Patterns of Co-Occurring Gray Matter Concentration Loss across the Huntington Disease Prodrome

Abstract

Huntington disease (HD) is caused by an abnormally expanded cytosine–adenine–guanine (CAG) trinucleotide repeat in the HTT gene. Age and CAG-expansion number are related to age at diagnosis and can be used to index disease progression. However, observed onset-age variability suggests that other factors also modulate progression. Indexing prodromal (pre-diagnosis) progression may highlight therapeutic targets by isolating the earliest-affected factors. We present the largest prodromal HD application of the univariate method voxel-based morphometry (VBM) and the first application of the multivariate method source-based morphometry (SBM) to, respectively, compare gray matter concentration (GMC) and capture co-occurring GMC patterns in control and prodromal participants. Using structural MRI data from 1050 (831 prodromal, 219 control) participants, we characterize control-prodromal, whole-brain GMC differences at various prodromal stages. Our results provide evidence for (1) regional co-occurrence and differential patterns of decline across the prodrome, with parietal and occipital differences commonly co-occurring, and frontal and temporal differences being relatively independent from one another, (2) fronto-striatal circuits being among the earliest and most consistently affected in the prodrome, (3) delayed degradation in some movement-related regions, with increasing subcortical and occipital differences with later progression, (4) an overall superior-to-inferior gradient of GMC reduction in frontal, parietal, and temporal lobes, and (5) the appropriateness of SBM for studying the prodromal HD population and its enhanced sensitivity to early prodromal and regionally concurrent differences.

Gray matter atrophy patterns in multiple sclerosis: A 10-year source-based morphometry study

“…The SBM approach allowed us to identify spatial patterns of GM volume common to the cohort of MS patients in this study. Although SBM has been suggested to be more sensitive in detecting GM atrophy than other methods such as VBM ( Ciarochi et al, 2016 , Kasparek et al, 2010 ), we did not detect differences at baseline between patients split on CDP status at the end of the study. Nonetheless, the CDP patient group experienced a significantly greater rate of GM atrophy in two of the identified patterns.…”

“…Although VBM is a conceptually simple approach to analyzing group data, our results suggest that it may lack a certain degree of sensitivity to GM atrophy, especially in a longitudinal setting. Similar discrepancies between SBM and VBM have been reported in cross-sectional studies of other neurological diseases such as schizophrenia ( Kasparek et al, 2010 ) and Huntington's disease ( Ciarochi et al, 2016 ). In the current study, Pattern 1, which underwent significantly greater atrophy in the CDP group, contained, in part, the anterior and posterior cingulate gyri, which were not identified by the VBM analysis.…”

Alzheimer Disease and Mild Cognitive Impairment: Integrated Pulsed Arterial Spin-Labeling MRI and 18F-FDG PET

“…We are not aware of any previous studies that analyzed pulsed ASL data in a setting similar to ours. So far, ICA studies that used source-based morphometry mainly analyzed structural MRI data in patients with schizophrenia (35,36) and, to a lesser degree, healthy participants (37,38) and patients with Huntington disease (39). Therefore, by applying ICA to three imaging modalities and especially by applying source-based morphometry to patients with AD and MCI for all three modalities, we offer an application of this method.…”

Dynamic functional network connectivity in Huntington's disease and its associations with motor and cognitive measures

“…The CAP‐Age product (CAP) score is defined as CAP = Age*(CAG − 33.66) (Zhang, et al, ), where age is measured at the time of the scan. CAP scores have been used to estimate time to HD onset and to index HD progression accounting for exposure time to the toxic protein effects of CAG expansion (Ciarochi et al, ; Lee et al, ; Liu et al, ; Paulsen, Long, Ross, et al, ; Ross et al, ; Tabrizi et al, ).…”

“…Structural studies have demonstrated that prediagnosis and postdiagnosis HD progression is characterized by striatal atrophy and cortical changes (Aylward et al, ; Ciarochi et al, ; Myers et al, ; Paulsen et al, ; Vonsattel et al, ). Complementing these results, functional connectivity studies have generally shown reduced activation in the basal ganglia and cortical regions, suggesting that functional alterations also happen before HD motor symptoms (Koenig et al, ; Paulsen et al, ; Thiruvady et al, ).…”