Publications
172 results found
Butler CR, Rhodes E, Blackmore J, et 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.
Sogorb-Esteve A, Nilsson J, Swift IJ, et al., 2022, Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia, ALZHEIMERS RESEARCH & THERAPY, Vol: 14
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- Citations: 3
Bouzigues A, Russell LL, Peakman G, et al., 2022, Anomia is present pre-symptomatically in frontotemporal dementia due to <i>MAPT</i> mutations, JOURNAL OF NEUROLOGY, Vol: 269, Pages: 4322-4332, ISSN: 0340-5354
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- Citations: 2
Poos JM, MacDougall A, van den Berg E, et 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
Benussi A, Alberici A, Samra K, et al., 2022, Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia, ALZHEIMERS & DEMENTIA, Vol: 18, Pages: 1408-1423, ISSN: 1552-5260
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- Citations: 15
van der Ende EL, Bron EE, Poos JM, et al., 2022, A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia, BRAIN, Vol: 145, Pages: 1805-1817, ISSN: 0006-8950
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- Citations: 18
Gazzina S, Grassi M, Premi E, et al., 2022, Structural brain splitting is a hallmark of <i>Granulin</i>-related frontotemporal dementia, NEUROBIOLOGY OF AGING, Vol: 114, Pages: 94-104, ISSN: 0197-4580
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- Citations: 1
Miller TD, Butler CR, 2022, Acute-onset amnesia: transient global amnesia and other causes, PRACTICAL NEUROLOGY, Vol: 22, Pages: 201-208, ISSN: 1474-7758
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- Citations: 1
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
Foster PH, Russell LL, Peakman G, et al., 2022, Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort, CORTEX, Vol: 150, Pages: 12-28, ISSN: 0010-9452
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- Citations: 1
Nelson A, Russell LL, Peakman G, et 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
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- Citations: 1
Savage SA, Baker J, Milton F, et 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
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- Citations: 1
McCarthy J, Borroni B, Sanchez-Valle R, et 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.
Argyropoulos GPD, Dell'Acqua C, Butler E, et al., 2022, Functional Specialization of the Medial Temporal Lobes in Human Recognition Memory: Dissociating Effects of Hippocampal versus Parahippocampal Damage, CEREBRAL CORTEX, Vol: 32, Pages: 1637-1652, ISSN: 1047-3211
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- Citations: 4
Wilson KM, Katona E, Glaria I, et al., 2022, Development of a sensitive trial-ready poly(GP) CSF biomarker assay for <i>C9orf72</i>-associated frontotemporal dementia and amyotrophic lateral sclerosis, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, ISSN: 0022-3050
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- Citations: 8
Oijerstedt L, Andersson C, Jelic V, et 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
Overman MJ, Drummond N, Butler CR, et 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
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- Citations: 2
Poos JM, Moore KM, Nicholas J, et 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
Peakman G, Russell LL, Convery RS, et 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
Moore K, Convery R, Bocchetta M, et al., 2022, A modified Camel and Cactus Test detects presymptomatic semantic impairment in genetic frontotemporal dementia within the GENFI cohort, APPLIED NEUROPSYCHOLOGY-ADULT, Vol: 29, Pages: 112-119, ISSN: 2327-9095
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- Citations: 15
Bruffaerts R, Gors D, Bárcenas Gallardo A, et 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.
Wilke C, Reich S, van Swieten JC, et al., 2022, Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study, ANNALS OF NEUROLOGY, Vol: 91, Pages: 33-47, ISSN: 0364-5134
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- Citations: 13
Landeiro F, Morton J, Gustavsson A, et al., 2022, Health economic modeling for Alzheimer's disease: Expert perspectives, ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS, Vol: 8
Premi E, Costa T, Gazzina S, et al., 2022, An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic <i>Granulin</i> Mutation Carriers, JOURNAL OF ALZHEIMERS DISEASE, Vol: 86, Pages: 205-218, ISSN: 1387-2877
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- Citations: 3
Wilson KM, Katona E, Glaria I, et al., 2021, Development of a sensitive trial-ready poly(GP) CSF biomarker assay for <i>C9orf72</i>-associated frontotemporal dementia and amyotrophic lateral sclerosis
<jats:title>Abstract</jats:title><jats:p>A GGGGCC repeat expansion in the <jats:italic>C9orf72</jats:italic> gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. We utilised the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the repeat expansion in CSF of people with <jats:italic>C9orf72</jats:italic>-associated FTD/ALS. We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intra- and inter-plate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) DPRs in the CSF of samples collected through the Genetic FTD Initiative. We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the <jats:italic>C9orf72</jats:italic> CSF sample with the lowest poly(GP) signal had 8-fold higher signal than controls and on average values from <jats:italic>C9orf72</jats:italic> samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing <jats:italic>C9orf72</jats:italic> repeat-containing transcripts.</jats:p>
de Rojas I, Hernández I, Montrreal L, et al., 2021, Genomic characterization of host factors related to SARS-CoV-2 infection in people with dementia and control populations: The GR@ACE/DEGESCO study., Journal of Personalized Medicine, Vol: 11, Pages: 1-11, ISSN: 2075-4426
Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.
Premi E, Giunta M, Iraji A, et al., 2021, Dissemination in time and space in presymptomatic<i> granulin</i> mutation carriers: a GENFI spatial chronnectome study, NEUROBIOLOGY OF AGING, Vol: 108, Pages: 155-167, ISSN: 0197-4580
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- Citations: 4
Bergstrom S, Oijerstedt L, Remnestal J, et al., 2021, A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study, MOLECULAR NEURODEGENERATION, Vol: 16
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- Citations: 6
Bussy A, Levy J, Best T, et al., 2021, Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia
<jats:title>Abstract</jats:title><jats:p>Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (<jats:italic>MAPT</jats:italic>), progranulin (<jats:italic>GRN</jats:italic>) and chromosome 9 open reading frame 72 (<jats:italic>C9orf72</jats:italic>). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the <jats:italic>C9orf72</jats:italic> group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity fo
Young AL, Bocchetta M, Russell LL, et al., 2021, Characterizing the Clinical Features and Atrophy Patterns of <i>MAPT</i>-Related Frontotemporal Dementia With Disease Progression Modeling, NEUROLOGY, Vol: 97, Pages: E941-E952, ISSN: 0028-3878
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- Citations: 14
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