Showing papers by "Fabrizio Tagliavini published in 2021"
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Itziar de Rojas1, Itziar de Rojas2, Sonia Moreno-Grau1, Sonia Moreno-Grau2 +356 more•Institutions (96)
TL;DR: In this article, a large genetic association study was performed by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190).
Abstract: 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.
97 citations
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TL;DR: In this paper, the authors investigated the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral angiopathy-related inflammation (CAA-ri).
Abstract: Background and Objectives
The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy–related inflammation (CAA-ri).
38 citations
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University of Brescia1, Vision-Sciences, Inc.2, Erasmus University Rotterdam3, University of Barcelona4, Laval University5, Karolinska Institutet6, Karolinska University Hospital7, University of Tübingen8, German Center for Neurodegenerative Diseases9, University of Milan10, Sunnybrook Health Sciences Centre11, University of Toronto12, University of Cambridge13, University of Western Ontario14, Katholieke Universiteit Leuven15, Allen Institute for Brain Science16, University of Lisbon17, University of Coimbra18, Montreal Neurological Institute and Hospital19, McGill University Health Centre20, Imperial College London21, University of Oxford22, University of Duisburg-Essen23, University of Manchester24, Ludwig Maximilian University of Munich25, University of Ulm26, University of Florence27, UCL Institute of Neurology28, Lille University of Science and Technology29
TL;DR: In this paper, the authors investigated behavioral symptom frequency and severity and their evolution and progression in different forms of genetic frontotemporal dementia (FTD) using a longitudinal cohort study.
Abstract: 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 inC9orf72, 78 inGRN, and 39 inMAPT. 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 aC9orf72expansion (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 aGRNvariant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had aMAPTvariant (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 withMAPTvariants 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 withC9orf72carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) andGRNcarriers (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 inGRNcarriers (23.8%-100% of patients) andMAPTcarriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common inC9orf72carriers (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 inC9orf72carriers, and depression and anxiety, which surged only in the late stages inGRNcarriers. 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.
33 citations
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Cognition and Brain Sciences Unit1, University of Cambridge2, Erasmus University Rotterdam3, University of Brescia4, University of Barcelona5, Laval University6, Karolinska University Hospital7, Karolinska Institutet8, German Center for Neurodegenerative Diseases9, University of Tübingen10, University of Milan11, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico12, Sunnybrook Research Institute13, Toronto Western Hospital14, University of Western Ontario15, Katholieke Universiteit Leuven16, University of Lisbon17, University of Coimbra18, McGill University Health Centre19, Montreal Neurological Institute and Hospital20, University of Oxford21, University of Duisburg-Essen22, University of Manchester23, University of Geneva24, University of Florence25, UCL Institute of Neurology26
TL;DR: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy, in familial frontotemporal dementia (FTD).
Abstract: Introduction The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.
32 citations
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University of Cambridge1, Erasmus University Rotterdam2, University of Brescia3, University of Barcelona4, Laval University5, Karolinska University Hospital6, Karolinska Institutet7, University of Tübingen8, University of Milan9, Sunnybrook Health Sciences Centre10, University of Toronto11, University of Western Ontario12, Katholieke Universiteit Leuven13, Allen Institute for Brain Science14, University of Lisbon15, University of Coimbra16, Montreal Neurological Institute and Hospital17, McGill University Health Centre18, University of Oxford19, University of Duisburg-Essen20, University of Manchester21, Ludwig Maximilian University of Munich22, German Center for Neurodegenerative Diseases23, University of Ulm24, University of Florence25, UCL Institute of Neurology26, Cognition and Brain Sciences Unit27, Radboud University Nijmegen28
TL;DR: It is tested whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy, and how this affects prognosis and survival of patients with frontotemporal dementia.
Abstract: Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.
28 citations
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UCL Institute of Neurology1, Massachusetts Institute of Technology2, Erasmus University Rotterdam3, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico4, University of Western Ontario5, University of Tübingen6, University of Paris7, University of Florence8, Sunnybrook Health Sciences Centre9, Cognition and Brain Sciences Unit10, Van Andel Institute11, University of Coimbra12, University of Brescia13, McGill University14, German Center for Neurodegenerative Diseases15, university of lille16
TL;DR: In this article, the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups were investigated using parcellation methods on volumetric 3-T-T1-weighted MRI scans.
27 citations
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16 citations
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TL;DR: In this paper, the authors presented a telemedicine system for patients with chronic neurological disorders, including Televisits and Teleneurorehabilitation in Lombardy, Italy.
