Publications by authors named "Florence Pasquier"

267 Publications

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

Brain 2021 Oct;144(9):2798-2811

Hurvitz Brain Sciences Program, Sunnybrook Research Institute; Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
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http://dx.doi.org/10.1093/brain/awab171DOI Listing
October 2021

Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study.

Neurobiol Aging 2021 Sep 8;108:155-167. Epub 2021 Sep 8.

Nueld Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.

The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states' DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.09.001DOI Listing
September 2021

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.

JAMA Netw Open 2021 Sep 1;4(9):e2125584. Epub 2021 Sep 1.

FORUM Pharmaceuticals Incorporated, Waltham, Massachusetts.

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.

Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.

Design, Setting, And Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021.

Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days.

Main Outcomes And Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]).

Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03).

Conclusions And Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible.

Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463943PMC
September 2021

A multimodal, longitudinal study of cognitive heterogeneity in early-onset Alzheimer's disease.

Eur J Neurol 2021 Sep 7. Epub 2021 Sep 7.

Department of Neurology, Lille University Hospital Centre, Memory Centre, Reference Centre for Early-Onset Alzheimer Disease and Related Disorders, Lille, France.

Background And Purpose: Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics.

Methods: We collected cognitive, behavioural, functional, neuroimaging, and laboratory data on 72 patients meeting the criteria for probable mild EOAD. The patients were first classified into clinical phenotype groups by a multidisciplinary board of clinicians. The patients' cognitive and functional decline was monitored for 24 months. A k-means clustering analysis was then used to determine clusters on the basis of the patients' neuropsychological test results.

Results: Two distinct clusters were identified: the patients in the first cluster (C1, n = 38) had a predominant memory impairment, whereas patients in the second (C2, n = 34) did not. Dyslipidaemia and the presence of ɛ4 apolipoprotein E allele were more frequent in C1, whereas the cognitive and functional decline was faster in the patients in C2. Moreover, posterior brain abnormalities were more severe in patients in C2 than in patients in C1.

Conclusions: By applying a k-means clustering analysis, we identified two clusters of patients in an EOAD cohort. The clusters differed with regard to certain clinical, imaging, and laboratory characteristics. This clustering procedure might be of value for managing patients with EOAD in general and for identifying those at risk of more rapid decline in particular.
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http://dx.doi.org/10.1111/ene.15097DOI Listing
September 2021

Molecular Landscape of Therapy-related Myeloid Neoplasms in Patients Previously Treated for Gynecologic and Breast Cancers.

Hemasphere 2021 Sep 18;5(9):e632. Epub 2021 Aug 18.

Département d'Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were (31%), (19%), (13%), (13%), (12%), (10%), (9%), and (9%). CHIP-AMs were detected in 66% of TRMN patients, with no impact on OS. Yet, patients with CHIP-AM were older and had a longer time interval between solid tumor diagnosis and TRMN. According to our modified ontogeny-based classifier, we observed that the patients with or mutations had more treatment lines and complex karyotypes, the "MDS-like" patients were older with more gene mutations, while patients with "De novo/pan-AML" mutations were younger with more balanced chromosomal translocations. Median OS within each subgroup was 7.5, 14.5, and 25.2 months, respectively, with statistically significant difference in multivariate analysis. These results support the integration of cytogenetic and molecular markers into the future TRMN classification to reflect the biological diversity of TRMN and its impact on outcomes.
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http://dx.doi.org/10.1097/HS9.0000000000000632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373540PMC
September 2021

Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms.

Blood 2021 Aug 18. Epub 2021 Aug 18.

Université Paris-Saclay, France.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells (HSC) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon alpha (IFNα) has demonstrated some efficacy in inducing molecular remission in MPN. In order to determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in MPN patients by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured several times per year the clonal architecture of early and late hematopoietic progenitors (84,845 measurements) and the global variant allele frequency in mature cells (409 measurements). Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSC. Our data support the hypothesis that IFNα targets JAK2V617F HSC by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSC and increases with high IFNα dosage in heterozygous JAK2V617F HSC. Besides, we found that the molecular responses of CALRm HSC to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and high dosage of IFNα correlates with worse outcomes. Together, our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dosage.
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http://dx.doi.org/10.1182/blood.2021010986DOI Listing
August 2021

Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort.

