Imperial College London

DrChristopherButler

Faculty of MedicineDepartment of Brain Sciences

Clinical Senior Lecturer in Dementia Research
 
 
 
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christopher.butler

 
 
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Department of Brain SciencesBuilding E - Sir Michael UrenWhite City Campus

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Summary

 

Publications

Publication Type
Year
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147 results found

Pérez-Millan A, Borrego-Écija S, van Swieten JC, Jiskoot L, Moreno F, Laforce R, Graff C, Masellis M, Tartaglia MC, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, de Mendonça A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Santana I, Pasquier F, Levin J, Otto M, Sorbi S, Tiraboschi P, Seelaar H, Langheinrich T, Rohrer JD, Sala-Llonch R, Sánchez-Valle R, Genetic FTD Initiative, GENFIet al., 2022, Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study., J Neurol

BACKGROUND AND OBJECTIVES: The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. METHODS: We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. RESULTS: A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. DISCUSSION: We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Journal article

Samra K, MacDougall AM, Peakman G, Bouzigues A, Bocchetta M, Cash DM, Greaves CV, Convery RS, van Swieten JC, Jiskoot L, Seelaar H, Moreno F, Sanchez-Valle R, Laforce R, Graff C, Masellis M, Tartaglia C, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, de Mendonça A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Tiraboschi P, Santana I, Pasquier F, Levin J, Otto M, Sorbi S, Rohrer JD, Russell LL, Genetic FTD Initiative GENFIet al., 2022, Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales., J Neurol

OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Journal article

Whiteside DJ, Malpetti M, Jones PS, Ghosh BCP, Coyle-Gilchrist I, van Swieten JC, Seelaar H, Jiskoot L, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonca A, Tagliavini F, Butler CR, Santana I, Le Ber I, Gerhard A, Ducharme S, Levin J, Danek A, Otto M, Sorbi S, Pasquier F, Bouzigues A, Russell LL, Rohrer JD, Rowe JB, Rittman Tet al., 2022, Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia, ALZHEIMERS & DEMENTIA, ISSN: 1552-5260

Journal article

Premi E, Giunta M, Iraji A, Rachakonda S, Calhoun V, Gazzina S, Benussi A, Gasparotti R, Archetti S, Bocchetta M, Cash D, Todd E, Peakman G, Convery R, van Swieten JC, Jiskoot L, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe J, Masellis M, Tartaglia C, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Butler CR, Santana I, Gerhard A, Ber IL, Pasquier F, Ducharme S, Levin J, Danek A, Sorbi S, Otto M, Rohrer JD, Borroni B, Genetic Frontotemporal dementia Initiative GENFIet al., 2022, Corrigendum to "Dissemination in time and space in presymptomatic granulin mutation carriers: A spatial chronnectome study" [Neurobiology of Aging Volume 108, December 2021, Pages 155-167]., Neurobiol Aging, Vol: 119, Pages: 140-144

Journal article

Woollacott IOC, Swift IJ, Sogorb-Esteve A, Heller C, Knowles K, Bouzigues A, Russell LL, Peakman G, Greaves C, Convery R, Heslegrave A, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Tartaglia MC, Finger E, van Swieten JC, Seelaar H, Jiskoot L, Sorbi S, Butler CR, Graff C, Gerhard A, Laforce R, Sanchez-Valle R, de Mendonca A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Otto M, Pasquier F, Santana I, Zetterberg H, Rohrer JDet al., 2022, C5F glial markers are elevated in a subset of patients with genetic frontotemporal dementia, ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, Vol: 9, Pages: 1764-1777, ISSN: 2328-9503

