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.

Fig. 1

Significant clusters from ALE meta-analyses displayed on a template brain (coordinates in Montreal Neurological Institute space, left is left). a Regions of volume loss in pre-HD subjects compared to controls were located in the bilateral striatum extending to the amygdala, hippocampus, right pallidum, posterior insula, occipital cortex and left thalamus. b Volume loss in symp-HD studies was observed in bilateral basal ganglia, inferior frontal gyrus and motor cortices (PMC, M1), extending to the left somatosensory cortex (SI, SII), parietal areas (IPC, IPS), insula and right midcingulate cortex. c Atrophy across all HD studies was detected in the same areas, except for the right motor cortex and left SII, and was additionally observed in left occipitoparietal areas. d Conjunction analysis. Common atrophy in pre-HD and symp-HD was found in the bilateral basal ganglia. e Contrast analysis. More pronounced atrophy in symp-HD compared to pre-HD was found in the right basal ganglia, bilateral inferior frontal gyrus and motor cortex, left somatosensory, parietal and occipital areas, insula and right midcingulate cortex.

Fig. 2

Significant clusters of correlation from meta-analyses displayed on a template brain (coordinates in Montreal Neurological Institute space, left is left). The likelihood of observing volume differences between HD subjects and controls covaried with study-specific parameters in the following manner: with CAG-repeat length in the right striatum (a); with age in the bilateral striatum and motor cortex and left somatosensory (SI, SII) and parietal (IPC, IPS) regions (b); with estimated disease burden in the right basal ganglia and bilateral motor cortex extending to the left SI and IPC (c); with estimated disease progression in the left caudate nucleus and bilateral motor cortex extending to the left SI (d), and with UHDRS motor scores in the right caudate nucleus, bilateral motor cortex and left somatosensory (SI, SII) and parietal (IPC, IPS) regions (e). The strongest association was observed between the estimated disease burden score and the likelihood of atrophy in the right striatum (displayed in the scatter plot). r_s = Spearman's rank correlation coefficient.