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IMPORTANCE: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04623242

Désormais reconnu par les autorités de santé, le COVID long est identifié comme une affection fréquente compliquant l’évolution de l’infection par le SARS-CoV-2. Son expression clinique polymorphe et parfois déroutante interroge sur son mécanisme. Les modes d’expression clinique suggèrent une large participation du système nerveux à travers une plainte cognitive quasi omniprésente. Cet article passe en revue les symptômes, les formes neurologiques et les explorations neuropsychologiques visant à objectiver un déficit cognitif chez ces patients. Les études publiées jusqu’à maintenant, confrontées au mode d’expression clinique, ne permettent pas de définir un profil neuropsychologique déficitaire à l’échelon des groupes et évoquent plus une atteinte fonctionnelle que lésionnelle. Chacune des séries, toutefois, mentionne un petit nombre de patients chez qui un déficit cognitif est objectivé. Les incertitudes sur les causes des formes prolongées de COVID, l’hétérogénéité des études publiées et la quasi-absence de données d’évolution temporelle doivent rendre prudents quant à l’interprétation de ces données, mais ne doivent en aucun cas retarder ou empêcher la prise en charge de ces patients.

To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).

Introduction: In Moyamoya angiopathy (MMA), mechanisms underlying cognitive impairment remain debated. We aimed to assess the association of cognitive impairment with the degree and the topography of cerebral hypoperfusion in MMA.Methods: A retrospective analysis of neuropsychological and perfusion MRI data from adults with MMA was performed. Ischemic and haemorrhagic lesion masks were created to account for cerebral lesions in the analysis of cerebral perfusion. Whole brain volume of hypoperfused parenchyma was outlined on perfusion maps using different Tmax thresholds from 4 to 12 s. Regional analysis produced mean Tmax values at different regions of interest. Analyses compared perfusion ratios in patients with and without cognitive impairment, with multivariable logistic regression analysis to identify predictive factors.Results: Cognitive impairment was found in 20/48 (41.7%) patients. Attention/processing speed and memory were equally impaired (24%) followed by executive domain (23%). After adjustment, especially for lesion volume, hypoperfused parenchyma volume outlined by Tmax > 4 s or Tmax > 5 s thresholds was an independent factor of cognitive impairment (OR for Tmax > 4 s = 1.06 [CI 95% 1.008–1.123]) as well as attention/processing speed (OR for Tmax > 4 s = 1.07 [CI 95% 1.003–1.133]) and executive domains (OR for Tmax > 5 s = 1.08 [CI 95% 1.004–1.158]). Regarding cognitive functions, patients with processing speed and flexibility impairment had higher frontal Tmax compared to other ROIs and to patients with normal test scores.Discussion: Cerebral hypoperfusion emerged as an independent factor of cognitive impairment in MMA particularly in attention/processing speed and executive domains, with a strong contribution of frontal areas.Conclusion: Considering this association, revascularization surgery could improve cognitive impairment.

L’Angiopathie Amyloïde Cérébrale sporadique (AAC) est une micro angiopathie cérébrale fréquente, liée à l’âge, caractérisée par l’accumulation de peptide amyloïde Aβ dans la paroi des artères lepto-méningées et des vaisseaux corticaux. C’est la cause principale d’hémorragies intracérébrales lobaires de la personne âgée. Son origine reste largement méconnue. Un défaut de clearance du peptide Aβ est largement évoqué dans sa physiopathologie. L’étude de sujets porteurs de mutations dans les rares formes héréditaires montre qu’une longue période pré-symptomatique est probable. L’hémorragie intracérébrale lobaire, avec son risque de récidive élevé, constitue l’avenue clinique la mieux connue. L’AAC est également à l’origine directe de déclin cognitif avec un risque évolutif élevé vers une démence. Elle est également à l’origine de manifestations neurologiques focales déficitaires transitoires (TFNE). L’existence d’une forme à composante inflammatoire suggère l’association d’une réponse auto-immune spécifique. L’identification de biomarqueurs permet de mieux en caractériser l’histoire naturelle et le risque évolutif : IRM (micro-saignements, micro infarctus corticaux, hémosidérose corticale, saignements méningés, atrophie corticale, hyper signaux de la substance blanche, dilatation des espaces péri vasculaires) TEP amyloïde, biomarqueurs amyloïdes du liquide cérébro-spinal, contribuent à créer une d’empreinte de la maladie. Si l’anatomo-pathologie reste un élément essentiel du diagnostic, ils ont permis d’affiner la probabilité du diagnostic de la maladie (critères de Boston modifiés). Aucune thérapeutique spécifique n’est à ce jour disponible mais nombre de développements sont en cours. Le contrôle strict de la pression artérielle, et la stratégie thérapeutique vis-à-vis des anticoagulants chez les patients à haut risque embolique sont des éléments clés de la prise en charge.