Journal article

Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, Russell LL, Cobigo Y, Wolf A, Goh S-YM, Petrucelli L, Gendron TF, Heller C, Clark AL, Taylor JC, Wise A, Ong E, Forsberg L, Brushaber D, Rojas JC, VandeVrede L, Ljubenkov P, Kramer J, Casaletto KB, Appleby B, Bordelon Y, Botha H, Dickerson BC, Domoto-Reilly K, Fields JA, Foroud T, Gavrilova R, Geschwind D, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grossman M, Hall MGH, Hsiung G-Y, Huey ED, Irwin D, Jones DT, Kantarci K, Kaufer D, Knopman D, Kremers W, Lago AL, Lapid M, Litvan I, Lucente D, Mackenzie IR, Mendez MF, Mester C, Miller BL, Onyike CU, Rademakers R, Ramanan VK, Ramos EM, Rao M, Rascovsky K, Rankin KP, Roberson ED, Savica R, Tartaglia MC, Weintraub S, Wong B, Cash DM, Bouzigues A, Swift IJ, Peakman G, Bocchetta M, Todd EG, Convery RS, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Finger E, van Swieten JC, Seelaar H, Jiskoot LC, Sorbi S, Butler CR, Graff C, Gerhard A, Langheinrich T, Laforce R, Sanchez-Valle R, de Mendonca A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Danek A, Otto M, Pasquier F, Santana I, Kornak J, Boeve BF, Rosen HJ, Rohrer JD, Boxer ALet al., 2022, Temporal order of clinical and biomarker changes in familial frontotemporal dementia, NATURE MEDICINE, ISSN: 1078-8956

Journal article

Schoenecker S, Martinez-Murcia FJ, Rauchmann B-S, Franzmeier N, Prix C, Wlasich E, Loosli SV, Bochmann K, Gorriz Saez J-M, Laforce R, Ducharme S, Tartaglia MC, Finger E, de Mendonca A, Santana I, Sanchez-Valle R, Moreno F, Sorbi S, Tagliavini F, Borroni B, Otto M, Synofzik M, Galimberti D, Vandenberghe R, van Swieten J, Butler C, Gerhard A, Graff C, Danek A, Rohrer JD, Masellis M, Rowe J, Levin Jet al., 2022, Frequency and Longitudinal Course of Motor Signs in Genetic Frontotemporal Dementia, NEUROLOGY, Vol: 99, Pages: E1032-E1044, ISSN: 0028-3878

Journal article

van der Ende EL, Heller C, Sogorb-Esteve A, Swift IJ, McFall D, Peakman G, Bouzigues A, Poos JM, Jiskoot LC, Panman JL, Papma JM, Meeter LH, Dopper EGP, Bocchetta M, Todd E, Cash D, Graff C, Synofzik M, Moreno F, Finger E, Sanchez-Valle R, Vandenberghe R, Laforce R, Masellis M, Tartaglia MC, Rowe JB, Butler C, Ducharme S, Gerhard A, Danek A, Levin J, Pijnenburg YAL, Otto M, Borroni B, Tagliavini F, de Mendonça A, Santana I, Galimberti D, Sorbi S, Zetterberg H, Huang E, van Swieten JC, Rohrer JD, Seelaar H, Genetic Frontotemporal Dementia Initiative GENFIet al., 2022, Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study., J Neuroinflammation, Vol: 19

BACKGROUND: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. METHODS: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). RESULTS: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. CONCLUSIONS: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research

Journal article

Butler CR, Rhodes E, Blackmore J, Cheng X, Peach RL, Veldsman M, Sheerin F, Cleveland ROet al., 2022, Transcranial ultrasound stimulation to human middle temporal complex improves visual motion detection and modulates electrophysiological responses, Brain Stimulation, Vol: 15, Pages: 1236-1245, ISSN: 1935-861X

BackgroundTranscranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound.ObjectivesWe aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds.MethodsWe used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT + stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials.ResultsCompared with sham and control site stimulation, TUS to hMT + improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation.ConclusionsThe results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.

Journal article

Sogorb-Esteve A, Nilsson J, Swift IJ, Heller C, Bocchetta M, Russell LL, Peakman G, Convery RS, van Swieten JC, Seelaar H, Borroni B, Galimberti D, Sanchez-Valle R, Laforce R, Moreno F, Synofzik M, Graff C, Masellis M, Tartaglia MC, Rowe JB, Vandenberghe R, Finger E, Tagliavini F, Santana I, Butler CR, Ducharme S, Gerhard A, Danek A, Levin J, Otto M, Sorbi S, Le Ber I, Pasquier F, Gobom J, Brinkmalm A, Blennow K, Zetterberg H, Rohrer JDet al., 2022, Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia, ALZHEIMERS RESEARCH & THERAPY, Vol: 14