J Neurol Neurosurg Psychiatry 2021 Aug 5. Epub 2021 Aug 5.

Department of Neurofarba, University of Florence, Firenze, Italy.

Background: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

Methods: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (, 187 , 193 ) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 92 88 ) and 145 non-carriers had available longitudinal data at a follow-up time point.

Results: Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: mutation carriers mean 83.4 (SD 27.0), mutation carriers 78.2 (28.8), mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: mutation carriers mean 2.6 (5.2), mutation carriers 3.2 (5.6), mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r=-0.77, p<0.001) and within each genetic group (r=-0.67 to -0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls -0.1 (6.0) for FRS, -0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers -0.5 (8.2), 0.2 (0.9), prodromal disease -2.3 (9.9), 0.6 (2.7), mild disease -10.2 (18.6), 3.0 (4.1), moderate disease -9.6 (16.6), 4.4 (4.0), severe disease -2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.

Conclusions: Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.
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http://dx.doi.org/10.1136/jnnp-2021-326868DOI Listing
August 2021

Plasma NfL levels and longitudinal change rates in and -associated diseases: from tailored references to clinical applications.

J Neurol Neurosurg Psychiatry 2021 Aug 4. Epub 2021 Aug 4.

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France

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 and 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 and 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. patients had higher levels than (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In 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.
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http://dx.doi.org/10.1136/jnnp-2021-326914DOI Listing
August 2021

The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort.

Alzheimers Res Ther 2021 07 12;13(1):127. Epub 2021 Jul 12.

Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.

Background: Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts.

Methods: We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis.

Results: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum.

Conclusions: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
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http://dx.doi.org/10.1186/s13195-021-00865-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276486PMC
July 2021

Diabetes Mellitus and Cognition: Pathway Analysis in the MEMENTO Cohort.

Neurology 2021 08 1;97(8):e836-e848. Epub 2021 Jul 1.

From INSERM, UMR 1219 (E.F., C.P.-L., G.C., C.D.), and INSERM, CIC1401-EC (E.F., G.C., C.D.), Université de Bordeaux; Pole de Sante Publique Centre (E.F., G.C., C.D.) and Pole de Gérontologie Clinique (I.B.-M.), Hospitalier Universitaire (CHU) de Bordeaux; CATI Multicenter Neuroimaging Platform (J.-F.M., M.-O.H., M. Ceccaldi), Paris; Neurospin CEA Paris Saclay University (J.-F.M.), Gif-sur-Yvette; Laboratoire d'Imagerie Biomédicale (M.-O.H.), INSERM, CNRS, Sorbonne Université; Médecine Nucléaire (M.-O.H.), AP-HP, Hôpital Pitié-Salpêtrière; IM2A, AP-HP, INSERM, UMR-S975, Groupe Hospitalier, Pitié-Salpêtrière Institut de la Mémoire et de la Maladie d'Alzheimer (S.B.), and INSERM, U-1127, 3 CNRS, UMR 7225, CATI (M. Chupin), Institut du Cerveau et de la Moelle Épinière, Sorbonne Université, Paris; INSERM UMR1027 (P.-J.O.), Université de Toulouse III Paul Sabatier; Centre Mémoire (CMRR) Distalz (F.P.), CHU, INSERM 1171, Université de Lille; Service de Gériatrie (O.H.), Hôpital Broca, Université Paris Descartes; Centre de Neurologie (C.P.), INSERM U1144, Cognitive Hôpital Lariboisière, Université de Paris; Department of Neurology, INSERM U1061, Clinical and Research Memory Center of Montpellier (A.G.), Gui de Chauliac Hospital, University of Montpellier; Institut de Neurosciences des Systèmes, CMMR, PACA Ouest (M. Ceccaldi), INSERM, CHU Timone APHM and Aix Marseille Université; Department of Geriatric Medicine (C.A.), Angers University Memory Clinic, Research Center on Autonomy and Longevity, UPRES EA 4638, Angers University Hospital, University of Angers, France; Department of Medical Biophysics (C.A.), Robarts Research Institute, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Canada; Centre Mémoire Ressource et Recherche de Lyon (CMRR) (P.K.-S.), Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, Hôpital des Charpennes, Hospices Civils de Lyon, Université de Lyon; Centre Mémoire de Ressources et de Recherches (Y.B.), CHU Dijon Bourgogne, EA7460, Université de Bourgogne, Dijon; Service de Neurologie Hôpital Saint-Louis AP-HP (C.B.), Paris; Departement de Neurologie (D.W.), UNIROUEN, INSERM U1245, CNR-MAJ, CHU de Rouen, Université de Normandie; CMRR Grenoble Arc Alpin (M.S.), CHU Grenoble; CMRR (E.B.), University Hospital Tours; Centre de Résonance Magnétique des Systèmes Biologiques (I.B.-M.), UMR 5536 Université de Bordeaux/CNRS; and Memory Resource and Research Centre of Clermont-Ferrand (I.J.), CHU de Clermont-Ferrand, Clermont Auvergne University, Clermont-Ferrand, France.

