Linking white matter and deep gray matter alterations in premanifest Huntington disease.
Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.
The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: afaria1@jhmi.edu.
Andreia V
AV
Faria
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA; Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
J Tilak
JT
Ratnanather
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA; Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Daniel J
DJ
Tward
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA; Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
David Soobin
DS
Lee
MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
Frieda
F
van den Noort
The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Dan
D
Wu
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA.
Timothy
T
Brown
Department of Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Hans
H
Johnson
Department of Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Jane S
JS
Paulsen
Division of Neurobiology, Department of Psychiatry, and Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University, Baltimore, MD, USA.
Christopher A
CA
Ross
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA; Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Applied Mathematics and Statistics, The Johns Hopkins University, Baltimore, MD, USA.
Laurent
L
Younes
Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA; Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Michael I
MI
Miller
D000328:Adult; D001931:Brain Mapping; D005260:Female; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018911:Trinucleotide Repeats / Q000235:genetics; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*
Atrophy; DTI; Diffeomorphometry; Huntington; MRI; Shape