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72and GRNcohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72and GRNpatients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRNpatients had higher levels than C9orf72(86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276and NCT04014673.

Dominantly inherited Alzheimer’s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4–7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

L’angiopathie amyloïde cérébrale (AAC) est une cause majeure d’hémorragie intracérébrale. Sa fréquence et son évolution chez les patients non-hémorragique reste cependant mal connue.

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Head injuries are risk factors for chronic depressive disorders, but this association remains poorly explored with regards to concussion.

Depuis 2016, les cliniciens francophones disposent d’une batterie spécifique d’évaluation des troubles du langage dans les maladies neurodégénératives (GREMOTS), utilisée en clinique comme en recherche.

Après une commotion cérébrale, la décision du retour au jeu avec contacts repose sur l’absence de symptômes commotionnels. Or, de récents travaux montrent qu’il persiste des anomalies cérébrales malgré la disparition des symptômes.

L’étude du sommeil apparaît à l’arrière plan de l’algorithme diagnostique des encéphalites auto-immunes (EAI) alors qu’il y est souvent perturbé. Les cohortes souvent limitées et hétérogènes n’ont pas encore permis de conclure à un patternd’altération du sommeil spécifique. L’objectif est d’essayer de définir un profil de perturbations du sommeil propre aux EAI, pouvant aider au diagnostic.

•In a multicentric cohort of 59 patients suffering from severe COVID-19, ASL perfusion was abnormal in 53, hypoperfusion occurred in 48 (with a predominant fronto-temporo-polar pattern), whereas hyperperfusion occurred in 9.•Post-contrast FLAIR leptomeningeal enhancement was the only parameter with a significant association with cerebral perfusion, as it was tightly linked to hyperperfusion.•Frontotemporal hypoperfusion was also found in quantitative subgroup analysis compared to healthy subjects.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

To estimate the prevalence of topographical memory impairment following posterior cerebral artery infarctions (PCAI) and define its anatomical correlations.

Initialement reconnu comme un syndrome de l’enfance, les données scientifiques indiquent qu’une proportion significative d’enfants atteints du trouble du déficit de l’attention avec ou sans hyperactivité (TDA/H) continue de présenter des symptômes à l’âge adulte. Le diagnostic reste clinique en dépit des caractéristiques cliniques, neuropsychologiques, biologiques, génétiques ou de neuroimagerie identifiées mais insuffisantes individuellement pour confirmer le diagnostic. Considérant que le TDA/H est basé sur un modèle neuropsychologique, nous examinerons dans un premier temps la nature des troubles cognitifs à travers les données issues des méta-analyses de l’adulte et la valeur prédictive des outils neuropsychologiques. Les résultats de ces études attestent que les fonctions d’inhibition, de flexibilité mentale, de vigilance et d’attention soutenue sont les plus sensibles à l’identification du TDAH de l’adulte. Si les valeurs prédictives positives des tests neuropsychologiques spécifiques de ces troubles sont bonnes, les valeurs prédictives négatives restent quant à elles insatisfaisantes.

