Neuropsychiatry and White Matter Microstructure in Huntington's Disease

Abstract

Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population.

Objective: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD.

Methods: DTI data were collected from 39 premanifest and 45 early-HD participants in the Track-HD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO).

Results: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain.

Conclusions: We demonstrate that white matter changes associated with both depression and irritability in HD occur at different stages of disease progression concomitant with their clinical presentation.

Keywords: Huntington’s disease; apathy; depression; diffusion tensor imaging; irritability.

Fig.1

Tracts in which reduced FA was correlated with increased levels of depression in those with high CPO; FWE -corrected threshold of P <  0.05. a) Results (red-yellow) are projected on a white matter skeleton (green), overlaid on a customized mean FA image. b) FA as a function of HADS depression (lower scatterplots), conditional on CPO (upper panel). The upper panel depicts the overlapping ranges of CPO that determine the subsample of each scatterplot. A linear regression line was fit for each scatterplot to aid interpretation.

Fig.2

Tracts in which reduced FA was correlated with increased levels of irritability/aggression in those with low CPO; FWE-corrected threshold of P <  0.05. a) Results (red-yellow) are projected on a white matter skeleton (green), overlaid on a customized mean FA image. FA as a function of PBA irritability/aggression (lower scatterplot), conditional on CPO (upper panel). The upper panel depicts the overlapping ranges of CPO that determine the subsample of each scatterplot. A linear regression line was fit for each scatterplot to aid interpretation.