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Hum Brain Mapp. 2016 Dec;37(12):4615-4628. doi: 10.1002/hbm.23332. Epub 2016 Aug 1.

Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.

Author information

1
Department of Neurology, Ulm University Hospital, Ulm, Germany.
2
Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom.
3
HD Research Group, UCL Institute of Neurology, Queen Square, London, United Kingdom.
4
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, United Kingdom.
5
Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
6
Department of Neurology, Freiburg Brain Imaging, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
7
Developmental Imaging and Biophysics Section, UCL Institute of Child Health, London, United Kingdom.
8
Centre for Brain Health, University of British Columbia, Vancouver, Canada.
9
CHDI Foundation Inc, Princeton, New Jersey.
10
George-Huntington-Institute, Technology-Park Muenster, Muenster, Germany.
11
Center for Molecular Medicine and Therapeutics and Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
12
Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.
13
APHP Department of Genetics, Groupe Hospitalier Pitié-Salpêtrière, and Institut Du Cerveau Et De La Moelle, INSERM U1127, CNRS UMR7225, UPMC Université Paris VI UMR_S1127, Paris, France.
14
Departments of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa.
15
Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, United Kingdom.

Abstract

While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016.

KEYWORDS:

biological trait; biological variation; cortical thickness; effective connectivity; grip force; principal component analysis; somatosensory evoked potentials

PMID:
27477323
DOI:
10.1002/hbm.23332
[Indexed for MEDLINE]

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