En 1911, le Dr Alois Alzheimer a décrit plusieurs crises convulsives chez l’un des premiers cas identifiés de la pathologie neuroévolutive portant désormais son nom. Cependant le lien physiopathologique entre la maladie d’Alzheimer (MA) et l’épilepsie est resté peu exploré pendant un siècle entier, ou bien seulement considéré comme un symptôme des formes familiales extrêmement rares de la MA. Tout a changé au début des années 2000, avec plusieurs publications décrivant, d’une part, une incidence accrue des crises d’épilepsie chez les patients atteints des formes sporadiques de la MA, et d’autre part, le rôle des plaques Aβ et des enchevêtrements neurofibrillaires dans les activités paroxystiques spontanées dans des modèles génétiques précliniques de la pathologie. Ces publications ont permis d’introduire la perspective d’un dysfonctionnement de réseaux neuronaux dans cette pathologie et ont déclenché une avalanche d’études sur la caractérisation de l’épilepsie chez les patients MA ainsi que sur les mécanismes sous-jacents de cette comorbidité. Ces travaux de recherche ont mis en évidence plusieurs interrelations entre l’épilepsie et la MA, commençant par l’impact des agrégats Aβ et Tau, mais également l’implication de facteurs liés aux perturbations du sommeil, l’altération du fonctionnement du système glymphatique ou bien des altérations des réseaux neuronaux de l’hippocampe, l’aire la plus touchée par les activités paroxystiques dans cette comorbidité. Finalement, des études chez des modèles animaux de la MA suggèrent une efficacité particulière de certains traitements antiépileptiques sur les activités paroxystiques et sur des symptômes de la MA. Ceci parait d’autant plus important au vue des nombreuses études chez les patients épileptiques dévoilant la contribution potentielle de ces activités paroxystiques au dysfonctionnement mnésique caractéristique de la MA ainsi qu’à la progression de la pathologie.

L’encéphalite auto-immune (EAI) est un groupe hétérogène de maladies inflammatoires du système nerveux, susceptible d’entraîner une altération du sommeil. Même si le nombre d’études sur le sommeil dans les EAI a augmenté ces dernières années, celles-ci sont basées sur des petites cohortes et n’étudient pas ou peu la microarchitecture et l’électrogenèse du sommeil.

C9orf72repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them.

To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene.

We conducted an event‐related functional magnetic resonance imaging experiment to better understand the potentially compensatory alternative brain networks activated by a clinically relevant face‐name association task in Alzheimer's disease (AD) patients and matched control subjects. We recruited 17 healthy subjects and 12 AD patients at an early stage of the disease. They underwent functional magnetic resonance imaging scanning in four sessions. Each of the sessions combined a “study” phase and a “test” phase. Face/name pairs were presented in each study phase, and subjects were asked to associate faces with names. In the test phase, a recognition task, faces seen in the study phase were presented each with four different names. The task required selection of appropriate previously associated names from the study phase. Responses were recorded for post hoc classification into those successfully or unsuccessfully encoded. There were significant differences between the groups in accuracy and reaction time. Comparison of correctly versus incorrectly encoded and recognized pairs in the two groups indicated bilateral hippocampal hypoactivation both when encoding and recognizing in the AD group. Moreover, patients showed bilateral hyperactivation of parts of the parietal and frontal lobes. We discuss whether hyperactivation of a frontoparietal network reflects compensatory strategies for failing associative memory in AD patients. Ann Neurol 2005;58:870–879

In order to determine the influence of a single dose of fluoxetine on the cerebral motor activation of lacunar stroke patients in the early phase of recovery, we conducted a prospective, double‐blind, crossover, placebo‐controlled study on 8 patients with pure motor hemiparesia. Each patient underwent two functional magnetic resonance imaging (fMRI) examinations: one under fluoxetine and one under placebo. The first was performed 2 weeks after stroke onset and the second a week later. During the two fMRI examinations, patients performed an active controlled motor task with the affected hand and a passive one conducted by the examiner with the same hand. Motor performance was evaluated by motor tests under placebo and under fluoxetine immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor task, hyperactivation in the ipsilesional primary motor cortex was found. Moreover, fluoxetine significantly improved motor skills of the affected side. We found that a single dose of fluoxetine was enough to modulate cerebral sensory‐motor activation in patients. This redistribution of activation toward the motor cortex output activation was associated with an enhancement of motor performance.

L’état de mal épileptique (EME) est une urgence thérapeutique aux étiologies multiples et à la physiopathologie complexe. Des anomalies de signal IRM spécifiques de l’EME (ASISE) sont décrites dans la littérature mais leurs implications cliniques sont mal connues. Nos objectifs étaient d’étudier l’incidence, les facteurs prédictifs et la valeur pronostique des ASISE à la phase aiguë de l’EME inaugural de l’adulte.

L’ictus amnésique est un syndrome amnésique brutal, antérograde et rétrograde, de résolution totale en moins de 24h.