Introduction Le passage de la barrière hémato-encéphalique est un défi majeur pour les grandes molécules telles que les anticorps monoclonaux réduisant la protéine amyloïde bêta (Aβ). Objectifs L’essai de Phase Ib/IIa Brainshuttle™ AD (NCT04639050) en cours évalue l’effet du trontinemab, anticorps bispécifique 2+1 Brainshuttle™. Les derniers résultats de sécurité et de biomarqueurs seront présentés. Méthodes Dans la partie d’escalade de dose, 60 participants ont été randomisés dans 4 cohortes de doses séquentielles. Les deux niveaux de dose les plus élevés (Cohortes 3 et 4) ont montré des résultats pharmacodynamiques et de sécurité favorables dans la partie d’escalade de dose et ont été étudiés plus en détail dans la partie d’expansion de dose, avec 60 participants supplémentaires par cohorte, avant de passer à une phase d’extension en ouvert. Résultats Les résultats montrent une réduction amyloïde significative sur l’imagerie par TEP amyloïde : dans la Cohorte 4, plus de 80 % des participants atteignent une clairance de l’amyloïde en dessous du seuil de positivité après 28 semaines de traitement, avec une réduction minimale de –47 CL(moyenne de –96 CL), sans aucun non-répondeur. Des effets précoces et prononcés sur les biomarqueurs dans le LCR et le plasma ont été observés. L’incidence des ARIA-E était inférieure à 5 %. Discussion Le trontinemab montre une pénétration cérébrale améliorée et une clairance de la plaque amyloïde dans l’étude de Phase Ib/IIa Brainshuttle™ AD, suggérant une absorption rapide, à des concentrations d’anticorps considérablement accrues, et un engagement amélioré dans tout le tissu cérébral, y compris dans les zones profondes. Conclusion Les résultats de biomarqueurs et de sécurité de l’étude BrainShuttle™ AD soutiennent la poursuite vers la phase pivotale du développement clinique du trontinemab dans la MA.

Background Although Alzheimer's disease (AD) is biologically well characterized, early and precise phenotypic diagnosis remains challenging, especially for atypical variants. Posterior cortical atrophy (PCA) is a rare form of AD with progressive neurovisual impairment related to degeneration in visual processing areas. Objective To investigate how alterations in eye movement metrics, measured through video-oculography (VOG), reflect dysfunction across distinct brain networks in various AD phenotypes, with particular emphasis on PCA. Methods This study compared oculomotor parameters derived from VOG saccade analysis in early AD patients exhibiting two clinical phenotypes, PCA-AD (n = 21) and amnestic mild cognitive impairment (aMCI-AD, n = 11), along with 27 age-matched controls. Parameters analyzed included saccade latency, gain, velocity, intrusions and antisaccade error rates. All patients exhibited cerebrospinal fluid biomarkers consistent with AD pathology. Results As expected, neuropsychological testing revealed more severe neurovisual and executive deficits in PCA-AD versus aMCI-AD, and greater memory storage impairment in aMCI. Oculomotor data showed that PCA-AD patients exhibited prolonged saccade latencies, reduced gain, slower vertical saccades, and increased antisaccade errors compared to controls and aMCI-AD. Receiver operating characteristic analysis combining key saccadic metrics demonstrated up to 90% sensitivity and specificity in distinguishing PCA from controls and aMCI. Conclusions These findings support the use of VOG oculomotor metrics as phenotypic biomarkers in differentiating AD clinical forms. In PCA, they reflect the dysfunction of visuo-spatial attentional networks and their interaction with subcortical eye movement control circuits.

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.

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.