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, Aβ/Aβ 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.
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http://dx.doi.org/10.1212/WNL.0000000000012440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397583PMC
August 2021

Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.

Leukemia 2021 Jun 25. Epub 2021 Jun 25.

INSERM, U1287, Gustave Roussy, Villejuif, France.

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
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http://dx.doi.org/10.1038/s41375-021-01319-wDOI Listing
June 2021

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Nat Med 2021 Jul 21;27(7):1187-1196. Epub 2021 Jun 21.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

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.
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http://dx.doi.org/10.1038/s41591-021-01369-8DOI Listing
July 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.

Alzheimers Dement (Amst) 2021 13;13(1):e12185. Epub 2021 May 13.

Douglas Mental Health University Institute Department of Psychiatry McGill University Montreal Canada.

Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT).

Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [], 163 progranulin [], and 73 microtubule-associated protein tau []) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT.

Results: All symptomatic mutation carrier groups and presymptomatic mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic mutation carriers. Performance on the FCSRT correlated with executive function, particularly in mutation carriers, but also with memory and naming tasks in the group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in and , but mainly temporal areas in mutation carriers.

Discussion: The FCSRT detects presymptomatic deficits in - and -associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD.
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http://dx.doi.org/10.1002/dad2.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116844PMC
May 2021

Primary Progressive Aphasia Associated With Mutations: New Insights Into the Nonamyloid Logopenic Variant.

Neurology 2021 07 12;97(1):e88-e102. Epub 2021 May 12.

From Sorbonne Université (D.S., M.H., L.S., S.E., A.C., S.B., D.R., A.M., R.L., B.D., A.B., O.C., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM), Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Reference Centre for Rare or Early Dementias (D.S., S.F., M.N.-L., M.H., A.F., L.S., S.E., D.R., A.M., R.L., B.D., M.T., R.M., I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Aramis Project Team (D.S., S.E., S.B., A.M., O.C.), Inria Research Center of Paris; Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière, Sorbonne Université; FrontLab (A.F., R.L., B.D., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM); Université Lille (V.D., F.P.), Inserm U1171, CHU Lille, DistAlz, LiCEND, CNR-MAJ; CMRR Service de Neurologie (P.C.), CHU de Limoges; Department of Neurology (J.P., A.G.), Toulouse University Hospital; ToNIC (J.P., A.G.), Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse; Normandie Université (D.W., D.H.), UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine; Rouen University Hospital (O.M.), Department of Neurology; Normandie Université (O.M.), UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen Normandie, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen; UF de Neurogénétique Moléculaire et Cellulaire (F.C.), Département de Génétique, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix; EPHE (A.C.), PSL Research University, Paris; CMRR Nouvelle Aquitaine/Institut des Maladies Neurodégénératives clinique (IMNc) (S.A.), CHU de Bordeaux Hôpital Pellegrin; Unit of Neurology of Memory and Language (M.S., J.L., C.R.-J.), GHU Paris Psychiatry and Neurosciences, University of Paris, Hôpital Sainte Anne; Université Paris-Saclay (M.S., J.L., C.R.-J.), CEA, CNRS, Inserm, BioMaps, Orsay; Aix Marseille Université (M.D.), INSERM, Institut de Neurosciences des Systèmes, Marseille; APHM (M.D.), Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille; CHU Nantes (C.B.-B.), Inserm CIC04, Department of Neurology, Centre Mémoire de Ressources et Recherche, Nantes; Centre de génétique (C.T.-R.), Hôpital d'Enfants, CHU Dijon Bourgogne; CMRR Département de Neurologie (F.S.), Hôpitaux Civils, Colmar, INSERM U1118, Université de Strasbourg, Faculté de Médecine, 67085 Strasbourg; CMRR (A.G.), Département de Neurologie, CHU de Montpellier, Inserm U1061, Université de Montpellier i-site MUSE; Department of Neurology (F.E.-B.), CMRR Angers University Hospital, Angers, France; Department of Advanced Medical and Surgical Sciences (C.C.), University of Campania Luigi Vanvitelli, Naples, Italy; and Department of Neurology (M.L.G.-T.), Memory and Aging Center, University of California, San Francisco.

