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National audience; IntroductionLa presbyacousie comme les maladies neurodégénératives apparaissent insidieusement avec l’âge. Enjeu majeur de santé publique, elles sont néanmoins sous diagnostiquées car la présence de l’une entrave l’objectivation de l’autre.ObjectifsIntégrer lors du bilan cognitif en hôpital de jour en centre mémoire un dépistage des troubles de la compréhension de la parole dans le bruit.MéthodesCent vingt-deux participants, dont 70 femmes, d’âge moyen 72,9 (60–87 ans) ont réalisé trois épreuves : questionnaire Hearing Handicap Inventory for Elderly-Screening (HHIES) mesure la gêne auditive ; test de compréhension de la parole dans le bruit (dispositif ambulatoire – Vocal Rapide dans le Bruit, VRB Leclercq et al., 2018) et échelle cognitive de Mattis. Des analyses corrélationnelles entre l’âge, le résultat du VRB, le score HHIE-S et à la Mattis ont été menées.RésultatsLes corrélations objectivent une association entre les capacités de compréhension de la parole dans le bruit et l’âge (r = 0,324, p < 0,001), la gêne auditive (r = 0,249, p = 0,006) et les troubles cognitifs globaux (r = −0,502, p < 0,001).DiscussionCes résultats confortent le lien établi entre l’âge et les capacités de compréhension de la parole dans le bruit. Ils objectivent un lien entre la plainte auditive et les capacités de compréhension de la parole dans le bruit et révèlent que ces capacités sont amoindries chez les personnes ayant des troubles cognitifs objectivés à l’échelle de la Mattis.ConclusionLe dépistage précoce d’un déficit auditif lors d’évaluations cognitives est indispensable puisque la surdité est le principal facteur modifiable de la démence.

In France, the management of patients with neurocognitive disorders is based on a network of memory clinics. The current operating mode is presented with projects aiming to its improvement, and potential evolution. Interviews were conducted at Memory resources and research centers (CMRR) as well as at the Regional health authorities (ARS) on organization, difficulties, innovation and projects for care management of patients suffering from Alzheimer's disease or related disorder. Twenty-seven semi-structured interviews were performed at the CMRR, and ten with the ARS. The collaboration with the medico-social and associative sectors was unequal. All CMRR were involved in clinical research. The links between ARS and CMRR were sometimes difficult with a lack of dialogue on the projects. However, many innovative plans have been led by the memory clinics and have sometimes been supported by the Health authorities: a therapeutic education program for patients with mild cognitive disorders, deployment of tele-medicine consultations to diagnose neurocognitive disorders in nursing home residents, setting of a network for management of behavioral disorders, creation of a mobile team specialized in clinical research, and creation of a multidisciplinary consultation following diagnosis to work on a personalized care plan. Experienced professionals mentioned a mature and efficient structure of the care management system thanks to the CMRRs' labeling and the different Alzheimer's national plans. However, this highly specialized system does not meet the demands of integrated care and should adapt to the increasing prevalence of patients. Therefore, structuration of primary care should be an emerging subject of reflection at national and international level.

Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.

The number of patients with young onset dementia (YOD) (that is before age 65) is estimated at 32,000 in France, and 5000 with onset dementia before 60 years. These patients differ from older ones by the greater number of rares causes (29%), heterogeneity of the presentation among the usual diseases, such as non-amnestic phenotypes of Alzheimer's disease, high frequency of frontal symptoms, and possible genetic origin. These aspects must be taken into account for the diagnosis, often more difficult than in older ones because patients have a little knowledge of the YOD, excepted in the genetics forms. YOD patients can still work or drive a car, and we should choose between the respect for autonomy and the security for the patient and their carers. YOD patients can be more often included in pharmacological trials because they have lower associated disorders. Individual non-pharmacological treatment should be priviledged because they don't easily accept collective activities with other patients over 60 years of age. Excepted for the very young patients (onset before 45), the survival is longer than in late onset dementia, with sometimes severe behavioral problems related to frontal syndrome. In France, the caregiving at home has been improved since the possibility for the YOD patients to receive a financial assistance reserved for the disabled patients, but admission to a nursing home before 60 is very difficult and increases the caregiver burden and perception of unfairness. There is a discrimination between young or older demented patients related to the great difficulty to meet the needs of younger patients, due to the rigidity of the medical and social systems. The presentation of a limited offer for the YOD patients must initiate reflections on our capacities to respect the autonomy and the dignity of the Alzheimer's patients regardless of age.