Journal article

Poos JM, MacDougall A, van den Berg E, Jiskoot LC, Papma JM, van der Ende EL, Seelaar H, Russell LL, Peakman G, Convery R, Pijnenburg YAL, Moreno F, Sanchez-Valle R, Borroni B, Laforce R, Doré M-C, Masellis M, Tartaglia MC, Graff C, Galimberti D, Rowe JB, Finger E, Synofzik M, Vandenberghe R, Mendonça A, Tiraboschi P, Santana I, Ducharme S, Butler C, Gerhard A, Levin J, Danek A, Otto M, Le Ber I, Pasquier F, van Swieten J, Rohrer JD, Genetic FTD Initiative GENFIet al., 2022, Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort., Neurology, Vol: 99, Pages: e281-e295

BACKGROUND AND OBJECTIVES: Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic). METHODS: C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage. RESULTS: A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1. DISCUSSION: We confirmed cognit

Journal article

Benussi A, Alberici A, Samra K, Russell LL, Greaves CV, Bocchetta M, Ducharme S, Finger E, Fumagalli G, Galimberti D, Jiskoot LC, Le Ber I, Masellis M, Nacmias B, Rowe JB, Sanchez-Valle R, Seelaar H, Synofzik M, GENFI Consortium, Rohrer JD, Borroni Bet al., 2022, Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia., Alzheimers Dement, Vol: 18, Pages: 1408-1423

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages.

Journal article

Gazzina S, Grassi M, Premi E, Alberici A, Benussi A, Archetti S, Gasparotti R, Bocchetta M, Cash DM, Todd EG, Peakman G, Convery RS, van Swieten JC, Jiskoot LC, Seelaar H, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Butler CR, Santana I, Gerhard A, Ber IL, Pasquier F, Ducharme S, Levin J, Danek A, Sorbi S, Otto M, Rohrer JD, Borroni B, Genetic Frontotemporal dementia Initiative GENFIet al., 2022, Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia., Neurobiol Aging, Vol: 114, Pages: 94-104

Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.

Journal article

Garcia-Martinez M, Sanchez-Juan P, Butler CR, 2022, A Review of Accelerated Long-Term Forgetting in Alzheimer's Disease: Current Situation and Prospects, NEUROPSYCHOLOGY, ISSN: 0894-4105

Journal article

Miller TD, Butler CR, 2022, Acute-onset amnesia: transient global amnesia and other causes, PRACTICAL NEUROLOGY, ISSN: 1474-7758

Journal article

Foster PH, Russell LL, Peakman G, Convery RS, Bouzigues A, Greaves C, Bocchetta M, Cash DM, van Swieten JC, Jiskoot LC, Moreno F, Sanchez-Valle R, Laforce R, Graff C, Masellis M, Tartaglia C, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, de Mendonca A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Tagliavini F, Santana I, Pasquier F, Levin J, Danek A, Otto M, Sorbi S, Rohrer JDet al., 2022, Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort, CORTEX, Vol: 150, Pages: 12-28, ISSN: 0010-9452

Journal article

McCarthy J, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Butler C, Gerhard A, Danek A, Levin J, Otto M, Frisoni G, Ghidoni R, Sorbi S, Jiskoot LC, Seelaar H, van Swieten JC, Rohrer JD, Iturria-Medina Y, Ducharme S, GENetic Frontotemporal Dementia Initiative GENFIet al., 2022, Data-driven staging of genetic frontotemporal dementia using multi-modal MRI., Hum Brain Mapp, Vol: 43, Pages: 1821-1835

Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

Journal article

van der Ende EL, Bron EE, Poos JM, Jiskoot LC, Panman JL, Papma JM, Meeter LH, Dopper EGP, Wilke C, Synofzik M, Heller C, Swift IJ, Sogorb-Esteve A, Bouzigues A, Borroni B, Sanchez-Valle R, Moreno F, Graff C, Laforce R, Galimberti D, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, Rowe JB, de Mendonca A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Pijnenburg YAL, Sorbi S, Zetterberg H, Niessen WJ, Rohrer JD, Klein S, van Swieten JC, Venkatraghavan V, Seelaar Het al., 2022, A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia, BRAIN, Vol: 145, Pages: 1805-1817, ISSN: 0006-8950

Journal article

Wilson KM, Katona E, Glaria I, Carcole M, Swift IJ, Sogorb-Esteve A, Heller C, Bouzigues A, Heslegrave AJ, Keshavan A, Knowles K, Patil S, Mohapatra S, Liu Y, Goyal J, Sanchez-Valle R, Laforce R, Synofzik M, Rowe JB, Finger E, Vandenberghe R, Butler CR, Gerhard A, Van Swieten JC, Seelaar H, Borroni B, Galimberti D, de Mendonca A, Masellis M, Tartaglia MC, Otto M, Graff C, Ducharme S, Schott JM, Malaspina A, Zetterberg H, Boyanapalli R, Rohrer JD, Isaacs AMet al., 2022, Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, ISSN: 0022-3050

