Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Flor A. Espinoza; Jessica A. Turner; Victor M. Vergara; Robyn L. Miller; Eva Mennigen; Jingyu Liu; Maria B. Misiura; Jennifer Ciarochi; Hans J. Johnson; Jeffrey D. Long; Henry J. Bockholt; Vincent A. Magnotta; Jane S. Paulsen; Vince D. Calhoun

doi:10.1089/brain.2017.0538

Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Flor A. Espinoza, Jessica A. Turner, Victor M. Vergara, Robyn L. Miller, Eva Mennigen, Jingyu Liu, Maria B. Misiura, Jennifer Ciarochi, Hans J. Johnson, Jeffrey D. Long, Henry J. Bockholt, Vincent A. Magnotta, Jane S. Paulsen, Vince D. Calhoun

School of Medicine

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.

Original language	English (US)
Pages (from-to)	166-178
Number of pages	13
Journal	Brain connectivity
Volume	8
Issue number	3
DOIs	https://doi.org/10.1089/brain.2017.0538
State	Published - Apr 2018

Keywords

CAG repeat length
group-independent component analysis
prodromal Huntington's disease
restingstate fMRI
within- and between-networks functional connectivity

ASJC Scopus subject areas

General Neuroscience

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10.1089/brain.2017.0538

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Espinoza, F. A., Turner, J. A., Vergara, V. M., Miller, R. L., Mennigen, E., Liu, J., Misiura, M. B., Ciarochi, J., Johnson, H. J., Long, J. D., Bockholt, H. J., Magnotta, V. A., Paulsen, J. S., & Calhoun, V. D. (2018). Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls. Brain connectivity, 8(3), 166-178. https://doi.org/10.1089/brain.2017.0538

Espinoza, FA, Turner, JA, Vergara, VM, Miller, RL, Mennigen, E, Liu, J, Misiura, MB, Ciarochi, J, Johnson, HJ, Long, JD, Bockholt, HJ, Magnotta, VA, Paulsen, JS & Calhoun, VD 2018, 'Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls', Brain connectivity, vol. 8, no. 3, pp. 166-178. https://doi.org/10.1089/brain.2017.0538

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title = "Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls",

abstract = "Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.",

keywords = "CAG repeat length, group-independent component analysis, prodromal Huntington's disease, restingstate fMRI, within- and between-networks functional connectivity",

author = "Espinoza, {Flor A.} and Turner, {Jessica A.} and Vergara, {Victor M.} and Miller, {Robyn L.} and Eva Mennigen and Jingyu Liu and Misiura, {Maria B.} and Jennifer Ciarochi and Johnson, {Hans J.} and Long, {Jeffrey D.} and Bockholt, {Henry J.} and Magnotta, {Vincent A.} and Paulsen, {Jane S.} and Calhoun, {Vince D.}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health (5R01NS040068, 1U01NS082083, 5R01 NS054893, P20GM103472, and R01REB020407) and the CHDI Foundation (A-5008). We thank the Predict-HD Investigators and coordinators of the Huntington Study Group; PREDICT-HD sites: University of Iowa, Cleveland Clinic, University College London, Indiana University, Washington University in St. Louis, University California San Francisco; the study participants; the National Research Roster for Huntington Disease Patients and Families; the Huntington{\textquoteright}s Disease Society of America. We acknowledge the assistance of Hans J. Johnson and Mark Lowe in imaging acquisition. Publisher Copyright: {\textcopyright} Copyright 2018, Mary Ann Liebert, Inc.",

year = "2018",

month = apr,

doi = "10.1089/brain.2017.0538",

language = "English (US)",

volume = "8",

pages = "166--178",

journal = "Brain connectivity",

issn = "2158-0014",

publisher = "Mary Ann Liebert Inc.",

number = "3",

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T1 - Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

AU - Espinoza, Flor A.

AU - Turner, Jessica A.

AU - Vergara, Victor M.

AU - Miller, Robyn L.

AU - Mennigen, Eva

AU - Liu, Jingyu

AU - Misiura, Maria B.

AU - Ciarochi, Jennifer

AU - Johnson, Hans J.

AU - Long, Jeffrey D.

AU - Bockholt, Henry J.

AU - Magnotta, Vincent A.

AU - Paulsen, Jane S.

AU - Calhoun, Vince D.

N1 - Funding Information: This work was supported by grants from the National Institutes of Health (5R01NS040068, 1U01NS082083, 5R01 NS054893, P20GM103472, and R01REB020407) and the CHDI Foundation (A-5008). We thank the Predict-HD Investigators and coordinators of the Huntington Study Group; PREDICT-HD sites: University of Iowa, Cleveland Clinic, University College London, Indiana University, Washington University in St. Louis, University California San Francisco; the study participants; the National Research Roster for Huntington Disease Patients and Families; the Huntington’s Disease Society of America. We acknowledge the assistance of Hans J. Johnson and Mark Lowe in imaging acquisition. Publisher Copyright: © Copyright 2018, Mary Ann Liebert, Inc.

PY - 2018/4

Y1 - 2018/4

N2 - Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.

AB - Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.

KW - CAG repeat length

KW - group-independent component analysis

KW - prodromal Huntington's disease

KW - restingstate fMRI

KW - within- and between-networks functional connectivity

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JO - Brain connectivity

JF - Brain connectivity

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ER -

Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Abstract

Keywords

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