Alzheimer's disease is a neurodegenerative disorder characterized by neuropathological lesions: amyloid deposits and neurofibrillary degeneration. However, the links between these two brain hallmarks are still poorly understood. Until now, mainly amyloid pathology has been targeted un many clinical trials without any success. Both new therapeutic strategies and diagnosis improvement are needed.

As the failure of several recent Phase III drug development programmes bears witness, the clinical development of “disease-modifying” drugs in Alzheimer’s disease has been confronted with challenging methodological difficulties. Taking into account the financial stakes involved taking drug candidates to the Phase III stage of development, and the risk of investing time and resources fruitlessly in the evaluation of poor candidate drugs, the crucial decision remains whether to proceed from Phase II to Phase III (Go/Nogo). The aim of Phase II studies is to select a molecule likely to be effective in Phase III, but also to eliminate candidate-drugs with an inadequate effect. No consensus currently exists on the best possible design of Phase II studies to inform the Go/Nogo decision optimally. The challenges in choosing the best study design relate to the target population, the end-point criteria used, in particular the use of biomarkers, the experimental protocol, and the study duration. The objective of the Round Table (RT) was to gather the opinions of French experts from the academic, industrial, and regulatory world in order to arrive at a consensus recommendation for the best possible design to be used in Phase II studies in Alzheimer’s disease.

Alzheimer's disease is a neurodegenerative disorder characterized by neuropathological lesions: amyloid deposits and neurofibrillary degeneration. However, the links between these two brain hallmarks are still poorly understood. Until now, mainly amyloid pathology has been targeted un many clinical trials without any success. Both new therapeutic strategies and diagnosis improvement are needed.

The roundtable 1 “Relevance of the evaluation criteria used in clinical trials for Alzheimer’s disease” made reference to the guideline published by the EMEA (European Medicines Agency) in July 2008 on the development of new treatments for Alzheimer’s disease (AD) and other dementias, and addressed principally two of the three indications listed in the guideline: symptomatic improvement and disease-modification (primary prevention was hardly discussed). The discussions focussed on two main aspects: improvement of the selection of patients in clinical trials and clinical evaluation and biomarkers. The following suggestions were made: – Reinforce the interest for clinical trials at the early stages of AD (including prodromal stage), particularly for disease-modifiers. – Strengthen the research centers’ expertise with biomarkers, in a perspective of subsequent use in clinical trials, either for the description of the patients included, or as part of selection criteria. Furthermore, ongoing intercenter validation studies, in France, of neuro-imaging and biomarker assays in CSF, are essential for preparing multicenter clinical trials. – Facilitate the conduct of ancillary studies with biomarkers, grafted on clinical studies. – Further develop the training and experience of raters with functional scales, which are now required as one of the two primary endpoints in pivotal clinical trials, and with the additional items of ADAS-cog (Alzheimer’s Disease Assessment scale, Cognitive sub scale), which are useful for the early stages of AD. – Improve knowledge of functional clinical scales by in depth analysis of available databases, through public/private collaborations. – Improve knowledge of relationship between rating scales used in clinical trials and tools used in clinical practice (which are usually different), in order to provide supporting evidence for the interpretation of the clinical relevance of clinical trials results. – Consider the potential needs of adaptation of rating scales to the societal changes, in particular for the evaluation of cognitive performance. – Discuss the possibility of measures for extending data protection for candidate disease-modifiers, considering the negative impact for all players of the constraints of duration and the difficulties of clinical trials. – Further discuss the ethics and acceptability of placebo-controlled monotherapy studies on durations of 6-9 months.