The growing prevalence of the Alzheimer's disease (AD) is an increasing public health concern that led to French recommendations for timely AD diagnosis and patient management as well as a territorial coverage of specialized structures [Memory Centers including Resources and Memory Research Centers (RMRC) and Memory Consultations (MC)]. In view of the potential availability of Disease Modifying Therapies (DMTs), this French observatory aimed to describe the current organization of the Memory Centers, and the care pathway of patients suffering from early AD. Overall, 12 of the 28 RMRC and 44 of the 250 MC solicited by the Federation of Memory Centers participated in this study. RMRC and MC differed in the practicing specialists (neurologists in 100 % and 41 % of the structures, respectively; geriatricians in 58 % and 95 %), and in the median yearly number of patients with early AD (192 and 99). The majority of patients were referred to RMRC and MC by a general practitioner (42 % and 51 %, respectively) or a private neurologist (19 % and 6 %). The time between referral and the first visit to the Memory Center was shorter in MC compared to RMRC (<3 months: 51 % versus 34 %). Cerebrospinal fluid biomarkers were assessed in the majority of patients in 75 % of RMRC and 14 % of MC. A care plan was proposed for the majority of patients whatever the Memory Center was (RMRC: 91 %, MC: 84 %) unlike psychological support (21 % and 29 %, respectively) and therapeutic education (14 % and 9 %). According to more than 2/3 of the RMRC the referral delays, the number of patients with early AD, and the monitoring schedule (including MRIs and clinical assessments) will be very impacted by the potential availability of DMTs. A similar impact was only perceived by around half of the MC. This study highlighted the key challenges raised by these new therapies.

BackgroundThe association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC.MethodsAll participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer.ResultsThe global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032).ConclusionsIn a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

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/).

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.

Cette étude française vise à évaluer l’impact du confinement national de 55 jours sur le métabolisme cérébral de patients atteints de troubles neurologiques. Une analyse TEP à l’échelle du voxel et sur cerveau entier a été conduite pour corréler le métabolisme 18F-FDG au nombre de journées passées en confinement après le 17 mars 2020 (chez 95 patients ; âge moyen : 54,3 ans ± 15,7 ; 59 hommes), par rapport à la même période en 2019 avant l’épidémie de SARS-CoV-2 (chez 212 patients ; âge moyen : 59,5 ans ± 15,8 ; 114 hommes), et aux 55 premiers jours du déconfinement (chez 188 patients ; âge moyen : 57,5 ans ± 16,5 ; 93 hommes). La durée du confinement était négativement corrélée au métabolisme du cortex sensori-moteur avec un effet prédominant sur le réseau pyramidal de l’hémisphère majeur et chez les patients les plus jeunes, incluant également l’amygdale gauche, avec une réversibilité seulement partielle après 55 jours de déconfinement. Un faible recouvrement était retrouvé avec le profil d’hypométabolisme décrit dans le COVID long (<9 %). La restriction des activités physiques, avec son déconditionnement associé, et l’isolement social pourraient entraîner des perturbations fonctionnelles des réseaux cérébraux sensorimoteurs et émotionnels. Ce profil métabolique semble distinct de celui rapporté dans le COVID long. D’autres études longitudinales sont nécessaires, avec un suivi plus long, pour évaluer les conséquences cliniques et, en particulier, l’impact sur la santé cognitive et mentale, et pour étendre ces résultats aux sujets sains dans ce contexte de confinement.

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

Background This work aimed to investigate the potential pathways involved in the association between social and lifestyle factors, biomarkers of Alzheimer’s disease and related dementia (ADRD), and cognition. Methods The authors studied 2323 participants from the Memento study, a French nationwide clinical cohort. Social and lifestyle factors were education level, current household incomes, physical activity, leisure activities, and social network from which two continuous latent variables were computed: an early to midlife (EML) and a latelife (LL) indicator. Brain magnetic resonance imaging (MRI), lumbar puncture, and amyloid-positron emission tomography (PET) were used to define three latent variables: neurodegeneration, small vessel disease (SVD), and AD pathology. Cognitive function was defined as the underlying factor of a latent variable with four cognitive tests. Structural equation models were used to evaluate cross-sectional pathways between social and lifestyle factors and cognition. Results Participants’ mean age was 70.9 years old, 62% were women, 28% were apolipoprotein-ε4 carriers, and 59% had a Clinical Dementia Rating (CDR) score of 0.5. Higher early to midlife social indicator was only directly associated with better cognitive function (direct β = 0.364 (0.322; 0.405), with no indirect pathway through ADRD biomarkers (total β = 0.392 (0.351; 0.429)). In addition to a direct effect on cognition (direct β = 0.076 (0.033; 0.118)), the association between latelife lifestyle indicator and cognition was also mostly mediated by an indirect effect through lower neurodegeneration (indirect β = 0.066 (0.042; 0.090) and direct β = − 0.116 (− 0.153; − 0.079)), but not through AD pathology nor SVD. Conclusions Early to midlife social factors are directly associated with higher cognitive functions. Latelife lifestyle factors may help preserve cognitive functions through lower neurodegeneration.

