Consistent Neurodegeneration and Its Association with Clinical Progression in Huntington's Disease: A Coordinate-Based Meta-Analysis

Abstract

Background: The neuropathological hallmark of Huntington's disease (HD) is progressive striatal loss starting several years prior to clinical onset. In the past decade, whole-brain magnetic resonance imaging (MRI) studies have provided accumulating evidence for widely distributed cortical and subcortical atrophy in the early course of the disease. Objective: In order to synthesize current morphometric MRI findings and to investigate the impact of clinical and genetic features on structural changes, we performed a coordinate-based meta-analysis of voxel-based morphometry (VBM) studies in HD. Methods: Twenty HD samples derived from 17 studies were integrated in the analysis comparing a total of 685 HD mutation carriers [345 presymptomatic (pre-HD) and 340 symptomatic (symp-HD) subjects] and 507 controls. Convergent findings across studies were delineated using the anatomical likelihood estimation approach. Effects of genetic and clinical parameters on the likelihood of observing VBM findings were calculated by means of correlation analyses. Results: Pre-HD studies featured convergent evidence for neurodegeneration in the basal ganglia, amygdala, thalamus, insula and occipital regions. In symp-HD, cerebral atrophy was more pronounced and spread to cortical regions (i.e. inferior frontal, premotor, sensorimotor, midcingulate, frontoparietal and temporoparietal cortices). Higher cytosine-adenosine-guanosine repeats were associated with striatal degeneration, while parameters of disease progression and motor impairment additionally correlated with cortical atrophy, especially in sensorimotor areas. Conclusion: This first quantitative meta-analysis in HD demonstrates the extent of striatal atrophy and further consistent extrastriatal degeneration before clinical conversion. Sensorimotor areas seem to be core regions affected in symp-HD and, along with widespread cortical atrophy, may account for the clinical heterogeneity in HD.

Functions of Huntingtin in Germ Layer Specification and Organogenesis

“…Finally, we found precocious elaboration of oligodendrocyte progenitors, which is consonant with previous reports of abnormalities in oligodendrocyte and white matter tracts in pre-symptomatic HD patients [48–51]. Overall, these findings of wide temporal and spatial neural developmental impairments may explain the presence of multiple foci of vulnerabilities in different brain regions reported in HD patients [52–54]. …”

Early grey matter changes in structural covariance networks in Huntington's disease

“…Still, neuropathological studies on HD report the presence of widespread cortical atrophy in addition to striatal atrophy (De la Monte et al, 1988). Reported voxel-wise subcortical volume changes in HD are, however, more prominent than cortical changes and the amount of cortical changes varies across voxel-based studies (Dogan et al, 2013, Whitwell and Josephs, 2007). …”

“…Furthermore, we compared our inter-regional findings with regional volumetric voxel-based analysis on the same data, as this approach is most often used to examine volume loss in HD (Dogan et al, 2013). …”

Surface-based morphometry reveals caudate subnuclear structural damage in patients with premotor Huntington disease

“…Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by abnormal trinucleotide repeat within the Huntingtin gene, ultimately causing widespread cellular disruption across the brain (Dogan et al 2013; Gusella et al 1996). There is considerable variability in age of onset, symptom severity, and rate of progression across affected individuals.…”