The very slow progression of behavioral disorders, initially isolated at the onset of frontotemporal dementia, easily results in their neglect, all the more so since the patients are anosognosic. In absence of cognitive decline, these patients, whatever carrying a neurological disease, are frequently led towards psychiatrists. Many psychiatric disorders may be evoked: depression, mania, compulsive obsessive disorder, psychopathy, alcoholic addiction, bulimia, schizophrenia, or Diogene syndrome. However, the diagnosis can often be easily corrected by a detailed clinical analysis. The knowledge of the 3 behavioral symptoms included in the diagnostic criteria can help to recognize frontotemporal dementia, even when imaging and neuropsychological data show mild abnormalities. In the last few years, various neuropsychological, biological and environmental mechanisms have been proposed to explain the behavioral disorders. These disorders are very difficult to tolerate by the caregivers because the patients appear to be asocial and show no affect. A detailed information of the changes related to the disease is important for the caregivers to accept the behavioral changes and to cope with them. However, over time, the occurrence of mutism may lead caregivers to regret the period of behavioral disorders.

La maladie d’Alzheimer est une véritable pathologieet non un simple effet du vieillissement même si ellese révèle, le plus souvent, aux âges avancés de la vie.La détérioration progressive intellectuelle et physiqueassociée à cette maladie est douloureusement ressentiepar les proches qui accompagnent au quotidienle patient. Les différentes ressources en termesd’information, de diagnostic et de prise en charge sontencore très hétérogènes sur le territoire.À la demande de la Direction générale de la santé,l’Inserm a réuni un groupe pluridisciplinaire d’expertsafin de réaliser, selon la procédure d’expertise collective,un bilan des avancées de la recherche fondamentale,clinique, en économie de la santé et en scienceshumaines et sociales sur la maladie d’Alzheimer, demanière à impulser les évolutions indispensables dansle domaine médical, médico-social et en recherche à lahauteur de l’enjeu de santé publique.Le groupe d’experts a émis des propositions pouraméliorer la diffusion des connaissances, le diagnosticet le traitement des patients, le soutien aux aidants,l’information et la sensibilisation de la populationet du corps médical. Il a souligné la nécessité d’unearticulation pertinente entre recherche fondamentale,recherche clinique, formation des professionnels etactions auprès des malades et de leur famille en lienavec les associations de patients.

Alzheimer's disease and related disorders (dementia) are a major public health problem due to the number of cases in the general population, the projections for the future, and the consequences of these diseases. We can estimate that about 850 000 cases of dementia were present in France in 2005 and this number will increase to 1,200,000 in 2020 and 2,100,000 in 2040 if the incidence and the duration of the disease did not change. The development of prevention is therefore necessary. Four ways of prevention are credible. The most important is the treatment of vascular risk factors and particularly hypertension. Other ways are nutritional factors, stimulating leisure activities and depression.

Alzheimer's disease (AD) is a neurodegenerative disorder with a decline in memory and cognitive abilities. During the past 20 years, research on AD has increased the knowledge of the physiopathological mechanisms leading to the disease. The major hallmarks of AD are amyloid plaques and neurofibrillary tangles, associated with a prevalent and early cholinergic deficit and an excitotoxicity with inflammation. These pathological mechanisms represent current and future therapeutic targets. cholinesterase inhibitors were the first therapeutic class that has consistently shown a clinical efficacy and safety in patients with mild to moderate ad. more recently glutamate receptor antagonists have been shown effective in the management of patients with moderate to severe AD. These two therapeutic classes could improve cognitive functions, slow the progression of the cognitive decline, prevent some behavioural changes and delay institutionalisation. However, AD represents a problem of public health and preventive and curative strategies have to be proposed.