Journal article

Bouzigues A, Russell LL, Peakman G, Bocchetta M, Greaves C, Convery RS, Todd E, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Tartaglia MC, Finger E, van Swieten JC, Seelaar H, Jiskoot L, Sorbi S, Butler CR, Graff C, Gerhard A, Langheinrich T, Laforce R, Sanchez-Valle R, de Mendonca A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Danek A, Otto M, Pasquier F, Santana I, Rohrer JDet al., 2022, Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations, JOURNAL OF NEUROLOGY, Vol: 269, Pages: 4322-4332, ISSN: 0340-5354

Journal article

Nelson A, Russell LL, Peakman G, Convery RS, Bouzigues A, Greaves C, Bocchetta M, Cash DM, Swieten JC, Jiskoot L, Moreno F, Sanchez-Valle R, Laforce R, Graff C, Masellis M, Tartaglia MC, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, Mendonca A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Santana I, Pasquier F, Levin J, Otto M, Sorbi S, Rohrer JDet al., 2022, The CBI-R detects early behavioural impairment in genetic frontotemporal dementia, ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, Vol: 9, Pages: 644-658, ISSN: 2328-9503

Journal article

Savage SA, Baker J, Milton F, Butler C, Zeman Aet al., 2022, Clinical outcomes in transient epileptic amnesia: A 10-year follow-up cohort study of 47 cases, EPILEPSIA, Vol: 63, Pages: 1115-1129, ISSN: 0013-9580

Journal article

Oijerstedt L, Andersson C, Jelic V, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonca A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Rohrer JD, Graff Cet al., 2022, Practice effects in genetic frontotemporal dementia and at-risk individuals: a GENFI study, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 93, Pages: 336-+, ISSN: 0022-3050

Journal article

Shafiei G, Bazinet V, Dadar M, Manera AL, Collins DL, Dagher A, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Butler C, Gerhard A, Danek A, Levin J, Otto M, Sorbi S, Jiskoot LC, Seelaar H, van Swieten JC, Rohrer JD, Misic B, Ducharme S, Frontotemporal Lobar Degeneration Neuroimaging Initiative FTLDNI, GENetic Frontotemporal dementia Initiative GENFIet al., 2022, Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia., Brain

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, 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, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

Journal article

Overman MJ, Drummond N, Butler CR, Ahmed Set al., 2022, Tracking the clinical progression of posterior cortical atrophy: implications for post-diagnostic and therapeutic interventions, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, ISSN: 0022-3050

Journal article

Poos JM, Moore KM, Nicholas J, Russell LL, Peakman G, Convery RS, Jiskoot LC, van der Ende E, van den Berg E, Papma JM, Seelaar H, Pijnenburg YAL, Moreno F, Sanchez-Valle R, Borroni B, Laforce R, Masellis M, Tartaglia C, Graff C, Galimberti D, Rowe JB, Finger E, Synofzik M, Vandenberghe R, de Mendonça A, Tiraboschi P, Santana I, Ducharme S, Butler C, Gerhard A, Levin J, Danek A, Otto M, Le Ber I, Pasquier F, van Swieten JC, Rohrer JD, Genetic FTD Initiative GENFIet al., 2022, Cognitive composites for genetic frontotemporal dementia: GENFI-Cog., Alzheimers Research & Therapy, Vol: 14, Pages: 1-12, ISSN: 1758-9193

BACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive comp

Journal article

Peakman G, Russell LL, Convery RS, Nicholas JM, Van Swieten JC, Jiskoot LC, Moreno F, Sanchez-Valle R, Laforce R, Graff C, Masellis M, Tartaglia MC, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, de Mendonça A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Tagliavini F, Santana I, Pasquier F, Levin J, Danek A, Otto M, Sorbi S, Rohrer JD, Genetic FTD Initiative GENFIet al., 2022, Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort., Journal of Neurology, Neurosurgery and Psychiatry, Vol: 93, Pages: 158-168, ISSN: 0022-3050