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.

1. Le traitement de la maladie d'Alzheimer (MA) est complexe, et repose actuellement sur une prise en soin globale du patient, comportant des approches médico-psycho-sociales dites « non médicamenteuses » et médicamenteuses.2. Les traitements « symptomatiques » autorisés dans la maladie d'Alzheimer ont pour objectif de ralentir le déclin cognitif et ses conséquences fonctionnelles.3. Les inhibiteurs de l'acétylcholinestérase (iAChE) montrent un bénéfice cognitif en comparaison au placebo, statistiquement significatif, mais de faible ampleur.4. Quand ils sont bien prescrits, le rapport entre bénéfices et risques des iAChE semble favorable.5. Malgré leur déremboursement en France en 2018, la majorité des patients traités ont poursuivi l'utilisation de ces traitements.6. Malgré l'arrivée possible de traitement pouvant modifier le cours évolutif de la MA, il reste nécessaire d'améliorer nos connaissances et compétences sur la prise en soins symptomatiques des patients.1. The treatment of Alzheimer's disease (AD) is complex, and is currently based on comprehensive care of the patient, including "non-drug" and "drug" approaches.2. Symptomatic treatments of AD aim to slow down cognitive decline and its functional consequences.3. Acetylcholinesterase inhibitors (iAChE) show a statistically significant, but small, cognitive benefit compared to placebo.4. When properly prescribed, the benefit/risk ratio of iAChE appears favorable.5. Despite their delisting in France in 2018, the majority of treated patients continued to use these treatments.6. Despite the possible arrival of disease modifying therapies, it is still necessary to improve our knowledge and skills in the symptomatic care of patients.

This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18 F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown.

