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Abstract Background The Clinical Dementia Rating (CDR) scale allows to detect the presence of dementia and to assess its severity, however its evaluation requires a significant time (45 min). We evaluated the agreement between two methods of collection of the CDR: face-to-face interview or based on the information available in the patient’s medical record. Methods The CLIMER study was conducted among patients attending a memory center. The CDR scale was evaluated during face-to-face interviews between neuropsychologists and patients and their caregivers and based on blind analysis of the information of the patients’ medical record by neuropsychologists. The agreement of the CDR sum of boxes (CDR-SB), the 5-point scale CDR and the different domains of the CDR evaluated between the different methods was measured using intraclass correlation (ICC) coefficient, Bland and Altman method, and linearly weighted Kappa. Results The study included 139 patients (means ± SD age 80.1 ± 6, 58.3% women, 71.9% with dementia). The ICC for the CDR-SB score assessed by face-to-face and with all the information available in the patient’s medical record was 0.95 (95% CI: 0.93–0.97). The mean difference between the CDR-SB score assessed by face-to-face and with the medical record was 0.098 ± 1.036, and 92.4% of the patients lay within the 95% limits of agreement. The ICC for the 5-point scale CDR assessed by face-to-face and with the patient’s medical record was 0.92 (95% CI: 0.88–0.95) when all the available information of the patient’s medical record was used. The linear weighted Kappa coefficients was 0.79 (95% CI: 0.68–0.91) for the 5-point scale CDR comparison between the two evaluation methods. The analysis by domain of the CDR showed ICC ranging from 0.65 to 0.91 depending of the domains and the methods of evaluation. Conclusion This study showed an excellent level of agreement of the evaluation of the CDR- SB and the 5-point scale CDR when using all the information of the patient’s medical record compared to the face-to-face interview. Trial registration https//clinicaltrials.gov/ct2/show/NCT04763941 Registration Date 02/17/2021.

Abstract Background The identification of factors involved in the conversion across the different Alzheimer’s disease (AD) stages is crucial to prevent or slow the disease progression. We aimed to assess the factors and their combination associated with the conversion across the AD stages, from mild cognitive impairment to dementia, at a mild, moderate or severe stage and to identify profiles associated with earliest/latest conversion across the AD stages. Methods In this study conducted on the real-life MEMORA cohort data collected from January 1, 2013, and December 31, 2019, three cohorts were selected depending on the baseline neurocognitive stage from a consecutive sample of patients attending a memory center, aged between 50 and 90 years old, with a diagnosis of AD during the follow-up, and with at least 2 visits at 6 months to 1 year of interval. A machine learning approach was used to assess the relationship between factors including socio-demographic characteristics, comorbidities and history of diseases, prescription of drugs, and geriatric hospitalizations, and the censored time to conversion from mild cognitive impairment to AD dementia, from the mild stage of dementia to the moderate or severe stages of AD dementia, and from the moderate stage of AD dementia to the severe stage. Profiles of earliest/latest conversion compared to median time to conversion across stages were identified. The median time to conversion was estimated with a Kaplan-Meier estimator. Results Overall, 2891 patients were included (mean age 77±9 years old, 65% women). The median time of follow-up was 28 months for mild cognitive impairment (MCI) patients, 33 months for mild AD dementia and 30 months for moderate AD dementia. Among the 1264 patients at MCI stage, 61% converted to AD dementia (median time to conversion: 25 months). Among the 1142 patients with mild AD dementia, 59% converted to moderate/severe stage (median time: 23 months) and among the 1332 patients with moderate AD dementia, 23% converted to severe stage (Q3 time to conversion: 22 months). Among the studied factors, cardiovascular comorbidities, anxiety, social isolation, osteoporosis, and hearing disorders were identified as being associated with earlier conversion across stages. Symptomatic treatment i.e. cholinesterase inhibitors for AD was associated with later conversion from mild stage of dementia to moderate/severe stages. Conclusion This study based on a machine learning approach allowed to identify potentially modifiable factors associated with conversion across AD stages for which timely interventions may be implemented to delay disease progression.

