Apathy and Striatal Gray Matter Patterns in Schizophrenia and Huntington’s Disease

Apathy is a symptom of many neurodegenerative and neuropsychiatric disorders, such as Huntington\u27s disease and schizophrenia. Apathy is often conceptualized as a combination of three domains, cognitive, behavioral, and emotional, characterized by impaired goal-directed behavior. The striatum has been shown to be significantly associated with executive functions and planned motor behavior via projection to the prefrontal cortex (PFC). Due to its connection to the PFC and its involvement in the basal ganglia motor circuit, the striatum is thought to be a significant part of the circuit that controls goal-directed behavior. The purpose of this study was to investigate the relationship between apathy severity and dorsal striatal grey matter concentration across several disorders, specifically Huntington\u27s disease and schizophrenia. With access to the PREDICT-HD and FBIRN datasets, structural MRI images and clinical assessments were collected from 823 and 178 participants, respectively. We employed the use of SBM to isolate relevant basal ganglia components and used the resulting loading coefficients for a multivariate analysis. In parallel, we also conducted a univariate analysis using segmented subcortical volumetric data. We then constructed a mixed linear model to examine the relationship between apathy and any gray matter patterns in the striatum. In Huntington’s disease, our results indicate that apathy is significantly related to the caudate and putamen atrophy with covarying in the medial PFC. In schizophrenia, our results indicate that apathy is significantly related to the putamen with covarying regions in the gyrus rectus and orbital medial PFC. We concluded that Huntington’s disease and schizophrenia manifest apathy in different ways in unique structures

Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460-1477, 2017. © 2017 Wiley Periodicals, Inc

Functional and structural neuroimaging in Huntington’s disease

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. LUMC / Geneeskund