INTRODUCTION:Functional prognosis of early-onset neurodegenerative dementia (EOD) remains poorly understood. METHODS:The Neurodegenerative Early-Onset Dementia (NEODEM) study is an ongoing prospective multicenter cohort study investigating factors associated with decline in daily activities in EOD. Detailed information on behavioral and psychological symptoms of dementia (BPSD) is collected as prognostic factor. RESULTS:Between May 2020 and May 2023, 162 patients with EOD, including 111 patients with early-onset Alzheimer's disease (AD) and 40 with frontotemporal dementia (FTD) variants, were enrolled in seven tertiary memory clinics in France. The median time from symptom onset to diagnosis was 3 years. By design, Clinical Dementia Rating (CDR) scale score was 0.5 or 1 at inclusion. Baseline level of autonomy was similar in early-onset AD and FTD, but MMSE scores were lower in AD. Baseline BPSD results are presented in the manuscript. CONCLUSION:Four-year longitudinal data, available from 2027, will help clarify the impact of baseline factors on future functional status, institutionalization, morbidity, and mortality.

BACKGROUND:Frailty is a prevalent condition among older adults with neurocognitive disorders. OBJECTIVES:To ascertain whether frailty contributes to the severity of cognitive impairment and neuropsychiatric symptoms, and its association with cerebral pathology measured in vivo by fluid and imaging biomarkers. DESIGN:We conducted cross-sectional and longitudinal analyses based on CLEM Study, a multicentre memory-clinic cohort that recruited participants between 2014 and 2018. SETTING:CLEM Study occurred in eight memory centres in France (Lyon, Paris, Strasbourg, Poitiers, Tours, Grenoble) and Monaco. PARTICIPANTS:A total of 168 participants (mean age 80.5 ± 4.8 years) with mild to moderate dementia due to at least one aetiological diagnosis between Alzheimer's disease, dementia with Lewy bodies or vascular dementia were included in the study. MEASUREMENTS:The participants were evaluated at baseline and followed up for two years. The concept of frailty was operationalised using a 45-item Frailty Index. Cognition was assessed using the ADAS-cog scale, while neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory. The cerebral pathological score, a proxy for brain pathologies, was a composite score based on the presence of several in vivo biomarkers: presynaptic dopaminergic denervation on 123I-FP-CIT SPECT (DaTscan®), vascular lesions on MRI, elevated blood-based pTau181, neurofilaments light-chain or glial fibrillary acid protein. Linear and mixed regression analyses were conducted to model the relationships between cognitive or neuropsychiatric symptoms, frailty and cerebral pathologic score, adjusted for age, sex and education. RESULTS:The findings indicate an impact of both frailty (β = 0.28, 95 % CI [0.14-0.43], p < 0.001) and cerebral pathological score (β = 0.30, 95 % CI [0.13-0.47], p = 0.002) on cognitive impairment. However, only frailty was associated with neuropsychiatric symptoms (β = 0.28, 95 % CI [0.14-0.43], p < 0.001), particularly with apathy (β = 0.40, 95 % CI [0.26-0.53], p < 0.001). We found an association between cerebral pathological score and longitudinal cognitive decline (β = 0.36, 95 % CI [0.19-0.53], p < 0.001) in exploratory analyses with available longitudinal data at 24 months (n = 74). CONCLUSIONS:Neurocognitive disorders are complex entities, where cognitive and neuropsychiatric symptoms are not fully influenced by the same factors. When cognitive symptoms seem more driven by cerebral pathology than frailty, neuropsychiatric symptoms appear to be more influenced by general state of frailty. Measuring and treating frailty might be a key factor in dealing with neuropsychiatric symptoms and their consequences.