Abstract Background Long-term exposure to anticholinergic and sedative drugs could be a modifiable risk factor for cognitive decline. The objective of this study was to measure the association between previous cumulative anticholinergic and sedative drug exposure (Drug Burden Index) and cognitive decline. Methods A cohort study (MEMORA cohort) was conducted in a French memory clinic for patients attending a consultation between November 2014 and December 2020, with at least 2 Mini-Mental State Examination (MMSE) measurements (≥ 6 months apart) and available medication data from the local Primary Health Insurance Fund database (n = 1,970). Drug Burden Index was linearly cumulated until each MMSE measurement and was used to categorise patients according to their level of exposure (no exposure, moderate, or high). The longitudinal association between Drug Burden Index and MMSE was assessed using a multivariate linear mixed model, adjusted for age, education level, anxiety disorders, depressive disorders, functional autonomy, and behavioural disorders. Results Overall, 1,970 patients were included with a mean follow-up duration of 2.78 years (± 1.54) and 2.99 visits per patients (5,900 MMSE + Drug Burden Index measurements collected). At baseline, 68.0% of patients had moderate cumulative anticholinergic and sedative drug exposure and a mean MMSE of 21.1. MMSE decrease was steeper in patients with moderate and high Drug Burden Index ( -1.74 and -1.70/year, respectively) than in patients with no exposure (-1.26/year) after adjusting for age, education, anxiety and depressive disorders, functional autonomy, and behavioural disorders (p

Abstract Background A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. Methods This retrospective longitudinal observational study involved 229 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. Results We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. Conclusion The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.

Abstract Background People with dementia (PwD) are known to have more chronic conditions compared to those without dementia, which can impact the clinical presentation of dementia, complicate clinical management and reduce overall quality of life. While primary care providers (PCPs) are integral to dementia care, it is currently unclear how PCPs adapt dementia care practices to account for comorbidities. This scoping review maps recent literature that describes the role for PCPs in the prevention, detection/diagnosis and management of dementia in the context of comorbidities, identifies critical knowledge gaps and proposes potential avenues for future research. Methods We searched for peer-reviewed literature published between 2017–2022 in MEDLINE, Cochrane Library, and Scopus using key terms related to dementia, primary care, and comorbidity. The literature was screened for relevance by title-abstract screening and subsequent full-text screening. The prioritized papers were categorized as either ‘Risk Assessment and Prevention’, ‘Screening, Detection, and Diagnosis’ or ‘Management’ and were further labelled as either ‘Tools and Technologies’, ‘Recommendations for Clinical Practice’ or ‘Programs and Initiatives’. Results We identified 1,058 unique records in our search and respectively excluded 800 and 230 publications during title-abstract and full-text screening. Twenty-eight articles were included in our review, where ~ 50% describe the development and testing of tools and technologies that use pre-existing conditions to assess dementia risk. Only one publication provides official dementia screening guidelines for PCPs in people with pre-existing conditions. About 30% of the articles discuss managing the care of PwD, where most were anchored around models of multidisciplinary care and mitigating potentially inappropriate prescribing. Conclusion To our knowledge, this is the first scoping review that examines the role for PCPs in the prevention, detection/diagnosis and management of dementia in the context of comorbidities. Given our findings, we recommend that future studies: 1) further validate tools for risk assessment, timely detection and diagnosis that incorporate other health conditions; 2) provide additional guidance into how comorbidities could impact dementia care (including prescribing medication) in primary care settings; 3) incorporate comorbidities into primary care quality indicators for dementia; and 4) explore how to best incorporate dementia and comorbidities into models/frameworks of holistic, person-centred care.

Abstract Aims The heart failure (HF) prognosis in older patients remains poor with a high 5‐years mortality rate more frequently attributed to noncardiovascular causes. The complex interplay between frailty and heart failure contribute to poor health outcomes of older adults with HF independently of ejection fraction. The aim of this position paper is to propose a practical management of frailty in older patients with heart failure. Methods A panel of multidisciplinary experts on behalf the Heart Failure Working Group of the French Society of Cardiology and on behalf French Society of Geriatrics and Gerontology conducted a systematic literature search on the interlink between frailty and HF, met to propose an early frailty screening by non‐geriatricians and to propose ways to implement management plan of frailty. Statements were agreed by expert consensus. Results Clinically relevant aspects of interlink between frailty and HF have been reported to identify the population eligible for screening and the most suitable screening test(s). The frailty screening program proposed focuses on frailty model defined by an accumulation of deficits including geriatric syndromes, comorbidities, for older patients with HF in different settings of care. The management plan of frailty includes optimization of HF pharmacological treatments and non‐surgical device treatment as well as optimization of a global patient‐centred biopsychosocial blended collaborative care pathway. Conclusion The current manuscript provides practical recommendations on how to screen and optimize frailty management in older patients with heart failure.