Stroke significantly increases the risk of dementia in subjects aged 55 years or more. Twenty to 25 p. 100 of patients are demented 5 years after a stroke. Age and supratentorial location of the vascular lesion are risk factors for post-stroke dementia. Volume, left side of the lesion, large middle cerebral artery infarction, lesions of the frontal lobe, second stroke, diabetes, aphasia, clinical features expressing the severity of the stroke event in the acute phase, mitral valve prolapse, atrial fibrillation, depression, concomitant hypoxic/ischemic disorders, and white matter changes have also been found as predictors of dementia. There are many different mechanisms of vascular pathology that may lead to dementia: ischemic or hemorrhagic lesions, large vessel disease including multi-infarct and strategic single infarct, small-vessel disease including lacunes and white matter changes, hypoperfusion.... Post-stroke dementia may not be due only to vascular lesion. Some post-stroke dementias have a progressive onset and course. The cognitive decline may pre-exist to the stroke, even when a dementia is not diagnosed. This suggests a degenerative process. Alzheimer's disease is frequent in ages when the majority of strokes occur. Alzheimer's and vascular diseases share common risk factors such as age, APOE4, hypertension, and smoking. Patients with low MMS scores and AD patients are at risk for stroke. Moreover, white matter changes are associated with stroke and Alzheimer's disease and may contribute to the cognitive decline. Many post-stroke dementias could be multifactorial. Even when vascular lesions and degenerative changes (mainly Alzheimer changes) are not severe enough, no their own, to be the cause of dementia, their summation may reduce the preclinical stage of the degenerative process.

The physiopathology of Alzheimer disease (AD) is complex. Associated factors, in particular at the vascular level with damaged small blood vessels, might be involved. Cerebral microbleeds(CMB) in particular, could be one of the key contributing factor in AD. The cumulative evidence suggested a sex-specific patterns of disease. Furthermore, statins might be interesting by pleitropic effects. The objectives of this study was to evaluate the interaction between vascular and neurodegenerative lesions in Alzheimer, the influence of sex, and the pharmacological modulation by atorvastatin. This experimental model is designed in a multimodal approach to ensure its scientific relevance and to fit with clinical research. The third objective is indeed to confront theresulting experimental data to the clinical data of cohorts of Alzheimer patients. With an original model of CMB in female mice, we folio wed-up them from 1.5 months to 12 months postsurgery.For the clinical part, we studied patients with AD from a database of a tertiary memory center, with standardized framework. In a translational way, we observed a cognitive and a non cognitiveimpact of CMBs, differently in wild-type mice and in diseased mice. Different outcome was noticed for young female mice. And Atorvastatine offered a mild neuroprotection particularly in presymptomatic stage. Finally, the mechanism implied will be studied, in particular the inflammatory pathway, and will help to propose targeted pharmacological modulation in order to prevent or limit the impact of CMB on AD, by offering a personalized approach.; La maladie d'Alzheimer (MA) est un processus multifactoriel. La dysfonction vasculaire pourrait être impliquée dans sa progression. Les microhémorragies cérébrales (MH) sont fréquentes chez les patients atteints de MA, et pourraient jouer un rôle clé dans le lien qui relie la dysfonction vasculaire à la MA. Le sexe pourrait également impacter sur la sévérité des lésions. Les statines ont été proposées en prévention de maladies neurodégénératives dont la MA. Leur intérêt est encore débattu mais ces molécules ont une action pléiotrope. Ce travail a pour objectif d'étudier l'impact des lésions microhémorragiques sur le déclin cognitif dans la MA, le rôle du sexe et la modulation pharmacologique par Atorvastatine, dans une perspective translationnelle,i.e. en considérant à la fois l'aspect expérimental chez l'animal et l'aspect clinique. Pour la partie expérimentale, nous avons étudié à partir d'un modèle original de MH chez les souris femelles saines et pathologiques. La MHC est créée par injection stéréotaxique de Collagénase (0,8|uUI/|iL). L'atorvastatine est administrée dans l'alimentation quotidienne des rongeurs(5mg/Kg/J). Le suivi était multimodal à trois temps différents : six semaines, six mois et douze mois après la chirurgie. Au plan clinique, nous avons étudié une base de données de patients atteints de la MA, suivis de façon standardisée. Notre travail a mis en évidence, dans une approche translationnelle, un impact cognitif et non cognitif des MHs, en présence ou non d'une maladie d'Alzheimer chez le sexe féminin. Nos résultats tendent à confirmer l'intérêt de l'atorvastatine dans la neuroprotection, grâce à ses effets pléiotropes. D'une manière générale,notre travail souligne, une fois de plus, l'intérêt d'une prise en charge personnalisée, et précoce de la MA.

