Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls.

Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls.Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson's Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson's Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients.The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson's Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05).With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders

DTI maps show negative fractional anisotropy (FA) (A), and positive mean diffusivity (MD) (B) and radial diffusivity (RD) (C) correlations with Wisconsin Card Sorting Test (WCST) Errors in all cirrhotic patients.

<p>Results are shown with a Threshold-Free Cluster Enhancement method at p<0.05 corrected. Rows show selected coronal, sagital and axial maxima coordenate slices on a MNI152 brain template image (MNI coordinates). Red-yellow voxels are negatively correlated FA values (A), blue-lightblue voxels are positively correlated MD values (B) and brown-lightbrown are positively correlated RD values (C) with WCST Errors scores. FWE = Family Wise Error; SLF = superior longitudinal fasciculus; CST = corticospinal tract; ILF = inferior longitudinal fasciculus; IFO = inferior frontal-occipital; CC = corpus callosum; CG = cingulate gyrus; UF = uncinate fasciculus; HC = hippocampus.</p

DTI maps show reduced fractional anisotropy (FA) (A) and increased radial diffusivity (RD) (B) in patients with falls compared to those without falls, including Psychometric Hepatic Encephalopathy Score (PHES) as a covariate.

<p>Results are shown with a Threshold-Free Cluster Enhancement method at p<0.05 corrected. Rows show selected coronal, sagital and axial maxima coordenate slices on a MNI152 brain template image (MNI coordinates). Red voxels have significantly decreased FA values (A), and brown-lightbrown voxels have significantly increased RD values (B). FWE = Family Wise Error; SLF = superior longitudinal fasciculus; CST = corticospinal tract; ILF = inferior longitudinal fasciculus; IFO = inferior frontal-occipital; CC = corpus callosum; CG = cingulate gyrus.</p

DTI maps show reduced fractional anisotropy (FA) (A) and increased mean diffusivity (MD) (B) and radial diffusivity (RD) (C) in patients with falls compared to those without falls.

<p>Results are shown with a Threshold-Free Cluster Enhancement method at p<0.05 corrected. Rows show results of selected coronal, sagital and axial coordenate slices on a MNI152 brain template image (MNI coordinates). Green voxels represent the FMRIB58 white matter skeleton mask. Red voxels have significantly decreased FA values (A), blue voxels imply significantly increased MD (B) and lightbrown voxels represent increased RD values (C). FWE = Family Wise Error; SLF = superior longitudinal fasciculus; CST = corticospinal tract; ILF = inferior longitudinal fasciculus; IFO = inferior frontal-occipital; CC = corpus callosum; CG = cingulate gyrus.</p

Neuromuscular evaluation of patients with falls and patients without falls.

<p>^a MRC: Medical Research Council.</p><p>^b ICARS: International Cooperative Ataxia Rating Scale.</p><p>^c UPDRS-III: Unified Parkinson’s Disease Rating Scale-part III.</p><p>Neuromuscular evaluation of patients with falls and patients without falls.</p

Cerebral MRI findings visually assessed in cirrhotic patients with falls and in those without falls.

<p>Cerebral MRI findings visually assessed in cirrhotic patients with falls and in those without falls.</p

Neuropsychological tests in patients with falls and patients without falls.

<p>^a Mini-Mental State Examination.</p><p>^b Parkinson’s Disease-Cognitive Rating Scale.</p><p>^c PHES: Psychometric Hepatic Encephalopathy Score.</p><p>^d WCST: Wisconsin Sorting Card Test.</p><p>Higher values indicate better results in all tests except for Number Connection Test A and B, Line Tracing Test, Serial Dotting Test and WCST Errors.</p><p>Neuropsychological tests in patients with falls and patients without falls.</p