Background: Psychosocial interventions for caregivers of patients with Alzheimer disease and relative dementias (ADRD) reported a caregiver burden improvement. Multicomponent intervention integrating pharmaceutical care has not yet been evaluated while ADRD patients and their caregivers are exposed to high risk of drug-related problems. The PHARMAID study aimed to assess the impact of personalized pharmaceutical care integrated to a psychosocial program on the burden of ADRD caregivers at 18 months. Methods: The PHARMAID RCT was conducted between September 2016 and June 2020 [ClinicalTrials.gov: NCT02802371]. PHARMAID study planned to enroll 240 dyads, i.e. ADRD patients and caregivers, whose inclusion criteria were: outpatient with mild or major neurocognitive disorders due to ADRD, living at home, receiving support from a family caregiver. Three parallel groups compared a control group with two interventional groups: psychosocial intervention and integrated pharmaceutical care at a psychosocial intervention. The main outcome was the caregiver burden assessed by the Zarit Burden Index (ZBI, score range 0–88) at 18 months. Results: Overall, 77 dyads were included (32% of the expected sample size). At 18 months, the mean ZBI scores were 36.7 ± 16.8 in the control group, 30.3 ± 16.3 for the group with psychosocial intervention, and 28.8 ± 14.1 in group with integrated pharmaceutical care at psychosocial intervention. No significant difference was demonstrated between the three groups (p = 0.326). Conclusions: The findings suggest that PHARMAID program had no significant impact on caregiver burden at 18 months. Several limitations have been highlighted and discussed by the authors in order to formulate recommendations for further research.

Abstract Background Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. Methods Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. Results The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. Conclusions Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. Trial registration Clinicaltrials.gov , NCT01926249

Abstract Background Alzheimer’s disease (AD) substantially increases health-related costs. This study investigates direct medical costs and characterizes the caregiver burden across AD stages. Methods This study analyzed data from the French Primary Health Insurance Fund claims database and reflected this public payer perspective. Outpatients (N = 1998) visiting a memory clinic at Lyon University Hospital in France between 2014 and 2019 were included. Real healthcare costs (ie, ambulatory medicine, paramedical care, pharmaceutical treatment, public and private hospital stays, and medical transportation) were collected for patients 1 year prior to the date of the first memory visit and 2 years following the first visit (reference year: 2019). Patients were grouped based on a clinical diagnosis of cognitively normal with a subjective cognitive complaint (SCC), all-cause mild cognitive impairment (MCI), or AD dementia. The severity of AD dementia was defined by the Mini-Mental State Examination score. Caregiver burden was measured using the mini Zarit Burden Interview. A generalized linear model was used for statistical analyses. Other patient nonmedical and indirect costs and caregiver costs were not included. Results The study sample included patients with SCC (n = 640), MCI (n = 630), mild (n = 212), moderate (n = 256), or moderately severe/severe AD dementia (n = 260). One year after the first consultation, mean total costs were higher with progressive cognitive deficit, with little difference between dementia groups (SCC = €8028; MCI = €9758; mild AD dementia = €10,558; moderate AD dementia = €10,544; moderately severe/severe AD dementia = €10,345; P < .001). Public hospital stays comprised the majority of direct medical costs during the first semester following the visit (49.4% of the total costs), regardless of the severity of cognitive deficit. Caregiver burden increased with the severity of cognitive deficit (P < .0001). Conclusions Direct medical costs and caregiver burden rose from SCC to AD dementia; in patients with AD dementia, the direct medical costs increased over the 2 years after the first consultation. These results, in conjunction with data from other care components, will be critical to elucidate the potential economic value of a therapeutic intervention that slows AD progression.

The evolution of functional autonomy loss leads to institutionalization of people affected by Alzheimer’s disease (AD), to an alteration of their quality of life and that of their caregivers. To predict loss of functional autonomy could optimize prevention strategies, aids and cost of care. The aim of this study was to develop and to cross-validate a model to predict loss of functional autonomy as assessed by Instrumental Activities of Daily Living (IADL) score. Outpatients with probable AD and with 2 or more visits to the Clinical and Research Memory Centre of the University Hospital were included. Four Tree-Augmented Naïve bayesian networks (6, 12, 18 and 24 months of follow-up) were built. Variables included in the model were demographic data, IADL score, MMSE score, comorbidities, drug prescription (psychotropics and AD-specific drugs). A 10-fold cross-validation was conducted to evaluate robustness of models. The study initially included 485 patients in the prospective cohort. The best performance after 10-fold cross-validation was obtained with the model able to predict loss of functional autonomy at 18 months (area under the curve of the receiving operator characteristic curve = 0.741, 27% of patients misclassified, positive predictive value = 77% and negative predictive value = 73%). The 13 variables used explain 41.6% of the evolution of functional autonomy at 18 months. A high-performing predictive model of AD evolution of functional autonomy was obtained. An external validation is needed to use the model in clinical routine so as to optimize the patient care.