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

Journal article

Landeiro F, Morton J, Gustavsson A, Potashman M, Lecomte P, Belger M, Thompson R, Roncancio-Diaz E, Jhuti G, Butler C, Jonsson L, Handels R, Gray AMet al., 2022, Health economic modeling for Alzheimer's disease: Expert perspectives, ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS, Vol: 8

Journal article

Bruffaerts R, Gors D, Bárcenas Gallardo A, Vandenbulcke M, Van Damme P, Suetens P, Van Swieten JC, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, De Mendonça A, Tagliavini F, Butler CR, Santana I, Gerhard A, Ducharme S, Levin J, Danek A, Otto M, Rohrer JD, Dupont P, Claes P, Vandenberghe R, Afonso S, Almeida MR, Anderl-Straub S, Andersson C, Antonell A, Archetti S, Arighi A, Balasa M, Barandiaran M, Bargalló N, Bartha R, Bender B, Benussi A, Black S, Bocchetta M, Borrego-Ecija S, Bras J, Canada M, Cantoni V, Caroppo P, Cash D, Castelo-Branco M, Convery R, Cope T, Fede GD, Díez A, Duro D, Fenoglio C, Ferreira CB, Fox N, Freedman M, Fumagalli G, Gabilondo A, Gasparotti R, Gauthier S, Gazzina S, Giaccone G, Gorostidi A, Greaves C, Guerreiro R, Heller C, Hoegen T, Indakoetxea B, Jelic V, Jiskoot L, Karnath HO, Keren R, Langheinrich T, Leitão MJ, Lladó A, Loosli S, Maruta C, Mead S, Meeter L, Miltenberger G, Van Minkelen R, Mitchell S, Moore K, Nicholas J, Öijerstedt L, Olives J, Ourselin S, Padovani A, Panman J, Papma JM, Peakman G, Pijnenburg Y, Premi E, Prioni Set al., 2022, Hierarchical spectral clustering reveals brain size and shape changes in asymptomatic carriers of C9orf72, Brain Communications, Vol: 4

Traditional methods for detecting asymptomatic brain changes in neurodegenerative diseases such as Alzheimer's disease or frontotemporal degeneration typically evaluate changes in volume at a predefined level of granularity, e.g. voxel-wise or in a priori defined cortical volumes of interest. Here, we apply a method based on hierarchical spectral clustering, a graph-based partitioning technique. Our method uses multiple levels of segmentation for detecting changes in a data-driven, unbiased, comprehensive manner within a standard statistical framework. Furthermore, spectral clustering allows for detection of changes in shape along with changes in size. We performed tensor-based morphometry to detect changes in the Genetic Frontotemporal dementia Initiative asymptomatic and symptomatic frontotemporal degeneration mutation carriers using hierarchical spectral clustering and compared the outcome to that obtained with a more conventional voxel-wise tensor- and voxel-based morphometric analysis. In the symptomatic groups, the hierarchical spectral clustering-based method yielded results that were largely in line with those obtained with the voxel-wise approach. In asymptomatic C9orf72 expansion carriers, spectral clustering detected changes in size in medial temporal cortex that voxel-wise methods could only detect in the symptomatic phase. Furthermore, in the asymptomatic and the symptomatic phases, the spectral clustering approach detected changes in shape in the premotor cortex in C9orf72. In summary, the present study shows the merit of hierarchical spectral clustering for data-driven segmentation and detection of structural changes in the symptomatic and asymptomatic stages of monogenic frontotemporal degeneration.

Journal article

Premi E, Costa T, Gazzina S, Benussi A, Cauda F, Gasparotti R, Archetti S, Alberici A, van Swieten JC, Sanchez-Valle R, Moreno F, Santana I, Laforce R, Ducharme S, Graff C, Galimberti D, Masellis M, Tartaglia C, Rowe JB, Finger E, Tagliavini F, de Mendonça A, Vandenberghe R, Gerhard A, Butler CR, Danek A, Synofzik M, Levin J, Otto M, Ghidoni R, Frisoni G, Sorbi S, Peakman G, Todd E, Bocchetta M, Rohrer JD, Borroni B, GENFI Consortium Memberset al., 2022, An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers., J Alzheimers Dis, Vol: 86, Pages: 205-218

BACKGROUND: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). OBJECTIVES: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. METHODS: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. RESULTS: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). CONCLUSION: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself.

Journal article

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