Neurodevelopmental disorders (NDDs) influence lifespan neurocognitive trajectories and can be conceptualized as falling on a continuum. However, transdiagnostic neurodevelopmental investigations in cognitive aging are rare. This preliminary, cross-sectional study aimed at exploring lifespan manifestations of neurodevelopmental vulnerabilities (DVs) in cognitive aging, while adopting a dimensional approach to NDDs. The objectives, covered from childhood to adulthood, were: 1) to describe NDDs-related domains of vulnerability; 2) to estimate DVs frequency; 3) to evaluate the persistence of DVs symptoms from childhood to adulthood; 4) to explore the link between DVs, demographics and neuropsychological performance. Cognitively healthy participants underwent a neuropsychological assessment and answered a retrospective questionnaire on NDDs symptoms in childhood and in adulthood. Using a k-means clustering based on questionnaire answers, participants were assigned to a DV+ (with DV) or a DV− (without) cluster. The final sample consisted in 84 participants [age: 69 (8); years of education: 14 (3); 57% females]. In childhood, self-management, reading and writing, school performance, and visuospatial difficulties were reported. In adulthood, difficulties were mainly in self-management. Clustering revealed a DV in 15% of individuals during childhood, and in 21% during adulthood. Throughout life, 86% of participants had a consistent cluster assignation, while 13% changed clusters between childhood and adulthood. Childhood self-management and scholar difficulties significantly predicted self-management difficulties in adulthood. Nevertheless, no link was found between DVs, demographics and neuropsychological performance. Results highlight the relevance of lifespan, dimensional investigations of NDDs; and are discussed in terms of cognitive reserve, compensation processes, heterotypic continuity and psychopathological progression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the French National Research Agency (grant number ANR-21- ce28-0020-01). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Toulouse universities gave ethical approval for this work (Research Ethics Committee file No. 2023_765) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Abnormal brain accumulation of amyloid-β peptides, represents one of the earliest biological indicators of Alzheimer’s disease (AD) risk. Estimation on amyloid positivity (A+) prevalence among older adults without dementia are needed to assess the epidemiological impact of AD diagnosis solely through biological markers. We combined data from the French MEMENTO clinical cohort, where amyloid status was assessed through reference procedures, with the nationally representative SHARE-HCAP survey. Using stabilized inverse odds of selection weights, we adjusted the MEMENTO sample to estimate the prevalence of A+ in the French population aged 65–85 without dementia and their five-year risk of developing AD dementia. A+ prevalence was 21.4% (95% CI: 18.4–24.7) in French adults aged 65–85 without dementia i.e. approximately 2.5 million individuals, reaching 27.5% in the 80–85 age group. Over five years of follow-up, the cumulative incidence of AD dementia was 22.7% among A+ individuals, 8.0% among cognitively normal A+ adults and 62.3% among those with mild cognitive impairment. While A+ is common in older adults without dementia, most do not develop dementia within five years. Defining AD by A+ could substantially increase diagnoses, raising major public health, ethical, and health system challenges, especially as new anti-amyloid therapies emerge.

INTRODUCTION:The cognitive and neuroimaging evolution during dementia with Lewy bodies (DLB) from the prodromal phase (Pro-DLB; subjective cognitive impairment [SCI] to mild cognitive impairment [MCI]) according to amyloid beta (Aβ) status is poorly understood. METHODS:The decline of Lewy-Memento patients with SCI or MCI was compared according to Aβ status across four groups: Pro-DLB, prodromal Alzheimer's disease (Pro-AD), Pro-DLB+AD, and a group without prodromal DLB and AD (no symptoms [NS]). We observed the evolution of cognitive, functional, quality of life measures, brain volumetry, and metabolism on fluorodeoxyglucose positron emission tomography. RESULTS:In the Pro-DLB and Pro-DLB+AD groups, Aβ+ patients had more cognitive and functional decline than the Aβ- patients. In the Pro-AD and NS groups, Aβ+ patients had more functional decline. Aβ+ Pro-AD showed a greater volume decline of the brain (left insula). DISCUSSION:The presence of amyloid lesions worsens very prodromal DLB patients over time, both cognitively and functionally, but without increasing atrophy. Highlights:Patients at a very prodromal stage, subjective cognitive impairment or mild cognitive impairment, had a clinical diagnosis of either prodromal Alzheimer's disease (Pro-AD), prodromal dementia with Lewy bodies (Pro-DLB), Pro-DLB+AD, or no diagnosis.Amyloid beta positive (Aβ+) patients had more functional decline, whatever the group.Aβ+ DLB patients (Pro-DLB and Pro-DLB+AD) had more global cognitive (Mini-Mental State Examination) decline.Aβ+ Pro-AD patients showed a greater volume decline of the left insula.