BackgroundMotor imagery practice (MIP) and anodal transcranial direct current stimulation (a-tDCS) are innovative methods with independent positive influence on motor sequence learning (MSL) in older adults.ObjectiveThe present study investigated the effect of MIP combined with a-tDCS over the primary motor cortex (M1) on the learning of a finger tapping sequence of the non-dominant hand in healthy older adults.MethodsThirty participants participated in this double-blind sham-controlled study. They performed three MIP sessions, one session per day over three consecutive days and a retention test 1 week after the last training session. During training / MIP, participants had to mentally rehearse an 8-element finger tapping sequence with their left hand, concomitantly to either real (a-tDCS group) or sham stimulation (sham-tDCS group). Before and after MIP, as well as during the retention test, participants had to physically perform the same sequence as fast and accurately as possible.ResultsOur main results showed that both groups (i) improved their performance during the first two training sessions, reflecting acquisition/on-line performance gains, (ii) stabilized their performance from one training day to another, reflecting off-line consolidation; as well as after 7 days without practice, reflecting retention, (iii) for all stages of MSL, there was no significant difference between the sham-tDCS and a-tDCS groups.ConclusionThis study highlights the usefulness of MIP in motor sequence learning for older adults. However, 1.5 mA a-tDCS did not enhance the beneficial effects of MIP, which adds to the inconsistency of results found in tDCS studies. Future work is needed to further explore the best conditions of use of tDCS to improve motor sequence learning with MIP.

Abstract Some of the behavioral disorders observed in Parkinson’s disease (PD) may be related to an altered processing of social messages, including emotional expressions. Emotions conveyed by whole body movements may be difficult to generate and be detected by PD patients. The aim of the present study was to compare valence judgments of emotional whole body expressions in individuals with PD and in healthy controls matched for age, gender and education. Twenty-eight participants (13 PD patients and 15 healthy matched control participants) were asked to rate the emotional valence of short movies depicting emotional interactions between two human characters presented with the “Point Light Displays” technique. To ensure understanding of the perceived scene, participants were asked to briefly describe each of the evaluated movies. Patients’ emotional valence evaluations were less intense than those of controls for both positive (p

Older drivers face the prospect of having to adjust their driving habits because of health problems, which can include neurocognitive disorders. Self-awareness of driving difficulties and the interaction between individual with neurocognitive disorders and natural caregiver seem to be important levers for the implementation of adaptation strategies and for the subsequent voluntary cessation of driving when the cognitive disorders become too severe. This study aims to evaluate an educational program for patient/natural caregiver dyads who wish to implement self-regulation strategies in driving activity, and to improve self-awareness of driving ability. The ACCOMPAGNE program is based on seven group workshops, which target the dyad. The workshops deal with the impact of cognitive, sensory and iatrogenic disorders on driving. They tackle questions about responsibility, and about autonomy and social life. They also provide alternative solutions aimed at maintaining outward-looking activities even if driving is reduced or stopped. A randomized controlled trial is planned to evaluate the effectiveness of the program 2 months and 6 months after inclusion, and to compare this to the effectiveness of conventional approaches. The main outcome of this trial (i.e., the implementation of self-regulated driving strategies), will be measured based on scores on the “Current Self-Regulatory Practices” subscale of the Driver Perception and Practices Questionnaire. The Driving Habits Questionnaire will be used to measure secondary outcomes (indicators of driving changes; indicators of changes in mood, quality of life and caregiver burden; and self-awareness of driving abilities). Indicators will be collected for both patients and natural caregivers. This cognitive, social and psychological program should allow older individuals with cognitive disorders to drive more safely, and help to maintain the quality of life and mood of both patient and natural caregiver despite driving limitations. The patient's care path would be optimized, as he/she would become an actor in the process of giving up driving, which will, most certainly, be needed at some point in the progress of neurocognitive disorders. This process ranges from becoming aware of driving difficulties, to implementing self-regulation strategies, through to complete cessation of driving when necessary.Clinical trial registration numberNCT04493957.

Abstract Background We aimed to propose a correction of the Lawton instrumental activity of daily living (IADL) score to take into account the possibility to have never done some activities, and measured its agreement and reliability with the usual IADL score. Methods A cross-sectional study was conducted in outpatients attending French memory clinics between 2014 and 2017. Lawton IADL, cognitive performance, diagnosis, neuropsychiatric symptoms, and sociodemographics characteristics were collected. A corrected IADL was calculated and its agreement with the usual IADL was assessed. Results The study included of 2391 patients (79.9 years old, 61.7% female). Based on the usual IADL, 36.9% of patients had never carried out at least one of the activities. This proportion reached 68.8% for men and 17.7% for women. Women had a mean IADL higher than men: 4.72 vs 3.49, this difference decreased when considering the corrected IADL: 4.82 vs 4.26 respectively. Based on Bland-Altman method, 93.5% of observations lied within the limits agreement. The ICC between the 2 scores was 0.98. The relationships between patients’ characteristics and the IADL scores were similar, regardless the usual or corrected version. Conclusions This corrected IADL score had an excellent degree of agreement with the usual version based the ICC. This simple correction could benefit both for the clinical practice by providing a more accurate description of the real clinical state of the patients allowing to manage them more precisely, and for research involving the evaluation of the functional abilities of patients.

