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Biol Psychiatry. 2018 Mar 1;83(5):456-465. doi: 10.1016/j.biopsych.2017.10.019. Epub 2017 Oct 26.

Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes.

Author information

1
Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square, London, United Kingdom.
2
Developmental Imaging and Biophysics Section, UCL Institute of Child Health, Queen Square, London, United Kingdom.
3
Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, Queen Square, London, United Kingdom; Department of Electronic Engineering, NED University of Engineering and Technology, Karachi, Pakistan.
4
APHP Department of Genetics, University Hospital Pitié-Salpêtrière; and ICM (Brain and Spine Institute) INSERM U1127, CNRS UMR7225, Sorbonne Universités - UPMC Paris VI UMR_S1127, Paris, France.
5
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
6
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
7
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
8
Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, Queen Square, London, United Kingdom.
9
Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square, London, United Kingdom; National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom. Electronic address: s.tabrizi@ucl.ac.uk.
10
University of British Columbia, Vancouver, Canada.
11
ICM and APHP, Pitié-Salpêtrière University Hospital, Paris, France.
12
Leiden University Medical Centre, Leiden, the Netherlands.
13
University College London, London, United Kingdom.
14
George Huntington Institute, Münster, Germany.
15
Monash University, Melbourne, Australia.
16
University of Ulm, Ulm, Germany.
17
University of Iowa, Iowa City, IA.
18
University of Manchester, Manchester, United Kingdom.

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.

KEYWORDS:

Connectome; Genetics; Huntington's disease; Imaging; Transcription; White matter

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