Long COVID is defined by the persistence or recurrence of symptoms after initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This condition affects 20% of patients at 5 weeks and 10% at 3 months, with a major impact on health care and social systems [[1]Greenhalgh T. Knight M. A'Court C. Buxton M. Husain L. Management of post-acute covid-19 in primary care.BMJ. 2020; 370: m3026Crossref PubMed Scopus (794) Google Scholar]. Long COVID has been described in all countries facing the pandemic. It corresponds to different realities, which can be associated [[1]Greenhalgh T. Knight M. A'Court C. Buxton M. Husain L. Management of post-acute covid-19 in primary care.BMJ. 2020; 370: m3026Crossref PubMed Scopus (794) Google Scholar]. On the one hand, patients may present with sequelae of acute coronavirus disease 2019 (COVID-19) (e.g. pulmonary fibrosis or stroke) as well as physical/psychological impairments following long stays in intensive care units. On the other hand, a group of often younger patients has emerged with mainly mild to moderate initial presentations and persistent or recurrent symptoms, dominated by fatigue and dyspnoea; loss of olfactory and gustatory function; subjective or mild cognitive impairment; sleep disturbances; and pain complaints (headache, chest pain or diffuse pain). These persistent or recurrent symptoms after SARS-CoV-2 infection in patients who have no morphological lesions on conventional imaging (CT scan or MRI) could correspond to dysfunction of brain regions, as suggested by [18F]fluorodeoxyglucose metabolic positron emission tomography (PET) imaging studies [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar,[3]Sollini M. Morbelli S. Ciccarelli M. Cecconi M. Aghemo A. Morelli P. et al.Long COVID hallmarks on [18F]FDG-PET/CT: a case–control study.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05294-3Crossref Scopus (75) Google Scholar]. Recent work has especially shown metabolic impairment of the olfactory bulbs within the fronto-basal region and dysfunction of a network of connected cerebral regions including limbic/paralimbic regions (especially the amygdala and hippocampus), the brainstem (pons/medulla) and cerebellum [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. Beyond olfaction, these hypometabolic brain regions are well known to be involved in memory, emotion, autonomous behaviours, motor skills and pain pathways. Among the 35 patients in this PET study (mean age 55 years) and after a mean delay of 3 months, 80% had dyspnoea, 66% had pain, 49% had memory/cognitive impairment, 46% had insomnia, 29% had hyposmia/anosmia and 26% had dysgeusia/ageusia [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. Interestingly, the identified pathway seems to describe the limbic network of Proust's famous madeleine: the smell is quickly followed by the taste, recognition (and, more broadly, the memory) and associated emotions. This limbic system is known to be closely linked on brainstem nuclei to the autonomic nervous system, which is also involved during emotional memory processing and whose dysregulation can lead to cardiovascular, muscular, gastrointestinal and respiratory symptoms (e.g. diarrhoea, dizziness, hypertension, palpitations or tremor) [[4]Mizuno-Matsumoto Y. Inoguchi Y. Carpels S.M.A. Muramatsu A. Yamamoto Y. Cerebral cortex and autonomic nervous system responses during emotional memory processing.PLoS One. 2020; 15e0229890Crossref PubMed Scopus (6) Google Scholar]. Additional analysis of the 35 patients in the PET study has confirmed an association between olfactory loss and memory complaints in this group (p = 0.027, Fisher's exact test; memory complaints in 80% of patients with olfactory loss versus 36% of patients without olfactory loss) [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. Olfactory function loss at the time of infection has also been reported to be among the main risk factors for subsequent memory impairment [[5]Almeria M. Cejudo J.C. Sotoca J. Deus J. Krupinski J. Cognitive profile following COVID-19 infection: clinical predictors leading to neuropsychological impairment.Brain Behav Immun Health. 2020; 9: 100163Crossref PubMed Scopus (183) Google Scholar]. The fronto-basal cortex is involved in attention and short-term memory linked to the olfactory sense. After being processed and refined in the olfactory bulb and piriform cortex, the olfactory sensory input is processed in the amygdala and hippocampus (two key brain areas involved in emotion and memory), making olfaction a privileged sense for accessing memories. Perturbations of the olfactory circuit and functioning can therefore result in emotional and cognitive dysfunctions, as described in animal models such as olfactory bulbectomy, a relevant model of depression. Accordingly, loss of olfaction is associated with depressed mood and anxiety in long COVID more strongly than are life-threatening symptoms such as shortness of breath [[6]Speth M.M. Singer-Cornelius T. Oberle M. Gengler I. Brockmeier S.J. Sedaghat A.R. Mood, anxiety and olfactory dysfunction in COVID-19: evidence of central nervous system involvement?.Laryngoscope. 2020; 130: 2520-2525Crossref PubMed Scopus (69) Google Scholar]. Impairments in both cognitive and olfactory functioning are prevalent in several brain disorders, for example in Parkinson's disease, Alzheimer's disease, mild cognitive impairment, and also in aging [[7]Attems J. Walker L. Jellinger K.A. Olfaction and aging: a mini-review.Gerontology. 2015; 61: 485-490Crossref PubMed Scopus (185) Google Scholar]. Along these lines, olfactory dysfunction negatively impacts the structural volumetry of the medial temporal lobe in early stages of Alzheimer's disease, and deafferentation of the hippocampus from olfactory inputs worsens memory decline [[8]Daulatzai M.A. Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer's disease.J Neural Transm (Vienna). 2015; 122: 1475-1497Crossref PubMed Scopus (47) Google Scholar]. As a consequence, strategies to enhance olfactory function have been suggested to improve cognitive decline [[8]Daulatzai M.A. Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer's disease.J Neural Transm (Vienna). 2015; 122: 1475-1497Crossref PubMed Scopus (47) Google Scholar], and alleviate anterograde and retrograde amnesia on recent and remote memories in these patients [[9]Glachet O. Moustafa A.A. Gallouj K. El Haj M. Smell your memories: positive effect of odor exposure on recent and remote autobiographical memories in Alzheimer's disease.J Clin Exp Neuropsychol. 2019; 41: 555-564Crossref PubMed Scopus (21) Google Scholar]. The olfactory system has also been proposed to be targeted as a therapeutic pathway through intranasal delivery of various drugs [[7]Attems J. Walker L. Jellinger K.A. Olfaction and aging: a mini-review.Gerontology. 2015; 61: 485-490Crossref PubMed Scopus (185) Google Scholar]. Interestingly, olfactory and memory impairments have been recently linked in Alzheimer's disease and COVID-19 through similar neurobiochemical features, especially involving angiotensin-converting enzyme 2 receptors and pro-inflammatory markers such as interleukin-1, interleukin-6, cytoskeleton-associated protein 4, galectin-9, and apolipoprotein E4 allele [[10]Rahman M.A. Islam K. Rahman S. Alamin M. Neurobiochemical cross-talk between COVID-19 and Alzheimer's disease.Mol Neurobiol. 