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Striatal and white matter predictors of estimated diagnosis for Huntington disease.

ABSTRACT: Previous MRI studies with participants prior to manifest Huntington disease have been conducted in small single-site samples. The current study reports data from a systematic multi-national study during the prodromal period of Huntington disease and examines whether various brain structures make unique predictions about the proximity to manifest disease. MRI scans were acquired from 657 participants enrolled at 1 of 32 PREDICT-HD research sites. Only prodromal Huntington disease participants (those not meeting motor criteria for diagnosis) were included and subgrouped by estimated diagnosis proximity (Near, Mid, and Far) based upon a formula incorporating age and CAG-repeat length. Results show volumes of all three subgroups differed significantly from Controls for total brain tissue, cerebral spinal fluid, white matter, cortical gray matter, thalamus, caudate, and putamen. Total striatal volume demonstrated the largest differences between Controls and all three prodromal subgroups. Cerebral white matter offered additional independent power in the prediction of estimated proximity to diagnosis. In conclusion, this large cross-sectional study shows that changes in brain volume are detectable years to decades prior to estimated motor diagnosis of Huntington disease. This suggests that a clinical trial of a putative neuroprotective agent could begin as much as 15 years prior to estimated motor diagnosis in a cohort of persons at risk for but not meeting clinical motor diagnostic criteria for Huntington disease, and that neuroimaging (striatal and white matter volumes) may be among the best predictors of diagnosis proximity.

SUBMITTER: Paulsen JS

PROVIDER: S-EPMC2892238 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Striatal and white matter predictors of estimated diagnosis for Huntington disease.

Paulsen Jane S JS Nopoulos Peggy C PC Aylward Elizabeth E Ross Christopher A CA Johnson Hans H Magnotta Vincent A VA Juhl Andrew A Pierson Ronald K RK Mills James J Langbehn Douglas D Nance Martha M

Brain research bulletin 20100410 3-4

Previous MRI studies with participants prior to manifest Huntington disease have been conducted in small single-site samples. The current study reports data from a systematic multi-national study during the prodromal period of Huntington disease and examines whether various brain structures make unique predictions about the proximity to manifest disease. MRI scans were acquired from 657 participants enrolled at 1 of 32 PREDICT-HD research sites. Only prodromal Huntington disease participants (th ...[more]

PMID: 20385209

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Project description: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.

Project description:BackgroundApathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited.ObjectivesTo disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease.MethodsForty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains.ResultsWe elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract.ConclusionsThe current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders.

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Striatal and white matter predictors of estimated diagnosis for Huntington disease.

Publications

Striatal and white matter predictors of estimated diagnosis for Huntington disease.

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