Abstract Background White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. Methods One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). Results WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition. Conclusion WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Abstract Background The functional autonomy assessment is essential to manage patients with a neurodegenerative disease, but its evaluation is not always possible during a consultation. To optimize ambulatory autonomy assessment, we compared the Lawton Instrumental Activities of Daily Living (IADL) questionnaire collected by telephone and face-to-face interviews. Methods A randomized, crossover study was carried out among patients attending a memory clinic (MC). The IADL questionnaire was collected for patients during telephone and face-to-face interviews between nurses and patients’ caregivers. The agreement between the two methods was measured using the proportion of participants giving the same response, Cohen’s kappa, intraclass correlation (ICC) coefficient, and Bland and Altman method. The associations between patients’ characteristics, events occurring between the two assessments, and agreement were assessed. Results Among the 292 patients (means ± SD age 81.5 ± 7, MMSE 19.6 ± 6, 39.7% with major neurocognitive disorders) analyzed, the proportion of agreement between the two modes was 89.4% for the total IADL score. Weighted kappa coefficient was 0.66 and ICC score was 0.91 for total IADL score. The mean difference between the IADL score by telephone or face-to-face was 0.32. Overall, 96.9% of measures lay within the 95% limits of agreement. The occurrence of fall was less likely associated with the probability to lie within the 95% limits of agreement (OR = 0.07 [0.02–0.27]). Conclusion The administration of IADL by telephone with the caregiver appears to be an acceptable method of assessment for MC patients compared to face-to-face interview. The events such as falls which could occur in a time close to the evaluation should be reported. Study registration ClinicalTrials.gov, NCT02654574 . Retrospectively registered: 13 January 2016

Different types of white matter hyperintensities (WMH) can be observed through MRI in the brain and spinal cord, especially Multiple Sclerosis (MS) lesions for patients suffering from MS and age-related WMH for subjects with cognitive disorders and/or elderly people. To better diagnose and monitor the disease progression, the quantitative evaluation of WMH load has proven to be useful for clinical routine and trials. Since manual delineation for WMH segmentation is highly time-consuming and suffers from intra and inter observer variability, several methods have been proposed to automatically segment either MS lesions or age-related WMH, but none is validated on both WMH types. Here, we aim at proposing the White matter Hyperintensities Automatic Segmentation Algorithm adapted to 3D T2-FLAIR datasets (WHASA-3D), a fast and robust automatic segmentation tool designed to be implemented in clinical practice for the detection of both MS lesions and age-related WMH in the brain, using both 3D T1-weighted and T2-FLAIR images. In order to increase its robustness for MS lesions, WHASA-3D expands the original WHASA method, which relies on the coupling of non-linear diffusion framework and watershed parcellation, where regions considered as WMH are selected based on intensity and location characteristics, and finally refined with geodesic dilation. The previous validation was performed on 2D T2-FLAIR and subjects with cognitive disorders and elderly subjects. 60 subjects from a heterogeneous database of dementia patients, multiple sclerosis patients and elderly subjects with multiple MRI scanners and a wide range of lesion loads were used to evaluate WHASA and WHASA-3D through volume and spatial agreement in comparison with consensus reference segmentations. In addition, a direct comparison on the MS database with six available supervised and unsupervised state-of-the-art WMH segmentation methods (LST-LGA and LPA, Lesion-TOADS, lesionBrain, BIANCA and nicMSlesions) with default and optimised settings (when feasible) was conducted. WHASA-3D confirmed an improved performance with respect to WHASA, achieving a better spatial overlap (Dice) (0.67 vs 0.63), a reduced absolute volume error (AVE) (3.11 vs 6.2 mL) and an increased volume agreement (intraclass correlation coefficient, ICC) (0.96 vs 0.78). Compared to available state-of-the-art algorithms on the MS database, WHASA-3D outperformed both unsupervised and supervised methods when used with their default settings, showing the highest volume agreement (ICC = 0.95) as well as the highest average Dice (0.58). Optimising and/or retraining LST-LGA, BIANCA and nicMSlesions, using a subset of the MS database as training set, resulted in improved performances on the remaining testing set (average Dice: LST-LGA default/optimized = 0.41/0.51, BIANCA default/optimized = 0.22/0.39, nicMSlesions default/optimized = 0.17/0.63, WHASA-3D = 0.58). Evaluation and comparison results suggest that WHASA-3D is a reliable and easy-to-use method for the automated segmentation of white matter hyperintensities, for both MS lesions and age-related WMH. Further validation on larger datasets would be useful to confirm these first findings.