2021; 58: 1017-1023Crossref PubMed Scopus (58) Google Scholar]. The areas of brain hypometabolism that have been found in long COVID are visually obvious on PET scans of many patients, and have been quantitatively identified at the group and individual levels [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. Their severity is associated with the severity of symptoms [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. The relationship of metabolism with clinical presentation is however complex because olfactory hypometabolism was also reported in patients without obvious loss of olfactory function. Nevertheless, absence of functional complaints does not exclude more subtle clinical alterations. The profile of hypometabolism identified in patients with long COVID does not seem to correspond to those in patients with depression, post-traumatic stress disorder or even fibromyalgia. If limbic alterations have also been described in these conditions, the association with concomitant hypometabolism of the brainstem and cerebellum is more atypical [[11]Pagani M. Castelnuovo G. Daverio A. La Porta P. Monaco L. Ferrentino F. et al.Metabolic and electrophysiological changes associated to clinical improvement in two severely traumatized subjects treated with EMDR—a pilot study.Front Psychol. 2018; 9: 475Crossref PubMed Scopus (4) Google Scholar]. The metabolic impairment of the olfactory bulbs is an important phenomenon to consider for further therapeutic interventions. COVID-19-related anosmia has been associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters [[12]de Melo G.D. Lazarini F. Levallois S. Hautefort C. Michel V. Larrous F. et al.COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters.Sci Transl Med. 2021; https://doi.org/10.1126/scitranslmed.abf8396Crossref PubMed Scopus (211) Google Scholar]. The olfactory clefts could therefore constitute the gateway through which SARS-CoV-2 accesses the brain, reaching the olfactory bulb and other contiguous and deep brain regions through angiotensin-converting enzyme 2 receptors [[2]Guedj E. Campion J.Y. Dudouet P. Kaphan E. Bregeon F. Tissot-Dupont H. et al.F-FDG brain PET hypometabolism in patients with long COVID.Eur J Nucl Med Mol Imaging. 2021; https://doi.org/10.1007/s00259-021-05215-4Crossref Scopus (175) Google Scholar]. In the absence of known remote lesions, the impairment of the olfactory bulb could then represent the origin of the more posteriorly located effects on cerebral function of other limbic regions (including amygdala and hippocampus), and also the brainstem and cerebellum, through diaschisis (decreased functional activity of cerebral regions from connected brain-damaged areas) as a result of deafferentation (loss of input). It is not known at this stage whether the infection or the inflammation could diffuse to more posterior regions in long COVID, from nose and olfactory bulbs to the deepest regions of the brain, causing irritation and dysregulation. Viral trans-synaptic progression has previously been demonstrated with other coronaviruses [[13]Baig A.M. Khaleeq A. Ali U. Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms.ACS Chem Neurosci. 2020; 11: 995-998Crossref PubMed Scopus (1404) Google Scholar]. Both RNA and protein of the virus have been found in the neurons of patients who died from severe SARS-CoV-2 infection [[14]Meinhardt J. Radke J. Dittmayer C. Franz J. Thomas C. Mothes R. et al.Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.Nat Neurosci. 2021; 24: 168-175Crossref PubMed Scopus (700) Google Scholar] and accompanied T-cell infiltration and microglial activation in euthanized macaques after apparent remission of COVID-19 [[15]Philippens I.H.C.H.M. Böszörményi K.P. Wubben J.A. Fagrouch Z.C. van Driel N. Mayenburg A.Q. et al.SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques.bioRxiv. 2021; https://doi.org/10.1101/2021.02.23.432474Crossref Scopus (0) Google Scholar]. Such neuroinflammation requires long-term follow up, considering the known relationships of neuroinflammation with the onset and progression of neurological and psychiatric diseases. These relationships are multifactorial, with several other determinants. They could nevertheless be found in a significant number of patients given the magnitude of the global pandemic. We cannot exclude the possibility that hypometabolism in the fronto-basal cortex could be a sign of a premorbid neural phenotype associated with increased vulnerability to long COVID. Nevertheless, we believe that the functional aspect of this remote effect is important because most patients recover after a few months in the absence of obvious brain lesions on brain MRI. This functional recovery could be accelerated by different strategies of rehabilitation [[7]Attems J. Walker L. Jellinger K.A. Olfaction and aging: a mini-review.Gerontology. 2015; 61: 485-490Crossref PubMed Scopus (185) Google Scholar,[9]Glachet O. Moustafa A.A. Gallouj K. El Haj M. Smell your memories: positive effect of odor exposure on recent and remote autobiographical memories in Alzheimer's disease.J Clin Exp Neuropsychol. 2019; 41: 555-564Crossref PubMed Scopus (21) Google Scholar]. In patients with persistent olfactory dysfunction, olfactory rehabilitation may act on the whole network and possibly on other symptoms, in addition to other approaches such as respiratory and cognitive rehabilitation or adapted physical activity. In this line, olfactory training markedly improved post-infectious olfactory dysfunction compared with no training by inducing neuroplastic changes in regional functional connectivity beyond olfactory pathways [[16]Kollndorfer K. Fischmeister F.P. Kowalczyk K. Hoche E. Mueller C.A. Trattnig S. et al.Olfactory training induces changes in regional functional connectivity in patients with long-term smell loss.Neuroimage Clin. 2015; 9: 401-410Crossref PubMed Scopus (87) Google Scholar]. In the future, the inflammatory and/or viral brain component of long COVID could be explored in vivo with more specific targets, for example, with PET imaging of neuroinflammation and microglial activation using translocator protein (TSPO) ligands. In the same way, follow-up metabolic PET studies are required to specify the correct relationship between the PET abnormalities and the temporal sequence of functional complaints, and especially earlier [18F]fluorodeoxyglucose PET examinations to investigate the hypothesis of brain hypometabolic dysfunction secondary to earlier brain hypermetabolic inflammation. If the hypothesis is borne out, the development of new therapeutic strategies should target the olfactory clefts in the most severely impaired patients who will have little or no recovery after rehabilitation, for example, by using intranasally administered anti-inflammatory or antiviral drugs to act [[7]Attems J. Walker L. Jellinger K.A. Olfaction and aging: a mini-review.Gerontology. 2015; 61: 485-490Crossref PubMed Scopus (185) Google Scholar], beyond functional effects, on the pathological impairment of Proust's madeleine brain network. EG wrote the first draft based on previous discussions with all co-authors. All co-authors contributed to improving the first draft until the validation of this final version. The authors declare that they have no conflicts of interest. No external funding was received for this study.

