Abstract
ObjectivesThe distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's.MethodsUsing diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease.ResultsWe find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases.InterpretationOur findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD.
Highlights
Huntington’s disease (HD) is a fully penetrant monogenic neurodegenerative disorder
Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association
Consistent with previous reports[2], this indicates that specific features of healthy white matter (WM) organization can predict decreases in corresponding structural connectivity in pre-HD relative to healthy controls
Summary
Huntington’s disease (HD) is a fully penetrant monogenic neurodegenerative disorder. As the timing of clinical onset can be predicted with relative certainty, it provides a unique opportunity to study the earliest structural changes in the brain occurring years before clinical onset.[1]. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Brain regions with stronger anatomical links to distant regions and fewer connections to neighboring regions in a healthy brain show greater white matter (WM) loss in patients with Huntington’s disease.[2] Such organizational principles are connected to the structural change seen in Alzheimer’s disease, frontotemporal dementia and corticobasal syndrome.[3]
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