Abstract: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March–September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
13 citations
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UCL Institute of Neurology1, University of London2, Erasmus University Rotterdam3, University College London4, University of Barcelona5, University of Brescia6, Laval University7, Sunnybrook Health Sciences Centre8, University of Toronto9, Karolinska Institutet10, Karolinska University Hospital11, University of Milan12, University of Cambridge13, University of Western Ontario14, University of Tübingen15, Allen Institute for Brain Science16, Katholieke Universiteit Leuven17, University of Lisbon18, University of Coimbra19, Montreal Neurological Institute and Hospital20, McGill University Health Centre21, University of Oxford22, University of Manchester23, University of Duisburg-Essen24, German Center for Neurodegenerative Diseases25, Ludwig Maximilian University of Munich26, University of Ulm27, University of Florence28, University of Paris29, French Institute of Health and Medical Research30, university of lille31
TL;DR: The Revised Self-Monitoring Scale (RSMS) was used as a measure of socioemotional sensitivity and correlated with disease severity in all groups and implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum.
Abstract: 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. 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. 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. The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
13 citations
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University of Tübingen1, Erasmus University Rotterdam2, University of Brescia3, University of Barcelona4, Laval University5, Karolinska Institutet6, Karolinska University Hospital7, University of Milan8, University of Cambridge9, Sunnybrook Health Sciences Centre10, University of Toronto11, University of Western Ontario12, Katholieke Universiteit Leuven13, Allen Institute for Brain Science14, University of Lisbon15, University of Coimbra16, Montreal Neurological Institute and Hospital17, McGill University Health Centre18, University of Oxford19, Imperial College London20, University of Duisburg-Essen21, University of Manchester22, Ludwig Maximilian University of Munich23, German Center for Neurodegenerative Diseases24, Martin Luther University of Halle-Wittenberg25, University of Ulm26, University of Florence27, UCL Institute of Neurology28, University Hospital of Basel29, Brigham and Women's Hospital30
TL;DR: In this article, a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage was provided.
Abstract: Objective While the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicentre cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. Methods We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the GENFI cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN or MAPT, and 174 mutation-negative within-family controls. Results In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, while pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Interpretation Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. This article is protected by copyright. All rights reserved.
13 citations
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Erasmus University Rotterdam1, University College London2, UCL Institute of Neurology3, VU University Medical Center4, University of Brescia5, University of Barcelona6, Laval University7, Karolinska Institutet8, Karolinska University Hospital9, University of Tübingen10, University of Milan11, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico12, Cambridge University Hospitals NHS Foundation Trust13, University of Toronto14, University of Western Ontario15, Katholieke Universiteit Leuven16, Allen Institute for Brain Science17, University of Lisbon18, University of Oxford19, Imperial College London20, University of Coimbra21, University of Paris22, University of Duisburg-Essen23, University of Manchester24, Montreal Neurological Institute and Hospital25, Douglas Mental Health University Institute26, German Center for Neurodegenerative Diseases27, Ludwig Maximilian University of Munich28, University of Ulm29, University of Florence30, French Institute of Health and Medical Research31, university of lille32
TL;DR: In this paper, the Free and Cued Selective Reminding Test (FCSRT) was used to assess episodic memory in genetic frontotemporal dementia (FTD).
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TL;DR: In this paper, a multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia.
Abstract: BACKGROUND A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. METHODS A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. RESULTS When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). CONCLUSION In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
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Montreal Neurological Institute and Hospital1, Erasmus University Rotterdam2, University of Brescia3, University of Barcelona4, Laval University5, Karolinska University Hospital6, University of Tübingen7, University of Cambridge8, Sunnybrook Health Sciences Centre9, Sunnybrook Research Institute10, Toronto Western Hospital11, University of Western Ontario12, Katholieke Universiteit Leuven13, University of Lisbon14, University of Oxford15, University of Manchester16, German Center for Neurodegenerative Diseases17, Ludwig Maximilian University of Munich18, University of Florence19, UCL Institute of Neurology20
TL;DR: In this article, a random forest classifier was used to individually predict frontotemporal dementia from deformation-based morphometry differences in isolation and together with semantic fluency.
Abstract: Introduction Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. Methods A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. Results Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. Conclusion Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.
