10 results on '"McColgan, Peter"'
Search Results
2. Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.
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Estevez-Fraga, Carlos, Altmann, Andre, Parker, Christopher S, Scahill, Rachael I, Costa, Beatrice, Chen, Zhongbo, Manzoni, Claudia, Zarkali, Angeliki, Durr, Alexandra, Roos, Raymund A C, Landwehrmeyer, Bernhard, Leavitt, Blair R, Rees, Geraint, Tabrizi, Sarah J, and McColgan, Peter
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HUNTINGTON disease ,GENE expression ,DIFFUSION magnetic resonance imaging ,NEURODEGENERATION ,TOPOGRAPHY ,GENE targeting - Abstract
Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.
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McColgan, Peter, Gregory, Sarah, Zeun, Paul, Zarkali, Angeliki, Johnson, Eileanoir B, Parker, Christopher, Fayer, Kate, Lowe, Jessica, Nair, Akshay, Estevez-Fraga, Carlos, Papoutsi, Marina, Zhang, Hui, Scahill, Rachael I, Tabrizi, Sarah J, and Rees, Geraint
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HUNTINGTON disease , *CYTOPLASMIC filaments , *PATHOLOGY , *LARGE-scale brain networks , *FUNCTIONAL connectivity - Abstract
Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease
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McColgan, Peter, Razi, Adeel, Gregory, Sarah, Seunarine, Kiran K., Durr, Alexandra, A.C. Roos, Raymund, Leavitt, Blair R., Scahill, Rachael I., Clark, Chris A., Langbehn, Doug R., Rees, Geraint, and Tabrizi, Sarah J.
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Male ,Psychiatric Status Rating Scales ,Brain Mapping ,Depressive Disorder ,brain network ,Apathy ,diffusion tractography ,Brain ,Huntington's disease ,Magnetic Resonance Imaging ,Cohort Studies ,Oxygen ,Huntington Disease ,depression ,Neural Pathways ,Image Processing, Computer-Assisted ,functional MRI ,Humans ,Female ,Research Articles ,Research Article - Abstract
Depression is common in premanifest Huntington's disease (preHD) and results in significant morbidity. We sought to examine how variations in structural and functional brain networks relate to depressive symptoms in premanifest HD and healthy controls. Brain networks were constructed using diffusion tractography (70 preHD and 81 controls) and resting state fMRI (92 preHD and 94 controls) data. A sub‐network associated with depression was identified in a data‐driven fashion and network‐based statistics was used to investigate which specific connections correlated with depression scores. A replication analysis was then performed using data from a separate study. Correlations between depressive symptoms with increased functional connectivity and decreased structural connectivity were seen for connections in the default mode network (DMN) and basal ganglia in preHD. This study reveals specific connections in the DMN and basal ganglia that are associated with depressive symptoms in preHD. Hum Brain Mapp 38:2819–2829, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
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- 2017
5. Targeting Huntingtin Expression in Patients with Huntington’s Disease
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Tabrizi, Sarah J, Leavitt, Blair R, Rosser, Anne, Kordasiewicz, Holly B, Czech, Christian, Swayze, Eric E, Norris, Daniel A, Baumann, Tiffany, Gerlach, Irene, Schobel, Scott A, Paz, Erika, Smith, Anne V, Landwehrmeyer, G Bernhard, Bennett, C Frank, Lane, Roger M, Teams, Phase 1–2a IONIS-HTTRx Study Site, McColgan, Peter, Hensman, Davina, Ghosh, Rhia, Flower, Michael, Libri, Vincenzo, Saunders, Edwina, Raymond, Lynn, Wild, Edward J, Decolongon, Joji, Li, Tuan, Fathinia, Panteha, Lang, Christina, Lewerenz, Jan, Lindenberg, Katrin, Ludolph, Albert C, Schneider, Ariane, Trautmann, Sonja, Uhl, Stefanie, Saft, Carsten, Weydt, Patrick, Kaminski, Barbara, Kaminski, Daniela, Hoffmann, Rainer, von Hein, Sarah M, Muhlack, Siegfried, Gold, Ralf, Collins, Lucy, Mason, Sarah, Scott, Kirsten, Barker, Roger A, Stoker, Tom, Greenland, Julia, Andresen, Katie, Shanmugam, Mohan, Abdelghani, Mowafak, Turgut, Tolga, Peeren, Siofra, Colaco, Olga, Owens, Rebecca, Subin, Sujamole, Blair, Nick F, Spruth, Eike Jakob, Beckmann, Janna, Krug, Henriette, Langenfurth, Anika, Crossley, Diana, Akhtar, Nasreen, Gavin, Jennie, De Souza, Jenny, Massey, Thomas, McLauchlan, Duncan, Craufurd, David, Cousins, Rebecca, Shastin, Dmitri, Peall, Kathryn, Bhatt, Harsh, Davison, Andrew, Bagshawe, Joanne, Gunning, Belinda, Hamandi, Khalid, Priller, Josef, and Rickards, Hugh
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Mutant ,HTT(RX) ,cerebrospinal fluid [Huntingtin Protein] ,Oligonucleotides ,Disease ,030204 cardiovascular system & hematology ,HTT protein, human ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,antagonists & inhibitors [Huntingtin Protein] ,Huntington's disease ,cerebrospinal fluid [Oligonucleotides] ,mental disorders ,Huntingtin Protein ,Medicine ,Humans ,In patient ,030212 general & internal medicine ,ddc:610 ,Injections, Spinal ,Mutation ,Dose-Response Relationship, Drug ,business.industry ,Nucleotides ,genetics [Huntingtin Protein] ,General Medicine ,Middle Aged ,medicine.disease ,chemical synthesis [Nucleotides] ,nervous system diseases ,drug therapy [Huntington Disease] ,Huntington Disease ,therapeutic use [Oligonucleotides] ,nervous system ,Cancer research ,Female ,business ,Trinucleotide repeat expansion ,pharmacology [Nucleotides] - Abstract
BACKGROUNDHuntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin.METHODSWe conducted a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial involving adults with early Huntington’s disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.RESULTSOf the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and −20%, −25%, −28%, −42%, and −38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).CONCLUSIONSIntrathecal administration of HTTRx to patients with early Huntington’s disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036. opens in new tab.)
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- 2019
6. Brain regions showing white matter loss in Huntington's Disease are enriched for synaptic and metabolic genes
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McColgan, Peter, Gregory, Sarah, Seunarine, Kiran K., Razi, Adeel, Papoutsi, Marina, Johnson, Eileanoir, Durr, Alexandra, Roos, Raymund A.C., Leavitt, Blair R., Holmans, Peter, Scahill, Rachael I., Clark, Chris A., Rees, Geraint, Tabrizi, Sarah J., Coleman, A., Decolongon, J., Fan, M., Petkau, T., Jauffret, C., Justo, D., Lehericy, S., Nigaud, K., Valabrègue, R., Schoonderbeek, A., 't Hart, E.P., Hensman Moss, D. J., Ghosh, R., Crawford, H., Papoutsi, M., Berna, C., Mahaleskshmi, D., Reilmann, R., Weber, N., Labuschagne, I., Stout, J., Landwehrmeyer, B., Orth, M., Mayer, I., Johnson, H., and Crawfurd, D.
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connectome ,Huntington’s Disease ,imaging ,genetics ,transcription ,white matter - Abstract
Background The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Methods Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants. Results We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. Conclusions These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss.
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- 2018
7. Identifying disease‐associated biomarker network features through conditional graphical model.
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Xie, Shanghong, Li, Xiang, McColgan, Peter, Scahill, Rachael I., Zeng, Donglin, and Wang, Yuanjia
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HUNTINGTON disease ,DISEASE risk factors ,GRAY matter (Nerve tissue) ,SYMPTOMS ,OLIGODENDROGLIA ,DENTAL adhesives - Abstract
Biomarkers are often organized into networks, in which the strengths of network connections vary across subjects depending on subject‐specific covariates (eg, genetic variants). Variation of network connections, as subject‐specific feature variables, has been found to predict disease clinical outcome. In this work, we develop a two‐stage method to estimate biomarker networks that account for heterogeneity among subjects and evaluate network's association with disease clinical outcome. In the first stage, we propose a conditional Gaussian graphical model with mean and precision matrix depending on covariates to obtain covariate‐dependent networks with connection strengths varying across subjects while assuming homogeneous network structure. In the second stage, we evaluate clinical utility of network measures (connection strengths) estimated from the first stage. The second‐stage analysis provides the relative predictive power of between‐region network measures on clinical impairment in the context of regional biomarkers and existing disease risk factors. We assess the performance of proposed method by extensive simulation studies and application to a Huntington's disease (HD) study to investigate the effect of HD causal gene on the rate of change in motor symptom through affecting brain subcortical and cortical gray matter atrophy connections. We show that cortical network connections and subcortical volumes, but not subcortical connections are identified to be predictive of clinical motor function deterioration. We validate these findings in an independent HD study. Lastly, highly similar patterns seen in the gray matter connections and a previous white matter connectivity study suggest a shared biological mechanism for HD and support the hypothesis that white matter loss is a direct result of neuronal loss as opposed to the loss of myelin or dysmyelination. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington’s disease
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McColgan, Peter, Seunarine, Kiran K., Razi, Adeel, Cole, James H., Gregory, Sarah, Durr, Alexandra, Roos, Raymund A. C., Stout, Julie C., Landwehrmeyer, Bernhard, Scahill, Rachael I., Clark, Chris A., Rees, Geraint, and Tabrizi, Sarah J.