Objective: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with (progranulin) mutations and to study their neuroanatomic correlates.

Methods: Patients with PPA carrying mutations (PPA-) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.

Results: Among the 235 patients with PPA, 45 (19%) carried mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).

Conclusions: This study shows that the most frequent PPA variant associated with mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming gene-specific therapies.
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http://dx.doi.org/10.1212/WNL.0000000000012174DOI Listing
July 2021

Is Fall Risk Systematically Evaluated in Memory Clinics? A National Survey of Practice in France.

J Alzheimers Dis 2021 ;81(4):1483-1491

Department of Geriatrics, CHU Lille, Lille, France.

Background: Falls are a major health problem in older persons but are still under-diagnosed and challenging to prevent. Current guidelines do not target high-risk populations, especially people living with dementia. In France, people with neurocognitive disorders are mainly referred to memory clinics (MCs).

Objective: We aimed to survey the routine practice of physicians working in MCs regarding fall risk assessment.

Methods: We conducted a cross-sectional survey in France from January to May 2019 among physicians working in MCs, through an anonymous online questionnaire: twenty-seven questions about the physician's background and their practice of fall risk assessment, especially use of clinical and paraclinical tools. We compared the results according to the age and the specialty of the physician.

Results: We obtained 171 responses with a majority of women (60%) and geriatricians (78%). All age classes and all French regions were represented. Most of respondents (98.8%) stated that they address gait and/or falls in outpatient clinic and 95.9%in day hospitals. When asked about how they assess fall risk, fall history (83%) and gait examination (68.4%) were the most widely used, while orthostatic hypotension (24%) and clinical standardized tests (25.7%) were less common. Among standardized tests, One-leg Balance, Timed Up and Go Test, and gait speed measurements were the most used. Geriatricians had more complete fall risk assessment than neurologists (e.g., 56%versus 13%for use of standardized tests, p < 0.0001).

Conclusion: Almost all physicians addressed the question of fall in MC, but practices are widely heterogeneous. Further investigations are needed to standardize fall risk assessment in MCs.
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http://dx.doi.org/10.3233/JAD-201585DOI Listing
September 2021

Differential early subcortical involvement in genetic FTD within the GENFI cohort.

Neuroimage Clin 2021 29;30:102646. Epub 2021 Mar 29.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich German Center for Neurodegenerative Diseases (DZNE), Munich Munich Cluster of Systems Neurology, Munich, Germany.

Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups.

Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more).

Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%).

Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
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http://dx.doi.org/10.1016/j.nicl.2021.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099608PMC
July 2021

Investigating the association between cancer and the risk of dementia: Results from the Memento cohort.

Alzheimers Dement 2021 09 3;17(9):1415-1421. Epub 2021 Mar 3.

CIC1401-EC, Inserm, Bordeaux, France.

Introduction: Studies on the association of cancer and risk of dementia are inconclusive due to result heterogeneity and concerns of survivor bias and unmeasured confounding.

Methods: This study uses data from the Memento cohort, a French multicenter cohort following persons with either mild or isolated cognitive complaints for a median of 5 years. Illness-death models (IDMs) were used to estimate transition-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancer in relation to dementia from time since study entry.

Results: The analytical sample (N = 2258) excluded 65 individuals without follow-up information. At the end of follow-up, 286 individuals were diagnosed with dementia, 166 with incident cancer, and 95 died. Incident cancer was associated with a reduced risk of dementia (HR = 0.58, 95% CI = 0.35-0.97), with a corresponding E-value of 2.84 (lower CI = 1.21).