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University of Barcelona1, Erasmus University Rotterdam2, University of Brescia3, Sunnybrook Research Institute4, Toronto Western Hospital5, Karolinska University Hospital6, University of Milan7, Laval University8, Cognition and Brain Sciences Unit9, University of Western Ontario10, Katholieke Universiteit Leuven11, University of Lisbon12, University of Coimbra13, German Center for Neurodegenerative Diseases14, University of Tübingen15, McGill University Health Centre16, McGill University17, Ludwig Maximilian University of Munich18, University of Manchester19, University of Ulm20, University of Oxford21, University of Geneva22, University of Florence23, UCL Institute of Neurology24, University of London25, University of Amsterdam26, Sunnybrook Health Sciences Centre27, University of Toronto28, Toronto Rehabilitation Institute29, University Health Network30, Karolinska Institutet31, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico32, University of Cambridge33, Mayo Clinic34
TL;DR: In this paper, the authors analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject and performed a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables such as gender, age, the estimated years to onset and education.
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TL;DR: In this article, the reproducibility of automated determination of the CSF core AD biomarkers was exploited to compare two large cohorts of patients diagnosed with different neurological disorders and enrolled in two centers with established expertise in Alzheimer's disease biomarkers.
Abstract: Amyloid-beta (Aβ) 42/40 ratio, tau phosphorylated at threonine-181 (p-tau), and total-tau (t-tau) are considered core biomarkers for the diagnosis of Alzheimer's disease (AD). The use of fully automated biomarker assays has been shown to reduce the intra- and inter-laboratory variability, which is a critical factor when defining cut-off values. The calculation of cut-off values is often influenced by the composition of AD and control groups. Indeed, the clinically defined AD group may include patients affected by other forms of dementia, while the control group is often very heterogeneous due to the inclusion of subjects diagnosed with other neurological diseases (OND). In this context, unsupervised machine learning approaches may overcome these issues providing unbiased cut-off values and data-driven patient stratification according to the sole distribution of biomarkers. In this work, we took advantage of the reproducibility of automated determination of the CSF core AD biomarkers to compare two large cohorts of patients diagnosed with different neurological disorders and enrolled in two centers with established expertise in AD biomarkers. We applied an unsupervised Gaussian mixture model clustering algorithm and found that our large series of patients could be classified in six clusters according to their CSF biomarker profile, some presenting a typical AD-like profile and some a non-AD profile. By considering the frequencies of clinically defined OND and AD subjects in clusters, we subsequently computed cluster-based cut-off values for Aβ42/Aβ40, p-tau, and t-tau. This approach promises to be useful for large-scale biomarker studies aimed at providing efficient biochemical phenotyping of neurological diseases.
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TL;DR: In this paper, the authors carried out a neuropathological and biochemical analysis on a series of Alzheimer's disease brain samples, gathering evidence about the heterogeneous involvement of microglia in AD.
Abstract: Alzheimer’s disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct pro- and/or anti-inflammatory cytokines, potentially affecting the expression of the disease. We carried out a neuropathological and biochemical analysis on a series of AD brain samples, gathering evidence about the heterogeneous involvement of microglia in AD. The neuropathological studies showed differences concerning morphology, density and distribution of microglial cells among AD brains. Biochemical investigations showed increased brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7 and CXCL13 in AD in comparison with control subjects. The molecular profiling achieved by measuring the brain levels of 25 inflammatory factors known to be involved in neuroinflammation allowed a stratification of the AD patients in three distinct “neuroinflammatory clusters”. These findings strengthen the relevance of neuroinflammation in AD pathogenesis suggesting, in particular, that the differential involvement of neuroinflammatory molecules released by microglial cells during the development of the disease may contribute to modulate the characteristics and the severity of the neuropathological changes, driving—at least in part—the AD phenotypic diversity.
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University College London1, University of London2, Erasmus University Rotterdam3, University of Barcelona4, Laval University5, Karolinska University Hospital6, Karolinska Institutet7, Sunnybrook Health Sciences Centre8, University of Toronto9, University of Cambridge10, University of Brescia11, University of Western Ontario12, University of Tübingen13, University of Milan14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, Katholieke Universiteit Leuven16, Allen Institute for Brain Science17, University of Lisbon18, Imperial College London19, University of Oxford20, University of Manchester21, University of Duisburg-Essen22, Montreal Neurological Institute and Hospital23, McGill University Health Centre24, University of Paris25, University of Coimbra26, university of lille27, French Institute of Health and Medical Research28, German Center for Neurodegenerative Diseases29, Ludwig Maximilian University of Munich30, University of Ulm31, University of Florence32
TL;DR: In this paper, the authors compared the clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) and the FTD Rating Scale (FRS) in the genetic forms of frontotemporal dementia (FTD).