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Adult ,Male ,Clinical Neurology ,tractography ,IN-DIFFUSION MRI ,CLINICAL B-VALUES ,CONNECTOME ,Basal Ganglia ,MECHANISMS ,17 Psychology And Cognitive Sciences ,PARKINSONS-DISEASE ,Thalamus ,Track-HD Investigators ,Neural Pathways ,Image Processing, Computer-Assisted ,Humans ,Longitudinal Studies ,Cerebral Cortex ,Science & Technology ,Neurology & Neurosurgery ,Neurosciences ,Putamen ,Brain ,Huntington's disease ,SPHERICAL-DECONVOLUTION ,Original Articles ,11 Medical And Health Sciences ,rich club ,Middle Aged ,ALZHEIMERS-DISEASE ,Neostriatum ,PATHOLOGY ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,Huntington Disease ,Case-Control Studies ,Female ,Neurosciences & Neurology ,Caudate Nucleus ,Life Sciences & Biomedicine ,Huntington’s disease - Abstract
Diffuse structural connectivity loss occurs early in Huntington’s disease. However, the organizational principles underlying these changes are unclear. Using whole brain diffusion tractography and graph theoretical analysis, McColgan, Seunarine et al. identify a specific role for highly connected rich club regions as a substrate for structural connectivity loss in Huntington’s disease., Huntington’s disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The ‘rich club’ is a pattern of organization established in healthy human brains, where specific hub ‘rich club’ brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington’s disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington’s disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington’s disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington’s disease and manifest Huntington’s disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighbouring regions. Our findings highlight the role of the rich club as a substrate for the structural connectivity loss seen in Huntington’s disease and have broader implications for understanding the connection between molecular and systems level pathology in neurodegenerative disease.
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- 2015
9. Longitudinal changes in functional connectivity of cortico-basal ganglia networks in manifests and premanifest huntington's disease.
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Gargouri, Fatma, Messé, Arnaud, Perlbarg, Vincent, Valabregue, Romain, McColgan, Peter, Yahia ‐ Cherif, Lydia, Fernandez ‐ Vidal, Sara, Ben Hamida, Ahmed, Benali, Habib, Tabrizi, Sarah, Durr, Alexandra, and Lehéricy, Stéphane
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Huntington's disease (HD) is a genetic neurological disorder resulting in cognitive and motor impairments. We evaluated the longitudinal changes of functional connectivity in sensorimotor, associative and limbic cortico-basal ganglia networks. We acquired structural MRI and resting-state fMRI in three visits one year apart, in 18 adult HD patients, 24 asymptomatic mutation carriers (preHD) and 18 gender- and age-matched healthy volunteers from the TRACK-HD study. We inferred topological changes in functional connectivity between 182 regions within cortico-basal ganglia networks using graph theory measures. We found significant differences for global graph theory measures in HD but not in preHD. The average shortest path length ( L) decreased, which indicated a change toward the random network topology. HD patients also demonstrated increases in degree k, reduced betweeness centrality bc and reduced clustering C. Changes predominated in the sensorimotor network for bc and C and were observed in all circuits for k. Hubs were reduced in preHD and no longer detectable in HD in the sensorimotor and associative networks. Changes in graph theory metrics ( L, k, C and bc) correlated with four clinical and cognitive measures (symbol digit modalities test, Stroop, Burden and UHDRS). There were no changes in graph theory metrics across sessions, which suggests that these measures are not reliable biomarkers of longitudinal changes in HD. preHD is characterized by progressive decreasing hub organization, and these changes aggravate in HD patients with changes in local metrics. HD is characterized by progressive changes in global network interconnectivity, whose network topology becomes more random over time. Hum Brain Mapp 37:4112-4128, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2016
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10. Basal ganglia-cortical structural connectivity in Huntington's disease.
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Novak, Marianne J.U., Seunarine, Kiran K., Gibbard, Clare R., McColgan, Peter, Draganski, Bogdan, Friston, Karl, Clark, Chris A., and Tabrizi, Sarah J.
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Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia-cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia-cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3-Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel-based analyses of probabilistic tractography were used to quantify basal ganglia-cortical structural connections. Canonical variate analysis was used to demonstrate disease-associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia-cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728-1740, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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