Dementia is a major Public Health issue, especially due to occidental populations ageing. Nevertheless, a definite etiologic diagnosis of dementia can only be obtained by the post mortem neuropathological and/or biochemical analysis of the brain. Brain lesions leading to dementia are various in nature (neurodegenerative, vascular, metabolic...) and are often associated. We analyzed the clinical, neuropathological and biochemical data from the autopsic cohort of demented patients followed-up in Lille Memory Center (127 brains collected between 1992 and 2009). We focused on the correlation between the clinical expression of dementia and the nature of the underlying brain lesions. We show that the frequent pathological associations can modify the clinical presentation of the patients, and therefore make the etiological diagnosis of dementia more difficult. In the specific domain of frontotemporal lobar degeneration (FTLD), we investigated the clinical-pathological correlations of 18 patients who presented with progressive speech or language disorders. We established strong correlations between the various clinical syndromes and specific underlying FTLD-related proteinopathies (tau, TDP-43). We identified a new mutation in the progranuline gene in one patient. Multidisciplinary analysis of dementia helps the clinicians in improving the in vivo prediction of the nature of brain lesions. Prediction of the pathology will soon be a challenging objective for cognition and behaviour specialists when set against a context of forthcoming curative, protein-target-specific drugs., Les démences représentent un problème de santé public majeur, notamment du fait du vieillissement des populations occidentales. Pourtant, le diagnostic étiologique de certitude d'un syndrome démentiel ne peut être obtenu que par l'analyse neuropathologique et/ou biochimique du tissu cérébral obtenu en post mortem. Les lésions cérébrales aboutissant au déclin cognitif ont des origines diverses (neurodégénératives, vasculaires, métaboliques...) et sont souvent associées. En analysant les données cliniques, neuropathologiques et biochimique issues de la cohorte autopsiques de patients déments suivis au Centre Mémoire de Ressources et de recherche du CHRU de Lille (127 cerveaux prélevés entre 1992 et 2009), nous avons étudié les corrélations entre l'expression clinique du syndrome démentiel et la nature des lésions cérébrales sous jacentes. Nous montrons que les fréquentes associations lésionnelles (lésions de maladie d'Alzheimer, de maladie à corps de Lewy, lésions vasculaires) ont des conséquences sur la pertinence du diagnostic étiologique du syndrome démentiel. Dans le domaine des dégénérescences lobaires frontotemporales (DLFT), nous avons étudié les corrélations clinicopathologiques de 18 patients ayant présenté des troubles inauguraux du langage ou de la parole. Nous avons pu établir des corrélations entre les syndromes cliniques et certaines protéinopathies (tau, TDP-43) associées aux DLFT. L'enquête génétique a permis de mettre en évidence une nouvelle mutation du gène de la progranuline chez un patient. L'analyse pluridisciplinaire des démences permet au clinicien de progresser dans la prédiction des lésions cérébrales du vivant du patient. Cette démarche s'avère indispensable dans l'optique du développement de traitements curatifs des démences neurodégénératives.