Abstract: 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 (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) 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: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 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: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 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 (rs=-0.77, p<0.001) and within each genetic group (rs=-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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TL;DR: This study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and3D-FLAIR, and adapting a longitudinal Pipeline to include high-resolution 2D- T2 may lead to further improvements.
Abstract: Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test–retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal (“long_T1s” and “long_T1s_FLAIR”) and one cross-sectional (“long_T1s_FLAIR_crossT2”). Volume reproducibility was quantified in magnitude (reproducibility error—RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4–3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1–7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (p = 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm3 had better RE (1–2%) and DICE (0.7–0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.
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University of Brescia1, Georgia Institute of Technology2, Georgia State University3, UCL Institute of Neurology4, Erasmus University Rotterdam5, University of Barcelona6, Laval University7, Karolinska Institutet8, University of Tübingen9, University of Milan10, University of Cambridge11, Sunnybrook Health Sciences Centre12, University of Toronto13, University of Western Ontario14, Allen Institute for Brain Science15, Katholieke Universiteit Leuven16, University of Lisbon17, University of Oxford18, University of Coimbra19, University of Manchester20, university of lille21, Ludwig Maximilian University of Munich22, University of Ulm23, University of Florence24
TL;DR: In this article, the authors investigated the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 non-carriers from the Genetic Frontotemporal dementia research Initiative cohort.
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Montreal Neurological Institute and Hospital1, Laval University2, University of Brescia3, University of Barcelona4, Karolinska University Hospital5, University of Tübingen6, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico7, University of Milan8, Cognition and Brain Sciences Unit9, Sunnybrook Health Sciences Centre10, Toronto Western Hospital11, University of Western Ontario12, Katholieke Universiteit Leuven13, Allen Institute for Brain Science14, University of Lisbon15, University of Coimbra16, Imperial College London17, University of Oxford18, University of Manchester19, University of Duisburg-Essen20, Ludwig Maximilian University of Munich21, German Center for Neurodegenerative Diseases22, University of Florence23, Erasmus University Rotterdam24, UCL Institute of Neurology25, Douglas Mental Health University Institute26
TL;DR: In this paper, the authors investigated whether neurodegeneration patterns in sporadic and genetic frontotemporal dementia are conditioned by connectome architecture and found that the anterior insula was the predominant group epicenter of brain atrophy.
Abstract: Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). We first identify distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally- connected neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, effectively modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability.
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Karolinska Institutet1, Erasmus University Rotterdam2, University of Brescia3, Laval University4, University of Tübingen5, University of Milan6, University of Cambridge7, Sunnybrook Health Sciences Centre8, University of Toronto9, University of Western Ontario10, University of Lisbon11, Ludwig Maximilian University of Munich12, University of Ulm13, UCL Institute of Neurology14
TL;DR: In this article, the authors examined practice effects in the GENetic Frontotemporal dementia Initiative (GENFI) cohort and found that there is a difference in practice effects between presymptomatic mutation carriers and mutation non-carriers.
Abstract: Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative diseases with an onset usually before the age of 65 years even if it can appear also in older ages.1
On cognitive tests, patients with FTD show deficits in executive functions, social cognition and language, whereas the initial performances in memory and visuoconstruction tasks usually are preserved.1 The general approach to detect cognitive decline in dementia is to repeat cognitive testing and observe changes over time. However, exposure to similar tasks could improve performance as the individual gets familiar with both the tasks themselves and the test setting (ie, practice effect or learning effect).2 3
Different attempts to adjust for practice effects in repeated testing have been proposed.4 However, recent research suggests that the phenomenon of practice effects can provide useful information. Patients with neurological and psychiatric conditions show lower practice effects than healthy controls, and individuals with mild cognitive impairment (MCI) that do not show practice effects are more likely to develop Alzheimer disease (AD) within a year than individuals with MCI that have preserved practice effects.3 In addition to the findings of lower practice effects in patients with dementia, Hassenstab et al 5 found that preclinical individuals who later progressed to AD had substantially reduced practice effects in episodic memory compared with cognitively stable individuals. Thus, absence of practice effects might serve as an early marker for cognitive decline.
To our knowledge, practice effects have never been investigated in FTD before. The aim of this study was to examine practice effects in the GENetic Frontotemporal dementia Initiative (GENFI) cohort. More specifically, we investigated whether there is a difference in practice effects between presymptomatic mutation carriers (PMC) and mutation non-carriers (NC).
### Participants
All participants (317 NC, 327 PMC and 159 affected mutation carriers (AMC)) were recruited …