Background: The Lifetime of Experiences Questionnaire (LEQ) assesses complex mental activity across the life-course and has been associated with brain and cognitive health. The different education systems and occupation classifications across countries represent a challenge for international comparisons. The objectives of this study were four-fold: to adapt and harmonise the LEQ across four European countries, assess its validity across countries, explore its association with brain and cognition and begin to investigate between-country differences in life-course mental activities.Method: The LEQ was administered to 359 cognitively unimpaired older adults (mean age and education: 71.2, 13.2 years) from IMAP and EU-funded Medit-Ageing projects. Education systems, classification of occupations and scoring guidelines were adapted to allow comparisons between France, Germany, Spain and United Kingdom. We assessed the LEQ's (i) concurrent validity with a similar instrument (cognitive activities questionnaire - CAQ) and its structural validity by testing the factors' structure across countries, (ii) we investigated its association with cognition and neuroimaging, and (iii) compared its scores between countries.Results: The LEQ showed moderate to strong positive associations with the CAQ and revealed a stable multidimensional structure across countries that was similar to the original LEQ. The LEQ was positively associated with global cognition. Between-country differences were observed in leisure activities across the life-course.Conclusions: The LEQ is a promising tool for assessing the multidimensional construct of cognitive reserve and can be used to measure socio-behavioural determinants of cognitive reserve in older adults across countries. Longitudinal studies are warranted to test further its clinical utility.

Abstract Background The identification of factors associated with functional impairment, in particular those which are potentially modifiable, may help to delay the advanced stages of functional dependence in patients with neurocognitive disorders such as Alzheimer’s disease and related disorders. The objectives of the MEMORA cohort are to investigate the factors associated, first with functional autonomy change over time, and secondarily with the cognitive performance and behavioral disorders changes over time. Methods The MEMORA study is a multicenter prospective cohort study carried out throughout the patient’s care pathway, in Memory centers of Lyon (France). The study will include 6780 patients at all stages of memory disorders in 6 years. The follow-up for each patient is planned for 3 years. The main outcome is the functional autonomy level change as assessed by the instrumental abilities of daily living (IADL) score. Patient characteristics include sociodemographic and clinical features, neuropsychological performance, pharmaceutical and non-pharmaceutical therapy. Discussion This study conducted in a context of routine care may help to identify the factors associated with functional impairment related to progressive neurocognitive disorders. Subsequently, interventions on potentially modifiable factors could be proposed to the patients to improve their management and delay functional dependence. Trial registration NCT02302482, registered 27 November 2014.

Abstract Background The symptoms related to neurocognitive disorders (NCD) may lead to caregiver burden increase. Involving caregivers in research may be an effective way of improving the practicalities and relevance of interventions. The aim of this study was to gather opinion and gain consensus on the caregivers ‘priorities, using a Delphi method and including aspects of needs in pharmaceutical dimension. Methods Observational study using a modified Delphi method. This study was conducted in the Clinical and Research Memory Center of the University Hospital of Lyon (France), between September 2015 and January 2016. The expert panel was composed of 68 informal caregivers of people with subjective cognitive decline or NCD living at home. Results Caregivers assigned a very high importance to the dimension “information needs about their relative’s disease”, i.e. information on the disease, the treatment and the research; and to “coping skills”, i.e. skills related to emotional support, communication, relationship evolution with the relative and skills to cope with behavioural crisis, behavioural and cognitive disorders. The aspect “coping with behavioural disorders” received a high selection rate (83%). Conclusions The main needs selected can be used to design relevant interventions and give guidance to policy to support caregivers. To meet caregiver’s needs, interventions should focus on information about disease and treatment and psychoeducational interventions.

Abstract Background One of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. Methods A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. Discussion This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. Trial registration NCT02052947.

Summary: Redox-active metals are thought to be implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). To address this point, we measured the concentrations of 12 elements and, for the first time, the stable isotope compositions of copper (redox-active) and zinc (redox-inactive) in human cerebrospinal fluids of 31 patients with ALS, 11 age-matched controls (CTRL), and 14 patients with Alzheimer disease. We first show that metal concentrations weakly discriminate patients with ALS from the two other groups. We then report that zinc isotopic compositions are similar in the three groups, but that patients with ALS have significantly 65copper-enriched isotopic compositions relative to CTRL and patients with AD. This result unambiguously demonstrates that copper is implicated in ALS. We suggest that this copper isotopic signature may result from abnormal protein aggregation in the brain parenchyma, and propose that isotopic analysis is a potential tool that may help unraveling the molecular mechanisms at work in ALS. : Nuclear Medicine; Isotope Chemistry; Neuroscience; Clinical Neuroscience Subject Areas: Nuclear Medicine, Isotope Chemistry, Neuroscience, Clinical Neuroscience

