title: Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.
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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gregory
authors.affiliation: HD Research Group, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.|Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Isabella Sm
authors.initials: IS
authors.lastname: Mayer
authors.affiliation: Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Lora
authors.identifier: 0000-0003-0945-0553
authors.initials: L
authors.lastname: Minkova
authors.affiliation: Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.|Department of Neurology, Freiburg Brain Imaging, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klöppel
authors.affiliation: Developmental Imaging and Biophysics Section, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Seunarine
authors.affiliation: Centre for Brain Health, University of British Columbia, Vancouver, Canada.
authors.forename: Lara
authors.initials: L
authors.lastname: Boyd
authors.affiliation: CHDI Foundation Inc, Princeton, New Jersey.
authors.forename: Beth
authors.initials: B
authors.lastname: Borowsky
authors.affiliation: George-Huntington-Institute, Technology-Park Muenster, Muenster, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Reilmann
authors.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Bernhard Landwehrmeyer
authors.affiliation: Center for Molecular Medicine and Therapeutics and Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Raymund Ac
authors.initials: RA
authors.lastname: Roos
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom.
authors.forename: Geraint
authors.initials: G
authors.lastname: Rees
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Rothwell
authors.affiliation: Departments of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa.
authors.forename: Douglas
authors.initials: D
authors.lastname: Langbehn
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000328:Adult; D000076103:Biological Variation, Individual; D001931:Brain Mapping; D003430:Cross-Sectional Studies; D056324:Diffusion Tensor Imaging; D005073:Evoked Potentials, Somatosensory; D005260:Female; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000503:physiopathology; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000503:physiopathology*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D009929:Organ Size; D025341:Principal Component Analysis; D062706:Prodromal Symptoms; D012146:Rest; D066191:Sensorimotor Cortex / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D019680:Trinucleotide Repeat Expansion; D066127:White Matter / Q000000981:diagnostic imaging* / Q000503:physiopathology*
keywords: biological trait; biological variation; cortical thickness; effective connectivity; grip force; principal component analysis; somatosensory evoked potentials