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.

In early 2020, COVID-19 outbreak struck France leading to a national lockdown between March 17th and May 11th . While standard in-person medical consultation was complicated, telemedicine dramatically expanded. In order to evaluate the impact of this unpreceded situation on clinical practice and use of psychoactive drug in dementia care, we conducted a nationwide clinical prospective and retrospective study.During the lockdown period, telemedicine patients' demographic and clinical data were retrospectively collected from 7 French memory clinics (telemedicine cohort). Clinical diagnoses, treatment changes, cognitive modifications since last consultations and living conditions during the lockdown were systematically retrieved. In Rouen site, we also included patients only reached by a secretary to propose a postponed visit after lockdown (no-telemedicine cohort) and patients seen in 2019 during the same period of the year (Rouen-2019). The primary outcome was any change in psychoactive drug and a specific analysis on sedative treatment increase was the secondary outcome, defined as any increase in the prescriptions of antipsychotics or benzodiazepines.The telemedicine cohort included 874 patients (73 from Rouen), while no-telemedicine control cohort and Rouen-2019 cohorts included respectively 86 and 234 patients (table 1). In the telemedicine cohort, treatments were modified for 10.7% of the patients with more treatment modification among the patients living with a relative (+5.8% (CI95% [0.2%; 11.4%] p=0.04) and among the patients with Alzheimer's disease (+12.2% (CI95% [7.1%; 17.3%] p<0.001). When comparing therapeutic strategies in 2020 and 2019 for Rouen site, 24.6% of the patients had their treatment modified in 2020 and 12.4% in 2019. That difference was however not statically significant with an adjusted percentage difference of -4% (CI95% [-10.8%; 3.4%] p=0.27, including the telemedicine and no-telemedicine cohorts for 2020.Telemedicine seems to have had only minor negative impacts on clinical practice in memory clinics.