BACKGROUND:Neurodevelopmental disorders (NDDs) may influence the course of Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, prior studies have focused on specific pairs of NDDs and variants of AD/FTD. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated the association between a neurodevelopmental vulnerability (DV) and the clinical presentation and age at onset of AD/FTD. METHODS:We prospectively and consecutively recruited 84 AD/FTD participants and 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and atypical (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. Participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k-means clustering based on the questionnaire, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV- (without) cluster. This data-driven approach enabled an unbiased classification of individuals with a DV, beyond traditional diagnostic labels. RESULTS:DV frequencies did not differ between the AD/FTD (18%) and control (15%) χ2 = 0.205; p = 0.651); and between typical (21%) and atypical (11%) subgroups (Fisher's test, p = 0.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV- patients (95% CI [-14, -3.0]; p = 0.005), with a median onset age of 58 years (IQR: 15). CONCLUSIONS:A DV could favor early-onset AD/FTD, but may not affect susceptibility to typical and atypical variants of AD/FTD. The underlying neurophysiological processes involved require future investigation, with implications for precision medicine and individualized treatment strategies. STUDY REGISTRATION NUMBERS:RnIPH 2023-71 and Research Ethics Committee file No. 2023_765.

The cognitive and neuroimaging evolution over the course of dementia with Lewy bodies (DLB) from prodromal stage - Pro-DLB (subjective (SCI) to mild cognitive impairment (MCI)) - is poorly understood. The aim of this study was to analyze from 5-year longitudinal data the trajectories of Pro-DLB patients. The "Lewy- MEMENTO" prospective clinical cohort recruited 773 patients for either SCI or MCI. The Pro-DLB group was compared to a group with prodromal Alzheimer's disease (Pro-AD), a group with "prodromal DLB and AD" (Pro-DLB + AD), and a group without prodromal DLB and AD (no symptom [NS]). We modeled the 5-year evolution of cognitive functions and the 2-year evolution of brain MRI volumetry on MRI and brain metabolism (FDG PET). The Pro-AD and Pro-DLB + AD groups had more cognitive and functional decline than the Pro-DLB and NS groups (P < .001). The Pro-DLB group had more cognitive decline than the NS group (P < .004). Incident dementia during the follow-up was higher in the Pro-AD (13.0 per 100 person-years) and Pro-DLB + AD (10.3) groups than in the Pro-DLB (1.02) and NS (0.44) groups (P < .001). The decline in the metabolism of the left orbitofrontal cortex was greater in the Pro-DLB + AD group. The volume decrease of hippocampi, entorhinal cortices, amygdalae, and left insula was higher in the Pro-AD and the pro-DLB + AD groups. Patients in the pro-DLB group had less cognitive, functional, brain volume, and metabolism decrease than patients in the Pro-AD and pro-DLB + AD groups. DLB would therefore be a less degenerative and more dysfunctional disease at the prodromal stage.

Purpose: 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). Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) <= 65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Data regarding Alzheimer’s disease (AD) occurrence in farming populations is lacking. This study aimed to investigate whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with AD than others, using nationwide data from the TRACTOR (Tracking and monitoring occupational risks in agriculture) project. Administrative health insurance data (digital electronic health/medical records and insurance claims) for the entire French agricultural workforce, over the period 2002–2016, on the entire mainland France were used to estimate the risk of AD for 26 agricultural activities with Cox proportional hazards model. For each analysis (one for each activity), the exposed group included all FMs that performed the activity of interest (e.g. crop farming), while the reference group included all FMs who did not carry out the activity of interest (e.g. FMs that never farmed crops between 2002 and 2016). There were 5067 cases among 1,036,069 FMs who worked at least one year between 2002 and 2016. Analyses showed higher risks of AD for crop farming (hazard ratio (HR) = 3.72 [3.47–3.98]), viticulture (HR = 1.29 [1.18–1.42]), and fruit arboriculture (HR = 1.36 [1.15–1.62]). By contrast, lower risks of AD were found for several animal farming types, in particular for poultry and rabbit farming (HR = 0.29 [0.20–0.44]), ovine and caprine farming (HR = 0.50 [0.41–0.61]), mixed dairy and cow farming (HR = 0.46 [0.37–0.57]), dairy farming (HR = 0.67 [0.61–0.73]), and pig farming (HR = 0.30 [0.18–0.52]). This study shed some light on the association between a wide range of agricultural activities and AD in the entire French FMs population.

Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension–dementia association are still poorly understood. We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension–dementia association.

Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP -negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

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. 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. 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. 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. Clinicaltrials.gov , NCT01926249

Le cas mystère de Grenoble concerne une jeune femme de 27 ans, éducatrice de rue. Elle a une histoire familiale traumatique et a présenté plusieurs épisodes dépressifs. Le parcours scolaire et universitaire a été parsemé d'embûches avec deux redoublements (CE1 et seconde). Elle n'a pas réussi son baccalauréat littéraire mais a validé une équivalence ce qui lui a permis finalement d'obtenir un diplôme d'état d'éducateur spécialisé à l'âge de 25 ans. Le parcours professionnel s'annonce cependant tout aussi éprouvant. Fatiguée de devoir utiliser son GPS au travail et devant des difficultés d'organisation et de calcul, elle consulte son généraliste qui l'adresse à la consultation des troubles neurodéveloppementaux (TND) de l'adulte du CMRR de Grenoble. Parallèlement, devant des idées suicidaires, elle se présente d'elle-même aux urgences psychiatriques de Voiron. La mise en arrêt de travail et le traitement psychotrope mis en place en hospitalisation, réduisent significativement la symptomatologie psychiatrique mais révèlent d'autant plus les symptômes neurologiques qui altèrent sa qualité de contact avec les autres et ses difficultés d'organisation. L'anamnèse et l'évaluation neuropsychologique permettent d'établir un diagnostic de TDAH associé à un autre syndrome neurodéveloppemental décrit dans la littérature, mais non répertorié dans le DMS V. À l'annonce diagnostique, elle réagit avec étonnement, satisfaite mais stupéfaite de n'avoir pas été diagnostiquée plus tôt.

Background and Objective Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints. Methods The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood A beta 42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. Results Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood A beta 42/40 was less efficient than CSF A beta 42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + A beta 42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + A beta 42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances. Discussion In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.

OBJECTIVE:Neurofilament 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 C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS:We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, 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. RESULTS:pNfL 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. GRN patients 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 C9orf72 patients, 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. CONCLUSIONS:This 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 NUMBERS:NCT02590276 and NCT04014673.

Objective To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. Methods The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ42/Aβ40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. Results There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: −0.061, 95% confidence interval: −0.089, −0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. Conclusion In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.

Neurodevelopmental disorders are frequent in the general population and are often lifelong conditions despite sometimes being masked by conscious or unconscious compensation and avoidance mechanisms. These conditions are often unknown or underestimated in adults, even when diagnosed in childhood. Neurodevelopmental disorders share similarities with and frequently interact in a complex way with neurodegenerative disorders. Considering these aspects during memory clinic assessments can provide a new perspective on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions is challenging but should improve diagnostic accuracy. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized and focused cognitive medicine and care.

INTRODUCTION:The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown.METHODS:A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms.RESULTS:Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups.DISCUSSION:Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.

Impairments of emotional processing have been reported in Alzheimer’s disease (AD), consistently with the existence of early amygdala atrophy in the pathology. In this study, we hypothesized that patients with AD might show a deficit of orientation toward emotional information under conditions of visual search. Eighteen patients with AD, 24 age-matched controls, and 35 young controls were eye-tracked while they performed a visual search task on a computer screen. The target was a vehicle with implicit (negative or neutral) emotional content, presented concurrently with one, three, or five non-vehicle neutral distractors. The task was to find the target and to report whether a break in the target frame was on the left or on the right side. Both control groups detected negative targets more efficiently than they detected neutral targets, showing facilitated engagement toward negative information. In contrast, patients with AD showed no influence of emotional information on engagement delays. However, all groups reported the frame break location more slowly for negative than for neutral targets (after accounting for the last fixation delay), showing a more difficult disengagement from negative information. These findings are the first to highlight a selective lack of emotional influence on engagement processes in patients with AD. The involvement of amygdala alterations in this behavioral impairment remains to be investigated.

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