Abstract Background The natural history and disease mechanisms of Alzheimer’s disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. Methods In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR]

Abstract Background Pharmacotherapy is necessary for the management of many diseases which number increased with aging. However, potentially inappropriate prescriptions and polymedication increases iatrogenic risks and can lead to adverse events. To limit the consequences of potentially harmful prescriptions, optimization of drug prescribing is a major stake of improving quality and safety of care in the elderly. The purpose of the OPTIM study is to study the impact of the optimization of drug prescribing on the evolution of functional autonomy at 18 months of follow-up. Methods A multicenter, open-label, Randomized Controlled Trial was designed to assess the impact of an optimization program of drug prescribing consisting in a clinical medication review by a pharmacist, in collaboration with specialist physician of the geriatric/memory center and the referent physician, on the evolution of functional autonomy level, measured during 18 months of follow-up. The study will include 302 elderly outpatients visiting geriatric and memory centers, randomly distributed in one of the two parallel groups. One group will benefit of the intervention, while the other will be considered as control group. The effect of the intervention on evolution of the level of autonomy function, defined with repeated measures, will be estimated in a generalized linear mixed model. The intervention will be considered significant if the interaction between time and the study group is significant. Secondary analysis will be conducted to assess the impact of the intervention on secondary clinical outcomes. Discussion The “OPTIM” program should enable optimization of drug prescribing in elderly patients and therefore slow or prevent progression to loss of functional autonomy. It should also help to strengthen collaboration between the hospital team of geriatric/neurologist, the pharmacist and the private practice who are all involved in caring for the patient’s health. The benefits for the patient are thus optimizing its medical management by linking health professionals met during his care pathway. In addition, pharmaceutical recommendations sent to referent physicians should help raise awareness of the prescription of drugs in these patients. Trial registration number clinicaltrials NCT02740764

Abstract Background Drugs with anticholinergic properties may be associated with various adverse clinical effects. The relationship between the anticholinergic (AC) burden and functional, global cognitive performance and behavior disturbances was assessed among elderly patients. Methods A cross-sectional study was conducted between January 2012 and June 2014 in a memory clinic among outpatients living at home and with subjective cognitive decline (SCD) or neurocognitive disorders (NCD). The AC burden was measured using the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS), the Anticholinergic Cognitive Burden (ACB), Chew’s score, Han’s score, and the number of drugs with AC activity. Functional, cognitive performance and behavior disturbances were assessed using the Instrumental Activities of Daily Living (IADL) scale (IADL), the Mini Mental State Examination (MMSE), and the Neuropsychiatric Inventory (NPI). Results Among 473 included patients, 46.3% were at major NCD. Patients took on average 5.3 ± 2.6 drugs. MMSE was lower when Han’s score (p = 0.04) and number of AC drugs were higher (p

Abstract Introduction Subjective cognitive complaints may be a signature of preclinical stage Alzheimer's disease. However, the link between subjective cognitive and non‐cognitive complaints and brain alterations remains unclear. Methods The relationship between cognitive and non‐cognitive complaints and brain biomarkers, measured by structural magnetic resonance imaging, was investigated in 2056 participants of the MEMENTO cohort of outpatients, who were dementia‐free at baseline. We assessed whether the cognitive status at inclusion or the presence of the apolipoprotein E gene variant (APOE) ε4 could modulate the association between the intensity of complaints and brain lesions. Results Smaller hippocampal volume was associated with higher memory complaints and discomfort in daily life. In APOE ε4 carriers, smaller whole‐brain white matter and gray matter volumes and gyrification indices in several regions of interest of the parietal and temporal lobes, in the entorhinal and the para‐hippocampal gyrus, were associated with higher memory complaint score. Conclusions The intensity of subjective complaints in not only memory but discomfort in daily life was associated with brain degeneration markers. The presence of APOE ε4 modulated the relationships between subjective memory complaints and brain alterations.

Abstract Objective To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures. Methods Change in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F‐fluorodeoxyglucose brain positron emission tomography (18F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up. Results Semantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency. Interpretation This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.

