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

Orth, Michael; Gregory, Sarah; Scahill, Rachael I; Mayer, Isabella Sm; Minkova, Lora; Klöppel, Stefan; Seunarine, Kiran K; Boyd, Lara; Borowsky, Beth; Reilmann, Ralf; Bernhard Landwehrmeyer, G; Leavitt, Blair R; Roos, Raymund Ac; Durr, Alexandra; Rees, Geraint; Rothwell, John C; Langbehn, Douglas; Tabrizi, Sarah J (2016). Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease. Human brain mapping, 37(12), pp. 4615-4628. Wiley-Blackwell 10.1002/hbm.23332

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > University Psychiatric Services > University Hospital of Geriatric Psychiatry and Psychotherapy

UniBE Contributor:

Klöppel, Stefan

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1065-9471

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Pascal Wurtz

Date Deposited:

04 Jun 2018 09:34

Last Modified:

28 Oct 2019 10:33

Publisher DOI:

10.1002/hbm.23332

PubMed ID:

27477323

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.101197

URI:

https://boris.unibe.ch/id/eprint/101197

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