mean ADAS-Cog, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, and Mini-Mental State Examination scores, the masitinib treatment arm reported improvements, with statistical significance between treatment arms at week 12 and/or week 24 (respectively, P = 0.016 and 0.030; P = 0.035 and 0.128; and P = 0.047 and 0.031). The mean treatment effect according to change in ADAS-Cog score relative to baseline at weeks 12 and 24 was 6.8 and 7.6, respectively. Adverse events occurred more frequently with masitinib treatment (65% vs. 38% of patients); however, the majority of events were of mild or moderate intensity and transitory. Severe adverse events occurred at a similar frequency in the masitinib and placebo arms (15% vs. 13% of patients, respectively). Masitinib-associated events included gastrointestinal disorders, oedema, and rash.ConclusionsMasitinib administered as add-on therapy to standard care during 24 weeks was associated with slower cognitive decline in Alzheimer's disease, with an acceptable tolerance profile. Masitinib may therefore represent an innovative avenue of treatment in Alzheimer's disease. This trial provides evidence that may support a larger placebo-controlled investigation.Trial registrationClinicaltrials.gov NCT0097611

Apports de l’évaluation gérontologique pour les patients cardiovasculaires très âgés

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Validation of the French version of the Vulnerable Elders Survey-13 (VES-13)

Abstract Background Identifying and assessing degree and type of frailty among older persons is a major challenge when targeting high risk populations to identify preventive interventions. The Vulnerable Elders Survey-(VES-13) is a simple instrument to identify frailty defined as risk for death, functional decline or institutionalization. Objective Translate VES-13 into French and validate it. Methods The French version of VES-13 was developed by forward-backward translation of the VES-13 survey instrument. The authors assessed its feasibility, construct validity, and ability to predict the combined outcomes of admission to institution or death at 18 months, in 135 persons over 70 years of age living in the community. Subjects were recruited from three settings: Group 1 – a health prevention center ( n = 45); Group 2 – an ambulatory care geriatric clinic ( n = 40); and Group 3 – an intermediate care hospital unit ( n = 50). The combined outcomes data were recorded by telephone interview with participants or a proxy. Results Feasibility of the French version, named Echelle de Vulnérabilité des Ainés-13 or EVA-13, was excellent. The scale classified 5 (11%) persons as vulnerable (score of 3 or more) in Group 1, 23 (58%) in Group 2 and 45 (90%) in Group 3 ( p < 0.001) with scores of 0.91 +/− 1.16, 4.27 +/− 3.17 and 6.90 +/− 3.17, respectively ( p < 0.001). At follow-up, among the 60 non-vulnerable subjects, 58 (96%) were alive and living at home, whereas 46 (65%) of the 70 vulnerable subjects were alive and living at home ( p < 0.001). Conclusions EVA-13 was determined to be valid and reliable

Dementia patients caregivers quality of life: the PIXEL study

International audienceBACKGROUND: Alzheimer's disease and related syndromes have heavy social and human consequences for the patient and his family. Beyond the neuropsychiatric effects of specific therapies for dementia, one of today's challenges is the quality of life for both patients and their informal caregivers. OBJECTIVES: This survey tends to determine parameters influencing caregivers' quality of life, and its possible link with patients' quality of life. METHODS: A scale measuring caregivers' quality of life, developed from data from previous PIXEL studies was used. It is a questionnaire composed of 20 items. The scale was related to the socio-demographic data of both patients and their main caregivers, to the ADRQL scale (Alzheimer Disease Related Quality Life) of Rabins for the QoL of dementia patients, to the patients medical and therapeutic data, specially a neuropsychological inventory: Folstein's cognition test, Cornell's depression scale, the fast battery of frontal assessment, Katz's dependence index, Cummings' neuropsychiatric inventory for behavioral and psychological symptoms of dementia and to a physician evaluation of caregiver's depression. RESULTS: One hundred patients diagnosed with dementia who live at home with their principal caregivers were recruited for this survey. Patients were 80.2 +/- 6.8 years old and caregivers were 65.7 +/- 12.8 years old. The caregivers' quality of life was correlated to the quality of life of the patients they cared for, the importance of behavioral disorders, and the duration of dementia evolution. Women caregivers had a worse quality of life and were more depressive than men. DISCUSSION: Caregivers' and patients' quality of life are related and both share a community of distress

Manual Dexterity and Aging: A Pilot Study Disentangling Sensorimotor From Cognitive Decline

International audienceManual dexterity measures can be useful for early detection of age-related functional decline and for prediction of cognitive decline. However, what aspects of sensorimotor function to assess remains unclear. Manual dexterity markers should be able to separate impairments related to cognitive decline from those related to healthy aging. In this pilot study, we aimed to compare manual dexterity components in patients diagnosed with cognitive decline (mean age: 84 years, N = 11) and in age comparable cognitively intact elderly subjects (mean age: 78 years, N = 11). In order to separate impairments due to healthy aging from deficits due to cognitive decline we also included two groups of healthy young adults (mean age: 26 years, N = 10) and middle-aged adults (mean age: 41 years, N = 8). A comprehensive quantitative evaluation of manual dexterity was performed using three tasks: (i) visuomotor force tracking, (ii) isochronous single finger tapping with auditory cues, and (iii) visuomotor multi-finger tapping. Results showed a highly significant increase in force tracking error with increasing age. Subjects with cognitive decline had increased finger tapping variability and reduced ability to select the correct tapping fingers in the multi-finger tapping task compared to cognitively intact elderly subjects. Cognitively intact elderly subjects and those with cognitive decline had prolonged force release and reduced independence of finger movements compared to young adults and middle-aged adults. The findings suggest two different patterns of impaired manual dexterity: one related to cognitive decline and another related to healthy aging. Manual dexterity tasks requiring updating of performance, in accordance with (temporal or spatial) task rules maintained in short-term memory, are particularly affected in cognitive decline. Conversely, tasks requiring online matching of motor output to sensory cues were affected by age, not by cognitive status. Remarkably, no motor impairments were detected in patients with cognitive decline using clinical scales of hand function. The findings may have consequences for the development of manual dexterity markers of cognitive decline

Interleukin-10 Production in Response to Amyloid-beta Differs between Slow and Fast Decliners in Patients with Alzheimer's Disease

International audienceWe investigated IL-10 and IL-6 production in amyloid-beta (A beta) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer's disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-beta 1 (TGF-beta 1) (-10, -25), interferon-beta (IFN-gamma) (-874), and tumor necrosis factor-alpha (TNF-alpha) (-308) genes were analyzed. IL-10 production after A beta stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-gamma low-producing genotype and fast progression was demonstrated. Investigations in a larger sample will clarify these findings

Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression

International audienceBackground: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-beta (A beta)-stimulated PBMC. Methods: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up = 5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. Results: TL (mean +/- SD) for HE, ADS, and ADFwas 2.3 +/- 0.1, 2.0 +/- 0.1, and 2.5 +/- 0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R-2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and A beta-stimulated PBMC from ADS (40.7 +/- 13.7 versus 59.0 +/- 27.0; p = 0.004) but not from ADF (39.7 +/- 14.4 versus 42.2 +/- 22.4). HE showed a trend toward significance (47.1 +/- 25.4 versus 55.3 +/- 27.9; p = 0.10). Conclusion: PBMC from ADF may be characterized by an impaired response induced by A beta and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression