Longitudinal change in regional brain volumes in prodromal Huntington disease

Abstract

Objective As therapeutics are being developed to target the underlying neuropathology of Huntington disease (HD), interest is increasing in methodologies for conducting clinical trials in the prodromal phase. This study was designed to examine the potential utility of structural MRI measures as outcome measures for such trials. Methods Data are presented from 211 prodromal individuals and 60 controls, scanned both at baseline and two-year follow-up. Prodromal participants were divided into groups based on proximity to estimated onset of diagnosable clinical disease: Far (>15 years from estimated onset); Mid (9–15 years); and Near (<9 years). Volumetric measurements of caudate, putamen, total striatum, globus pallidus, thalamus, total gray and white matter, and CSF were performed. Results All prodromal groups showed a faster rate of atrophy than Controls in striatum, total brain, and cerebral white matter (especially in the frontal lobe). Neither prodromal participants nor Controls showed significant longitudinal change in cortex (either total cortical gray or within individual lobes). When normal age-related atrophy (i.e., change observed in the Control group) was taken into account, there was more statistically significant disease-related atrophy in white matter than in striatum. Conclusion Measures of volume change in striatum and white matter volume, particularly in the frontal lobe, may serve as excellent outcome measures for future clinical trials in prodromal HD. Clinical trials using white matter or striatal volume change as an outcome measure will be most efficient if the sample is restricted to individuals who are within 15 years of estimated onset of diagnosable disease.

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

“…Given the resilience of these findings, which have been demonstrated consistently across multiple studies in preHD,22, 23, 24, 25, 26, 27, 28, 29 we would suggest that analyses of subcortical volume becomes a minimum requirement for any future preclinical disease modifying trials in HD. Notably, structural volumetric analyses are likely to be more robust across scanners than resting‐state functional neuroimaging measures; therefore, they are also more likely to form a tractable basis for a standardized polymarker that can be used to integrate findings across studies and sites.…”

An image‐based model of brain volume biomarker changes in Huntington's disease

“…The much larger dataset we use here allows us to specify an EBM with a well‐defined ordering of events and demonstrate that it is robust under cross‐validation. Interestingly, our approach reveals that the spread of atrophy in early‐stage HD is not limited to the basal ganglia and white matter (compared to prodromal observations, e.g., 15), but that changes in these volumes occur first. We show the novel staging system, the resulting EBM provides, gives strong prediction of conversion using only imaging data.…”

Mitochondrial dynamics and quality control in Huntington's disease

“…While HD onset is most frequent in the 4th decade of life, the age of onset is inversely correlated with the polyQ expansion size, and very large expansions may cause juvenile or even infantile HD (Ross and Tabrizi, 2011;Seneca et al, 2004). Significantly, despite ubiquitous expression of mHtt in the brain and peripheral tissues, preferential atrophy of the striatum is observed even prior to onset of the manifestations of disease (Aylward et al, 2011;Paulsen et al, 2010). Striatal atrophy stems from the degeneration of GABAergic medium spiny neurons (MSNs), which normally constitute approximately 95% of the striatal neuronal population (Ehrlich, 2012).…”