Usefulness of data from magnetic resonance imaging to improve prediction of dementia: population based cohort study

© BMJ Publishing Group Ltd 2015. OBJECTIVE: To determine whether the addition of data derived from magnetic resonance imaging (MRI) of the brain to a model incorporating conventional risk variables improves prediction of dementia over 10 years of follow-up. DESIGN: Population based cohort study of individuals aged ≥65. SETTING: The Dijon magnetic resonance imaging study cohort from the Three-City Study, France. PARTICIPANTS: 1721 people without dementia who underwent an MRI scan at baseline and with known dementia status over 10 years' follow-up. MAIN OUTCOME MEASURE: Incident dementia (all cause and Alzheimer's disease). RESULTS: During 10 years of follow-up, there were 119 confirmed cases of dementia, 84 of which were Alzheimer's disease. The conventional risk model incorporated age, sex, education, cognition, physical function, lifestyle (smoking, alcohol use), health (cardiovascular disease, diabetes, systolic blood pressure), and the apolipoprotein genotype (C statistic for discrimination performance was 0.77, 95% confidence interval 0.71 to 0.82). No significant differences were observed in the discrimination performance of the conventional risk model compared with models incorporating data from MRI including white matter lesion volume (C statistic 0.77, 95% confidence interval 0.72 to 0.82; P=0.48 for difference of C statistics), brain volume (0.77, 0.72 to 0.82; P=0.60), hippocampal volume (0.79, 0.74 to 0.84; P=0.07), or all three variables combined (0.79, 0.75 to 0.84; P=0.05). Inclusion of hippocampal volume or all three MRI variables combined in the conventional model did, however, lead to significant improvement in reclassification measured by using the integrated discrimination improvement index (P=0.03 and P=0.04) and showed increased net benefit in decision curve analysis. Similar results were observed when the outcome was restricted to Alzheimer's disease. CONCLUSIONS: Data from MRI do not significantly improve discrimination performance in prediction of all cause dementia beyond a model incorporating demographic, cognitive, health, lifestyle, physical function, and genetic data. There were, however, statistical improvements in reclassification, prognostic separation, and some evidence of clinical utility

Neurobiol Aging

GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02149160

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Prevalence of dementia among older people from rural Hmong and non-Hmong communities living in Vangvieng, Lao People's Democratic Republic.

International audienceBackground: The global prevalence of dementia has been estimated at 44.35 million in 2013 and is expected to rise to 135.46 million by 2050. Southeast Asia will not be spared by this epidemic as the proportionate increase of affected people will be one of the highest, reaching 340% (Prince et al., 2013).Aim: The aim of this study was to estimate the prevalence of dementia among older people in Lao PDR and investigate the factors associated with dementia in those communities.Methods: A cross sectional 2-stage study among people aged 65 years old and over living in Vangvieng (province of Vientiane) was carried out. Socio-demographic data and medical history were collected. Participants were screened using the Community Screening Instrument for Dementia (CSI-D), those who obtained a poor performance where assessed by a neurologist and performed further psychometrical tests. Diagnosis of dementia followed the DSM-IV criteria.This study was approved by the Ethics Committee of the Ministry of Health of Lao PDR.Results: In total, 471 elderly were included in this study, with a mean age of 74.1 ± 6.9 years. After neurological assessment, the prevalence of dementia was estimated at 9.1% (95% CI [6.7–12.1]) in this rural area of Laos, and wasn't different between Hmong (9.2%, 95% CI [5.8–13.7]) and non-Hmong (9.1%, 95% CI [5.8–13.4]; p = 0.976) ethnic groups.Conclusion: This first population-based study in Lao PDR showed a high crude prevalence of dementia, close to the estimates for other Asian or LMIC countries

Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer’s disease who failed to benefit from previous cholinesterase inhibitor treatment.

International audienc

Everyday-like memory for objects in ageing and Alzheimer's disease assessed in a visually complex environment: The role of executive functioning and episodic memory

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Clustering and switching processes in semantic verbal fluency in the course of Alzheimer's disease subjects: Results from the PAQUID longitudinal study.: Verbal fluency in pre-clinical AD

International audienceReduced semantic fluency performances have been reported in the preclinical phase of Alzheimer's disease (AD). To investigate the cognitive processes underlying this early deficit, this study analyzed the verbal production of predemented subjects for the animals category with the qualitative parameters related to clustering (i.e. the ability to generate words belonging to semantic subcategories of animals) and switching (i.e. the ability to shift from one subcategory to another) proposed by Troyer. This qualitative analysis was applied to the PAQUID (Personnes Ag? QUID) cohort, a 17-year longitudinal population-based study. The performances on the animal verbal fluency task of 51 incident cases of possible and probable AD were analyzed at the onset of dementia, 2 years and 5 years before dementia onset. Each case was matched for age, sex and education to two control subjects leading to a sample of 153 subjects. The mean cluster size and the raw number of switches were compared in the two samples. The results revealed a significantly lower switching index in the future AD subjects than in the elderly controls including 5 years before dementia incidence. A significant decline in this parameter was evidenced all along the prodromal phase until the clinical diagnosis of dementia. In contrast, the mean cluster size could not discriminate the two groups. Therefore the results support the hypothesis that impaired shifting abilities - rather than semantic memory storage degradation - could explain the early decline in semantic fluency performance occurring in the predementia phase of AD

Neuropsychology

OBJECTIVE:To evaluate whether visual cues are helpful for virtual spatial navigation and memory in Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI). METHOD:20 patients with AD, 18 patients with MCI and 20 age-matched healthy controls (HC) were included. Participants had to actively reproduce a path that included 5 intersections with one landmark at each intersection that they had seen previously during a learning phase. Three cueing conditions for navigation were offered: salient landmarks, directional arrows and a map. A path without additional visual stimuli served as control condition. Navigation time and number of trajectory mistakes were recorded. RESULTS:With the presence of directional arrows, no significant difference was found between groups concerning the number of trajectory mistakes and navigation time. The number of trajectory mistakes did not differ significantly between patients with AD and patients with MCI on the path with arrows, the path with salient landmarks and the path with a map. There were significant correlations between the number of trajectory mistakes under the arrow condition and executive tests, and between the number of trajectory mistakes under the salient landmark condition and memory tests. CONCLUSION:Visual cueing such as directional arrows and salient landmarks appears helpful for spatial navigation and memory tasks in patients with AD and patients with MCI. This study opens new research avenues for neuro-rehabilitation, such as the use of augmented reality in real-life settings to support the navigational capabilities of patients with MCI and patients with AD. (PsycINFO Database Recor

Symptomatic treatments in Alzheimer's disease in 2016: a study from Memory centers in France

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