Early Alzheimer's disease can involve social disinvestment, possibly as a consequence of impairment of nonverbal communication skills. This study explores whether patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage have impaired recognition of emotions in facial expressions, and describes neuroanatomical correlates of emotion processing impairment. As part of the ongoing PACO study (personality, Alzheimer's disease and behaviour), 39 patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage and 39 matched controls completed tests involving discrimination of four basic emotions-happiness, fear, anger, and disgust-on photographs of faces. In patients, automatic volumetry of 83 brain regions was performed on structural magnetic resonance images using MAPER (multi-atlas propagation with enhanced registration). From the literature, we identified for each of the four basic emotions one brain region thought to be primarily associated with the function of recognizing that emotion. We hypothesized that the volume of each of these regions would be correlated with subjects' performance in recognizing the associated emotion. Patients showed deficits of basic emotion recognition, and these impairments were correlated with the volumes of the expected regions of interest. Unexpectedly, most of these correlations were negative: better emotional facial recognition was associated with lower brain volume. In particular, recognition of fear was negatively correlated with the volume of amygdala, disgust with pallidum, and happiness with fusiform gyrus. Recognition impairment in mild stages of Alzheimer's disease for a given emotion was thus associated with less visible atrophy of functionally responsible brain structures within the patient group. Possible explanations for this counterintuitive result include neuroinflammation, regional β-amyloid deposition, or transient overcompensation during early stages of Alzheimer's disease.

Recognition of social hierarchy is a key feature that helps us navigate through our complex social environment. Neuroimaging studies have identified brain structures involved in the processing of hierarchical stimuli but the precise temporal dynamics of brain activity associated with such processing remains largely unknown. Here, we used electroencephalography to examine the effect of social hierarchy on neural responses elicited by faces. In contrast to previous studies, the key manipulation was that a hierarchical context was constructed, not by varying facial expressions, but by presenting neutral-expression faces in a game setting. Once the performance-based hierarchy was established, participants were presented with high-rank, middle-rank and low-rank player faces and had to evaluate the rank of each face with respect to their own position. Both event-related potentials and task-related oscillatory activity were investigated. Three main findings emerge from the study. First, the experimental manipulation had no effect on the early N170 component, which may suggest that hierarchy did not modulate the structural encoding of neutral-expression faces. Second, hierarchy significantly modulated the amplitude of the late positive potential (LPP) within a 400-700 ms time-window, with more a prominent LPP occurring when the participants processed the face of the highest-rank player. Third, high-rank faces were associated with the highest reduction of alpha power. Taken together these findings provide novel electrophysiological evidence for enhanced allocation of attentional resource in the presence of high-rank faces. At a broader level, this study brings new insights into the neural processing underlying social categorization.

BACKGROUND: In everyday life, signals of danger, such as aversive facial expressions, usually appear in the peripheral visual field. Although facial expression processing in central vision has been extensively studied, this processing in peripheral vision has been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Using behavioral measures, we explored the human ability to detect fear and disgust vs. neutral expressions and compared it to the ability to discriminate between genders at eccentricities up to 40°. Responses were faster for the detection of emotion compared to gender. Emotion was detected from fearful faces up to 40° of eccentricity. CONCLUSIONS: Our results demonstrate the human ability to detect facial expressions presented in the far periphery up to 40° of eccentricity. The increasing advantage of emotion compared to gender processing with increasing eccentricity might reflect a major implication of the magnocellular visual pathway in facial expression processing. This advantage may suggest that emotion detection, relative to gender identification, is less impacted by visual acuity and within-face crowding in the periphery. These results are consistent with specific and automatic processing of danger-related information, which may drive attention to those messages and allow for a fast behavioral reaction.

BACKGROUND:In ecological situations, threatening stimuli often come out from the peripheral vision. Such aggressive messages must trigger rapid attention to the periphery to allow a fast and adapted motor reaction. Several clues converge to hypothesize that peripheral danger presentation can trigger off a fast arousal network potentially independent of the consciousness spot. METHODOLOGY/PRINCIPAL FINDINGS:In the present MEG study, spatio-temporal dynamics of the neural processing of danger related stimuli were explored as a function of the stimuli position in the visual field. Fearful and neutral faces were briefly presented in the central or peripheral visual field, and were followed by target faces stimuli. An event-related beamformer source analysis model was applied in three time windows following the first face presentations: 80 to 130 ms, 140 to 190 ms, and 210 to 260 ms. The frontal lobe and the right internal temporal lobe part, including the amygdala, reacted as soon as 80 ms of latency to fear occurring in the peripheral vision. For central presentation, fearful faces evoked the classical neuronal activity along the occipito-temporal visual pathway between 140 and 190 ms. CONCLUSIONS:Thus, the high spatio-temporal resolution of MEG allowed disclosing a fast response of a network involving medial temporal and frontal structures in the processing of fear related stimuli occurring unconsciously in the peripheral visual field. Whereas centrally presented stimuli are precisely processed by the ventral occipito-temporal cortex, the related-to-danger stimuli appearing in the peripheral visual field are more efficient to produce a fast automatic alert response possibly conveyed by subcortical structures.