Discussion: This study supports a protective relationship between incident cancer and dementia, encouraging further investigations to understand potential underlying mechanisms.
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http://dx.doi.org/10.1002/alz.12308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518910PMC
September 2021

Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort.

Blood Adv 2021 01;5(1):176-184

Cote d'Azur University, Hematology Department, Centre Hospitalier Universitaire de Nice, Nice, France.

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD <10-3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P < .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients <60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years.
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http://dx.doi.org/10.1182/bloodadvances.2020003159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805314PMC
January 2021

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network.

Alzheimers Res Ther 2021 01 8;13(1):19. Epub 2021 Jan 8.

Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, CNRMAJ, LiCEND, DistAlz, F-59000, Lille, France.

Background: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator.

Methods: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE).

Results: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients.

Conclusions: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
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http://dx.doi.org/10.1186/s13195-020-00753-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796569PMC
January 2021

Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia.

JAMA Netw Open 2021 01 4;4(1):e2030194. Epub 2021 Jan 4.

Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD.

Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD.

Design, Setting, And Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic.

Main Outcomes And Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation.

Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers.

Conclusions And Relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788468PMC
January 2021

The "authentic subjective experience" of memory in Alzheimer's disease.

Transl Neurosci 2020 3;11(1):201-207. Epub 2020 Jun 3.

Univ. Lille, CNRS, CHU Lille, UMR 9193 - SCALab - Sciences Cognitives et Sciences Affectives, F-59000 Lille, France.

Most research has mainly focused on the decline of the subjective experience in Alzheimer's disease (AD). However, few attempts have been made to evaluate whether subjective experience may be maintained in AD. In this narrative review, we attempt to provide a positive view, according to which patients with AD can enjoy, to some extent, subjective experience during memory retrieval. Memory and expression difficulties (e.g., aphasia) limit the ability of patients with AD to describe their memories, resulting in a little specificity of reported memories. However, according to the "authentic subjective experience" view, we propose in this study that the ability to mentally relive these memories could be preserved in the patients. By proposing the authentic subjective experience view, we attempt to provide an alternative view to the general consideration that the patients suffer a diminished subjective experience. This view can contribute to a larger clinical framework that gives a positive meaning to the subjective experience of patients with AD. Furthermore, several clinical and empirical implications can be drawn from the authentic subjective experience view, including the possibility to evaluate behavioral correlates of the subjective experience in AD.
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http://dx.doi.org/10.1515/tnsci-2020-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712381PMC
June 2020

Clinical relevance of brain atrophy subtypes categorization in memory clinics.

Alzheimers Dement 2021 04 15;17(4):641-652. Epub 2020 Dec 15.

Univ. Bordeaux, Inserm U1219, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Pôle de Sante Publique, CHU de Bordeaux, Bordeaux, France.

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.
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http://dx.doi.org/10.1002/alz.12231DOI Listing
April 2021

Plasma microRNA signature in presymptomatic and symptomatic subjects with -associated frontotemporal dementia and amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2021 May 25;92(5):485-493. Epub 2020 Nov 25.

Univ Rennes, Inria, CNRS, IRISA, F-35000 Rennes, France

Objective: To identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in patients and presymptomatic carriers.

Methods: The PREV-DEMALS study is a prospective study including 22 patients, 45 presymptomatic mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.

Results: Four miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of -associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.

Conclusions: We identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for -associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.

Trial Registration Number: NCT02590276.
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http://dx.doi.org/10.1136/jnnp-2020-324647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053348PMC
May 2021

JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML.

J Exp Med 2021 02;218(2)

INSERM U944, Centre National de la Recherche Scientifique (CNRS) UMR7212, IRSL, Hôpital Saint-Louis, Paris, France.

Interferon α (IFNα) is used to treat JAK2V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.
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http://dx.doi.org/10.1084/jem.20201268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579737PMC
February 2021

The Clinical Value of the Faux Pas Test for Diagnosing Behavioral-Variant Frontotemporal Dementia.

J Geriatr Psychiatry Neurol 2020 Oct 8:891988720964253. Epub 2020 Oct 8.

Equipe NACA, Laboratoire PSITEC, EA 4072, UFR de Psychologie, Univ-Lille, Pont de Bois, Villeneuve d'Ascq, France.

Objective: We studied the clinical value of the faux pas test to diagnose behavioral-variant frontotemporal dementia.

Methods: The faux pas test was administered to patients referred to a memory clinic in a context of behavioral disturbances. The diagnosis of behavioral-variant frontotemporal dementia (n = 14) or not (n = 25) was confirmed after a 3 years follow-up.

Results: The faux pas test displayed a high sensitivity for behavioral-variant frontotemporal dementia (.83) however its specificity was only moderate (.64).

Conclusions: Our results confirm that the FPT capture's specific cognitive impairments in patients with behavioral-variant frontotemporal dementia. However, some patients with psychiatric disease or other neurological diseases may also show impaired scores.
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http://dx.doi.org/10.1177/0891988720964253DOI Listing
October 2020

Twenty-year trends in patient referrals throughout the creation and development of a regional memory clinic network.

Alzheimers Dement (N Y) 2020 26;6(1):e12048. Epub 2020 Aug 26.

Inserm CHU Lille Lille Neurosciences & Cognition UMR-S1172 Degenerative and Vascular Cognitive Disorders Univ. Lille Lille France.

Introduction: Memory clinics (MCs) are the main model for dementia diagnosis and care. Following the development of a MC network in Northern France, our objectives were to assess its impact on patient characteristics over 20 years.

Methods: The characteristics of new consultants were studied from 1997 to 2016.

Results: New consultants increased from 774 per year in 1997 to 26258 per year in 2016, as the number of MCs increased from 12 to 29. Over time, patients were progressively older and less educated, and more were living alone. A greater proportion of patients were referred by specialists. Referral delay and home-to-MC distance kept decreasing. The oldest patients were referred at a progressively less-severe stage. The proportion of young patients kept increasing in the tertiary referral center.

Discussions: The development of a region-wide MC network led to increased referral of vulnerable patients and differentiation of the tertiary referral center over time.
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http://dx.doi.org/10.1002/trc2.12048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449245PMC
August 2020

Visit-to-Visit Blood Pressure Variability Is Associated With Cognitive Decline and Incident Dementia: The S.AGES Cohort.

Hypertension 2020 10 31;76(4):1280-1288. Epub 2020 Aug 31.

From the EA 4468, Université Paris Descartes, Sorbonne Paris Cité, France (L.R., M.P., O.H., J.-S.V.).

To investigate the impact of visit-to-visit systolic blood pressure variability (BPV), diastolic BPV, mean arterial pressure variability, and pulse pressure variability on cognitive decline and incident dementia in noninstitutionalized patients aged ≥65 years. A total of 3319 subjects from the S.AGES (Sujets AGÉS-Aged Subjects) cohort underwent clinical examinations every 6 months during 3 years. Variability was evaluated using standard deviation (SD), coefficient of variation, average real variability, successive variation, variation independent of mean, and residual SD. Cognition was assessed using the Mini-Mental State Examination and dementia with the Diagnostic Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used. Higher systolic BPV was associated with poorer cognition independently of baseline SBP: adjusted 1-SD increase of coefficient of variation: β (SE)=-0.12 (0.06), =0.04. Similar results were observed for diastolic BPV and mean arterial pressure variability: β (SE)=-0.20 (0.06), <0.001 for both. Higher pulse pressure variability was no longer associated with cognitive function after adjustment for age, except with residual SD (=0.02). Among the 3319 subjects, 93 (2.8%) developed dementia. Higher systolic BPV was associated with greater dementia risk (adjusted 1-SD increase of coefficient of variation: hazard ratios=1.23 [95% CI, 1.01-1.50], =0.04). Similar results were found for diastolic BPV and mean arterial pressure variability (<0.01). Pulse pressure variability was not associated with dementia risk. Beyond hypertension, higher BPV is a major clinical predictor of cognitive impairment and dementia. Further studies are needed to assess whether controlling BP instability could be a promising interventional target in preserving cognition among older adults.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14553DOI Listing
October 2020

Does amnesia specifically predict Alzheimer's pathology? A neuropathological study.

Neurobiol Aging 2020 11 20;95:123-130. Epub 2020 Jul 20.

Univ Lille, Lille Neuroscience & Cognition (Inserm UMRS1172) Degenerative and Vascular Cognitive Disorders, CHU Lille, Laboratory of Excellence Distalz (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Lille, France.

Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.011DOI Listing
November 2020
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