Manifest Huntington Disease Research Articles

Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease.

Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington's disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance. Three groups of participants were recruited: (1) Imminent and early manifest HD (early HD, n = 8); (2) premanifest (presymptomatic) CAG+ (preHD, n = 10); and (3) CAG unexpanded (CAG-) controls (n = 12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional MRI during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis. Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG- group decreased progressively in a well-documented reward detection network that includes the presupplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG- group. These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Striatal and white matter predictors of estimated diagnosis for Huntington disease

Previous MRI studies with participants prior to manifest Huntington disease have been conducted in small single-site samples. The current study reports data from a systematic multi-national study during the prodromal period of Huntington disease and examines whether various brain structures make unique predictions about the proximity to manifest disease. MRI scans were acquired from 657 participants enrolled at 1 of 32 PREDICT-HD research sites. Only prodromal Huntington disease participants (those not meeting motor criteria for diagnosis) were included and subgrouped by estimated diagnosis proximity (Near, Mid, and Far) based upon a formula incorporating age and CAG-repeat length. Results show volumes of all three subgroups differed significantly from Controls for total brain tissue, cerebral spinal fluid, white matter, cortical gray matter, thalamus, caudate, and putamen. Total striatal volume demonstrated the largest differences between Controls and all three prodromal subgroups. Cerebral white matter offered additional independent power in the prediction of estimated proximity to diagnosis. In conclusion, this large cross-sectional study shows that changes in brain volume are detectable years to decades prior to estimated motor diagnosis of Huntington disease. This suggests that a clinical trial of a putative neuroprotective agent could begin as much as 15 years prior to estimated motor diagnosis in a cohort of persons at risk for but not meeting clinical motor diagnostic criteria for Huntington disease, and that neuroimaging (striatal and white matter volumes) may be among the best predictors of diagnosis proximity.

Platform presentation—Impairments in Precision Grip Control in Pre-symptomatic Huntington's Disease

Background Precision grip control is important for accurate object manipulation and requires coordination between horizontal (grip) and vertical (load) fingertip forces. Manifest Huntington's disease (HD) subjects demonstrate excessive and highly variable grip force, and delayed coordination between grip and load forces. Because the onset of these impairments is unknown, we examined precision grip control in presymptomatic HD (pre-HD) subjects. Methods Fifteen pre-HD and 15 age- and gender-matched controls performed the precision grip task in a seated position. Subjects grasped and lifted an object instrumented with a force transducer that measured horizontal grip and vertical load forces. Outcomes were preload time, loading time, maximum grip force, average grip force during the hold phase, and variability for all measures, and were computed from pre-defined events, such as onset of grip force (>0.1 N), onset of load force (>0.1 N), and maximum grip force during the trial. We measured static grip force in a 3-second window during the hold phase. Pre-HD subjects were administered the UHDRS, and predicted years to onset was calculated using a probabilistic model (Langbehn DR, et al., Clin Genet 2004;65:267–277). Results Preload time and loading time was slower for pre-HD subjects (158.97 ms, 123.0 ms), compared with controls (64.97 ms, 57.2 ms). Variability (SD) of preload and loading time was higher in pre-HD subjects (61, 55.15) than in controls (35.74, 22.08). Variability in maximum and static grip force was higher in pre-HD subjects (0.22, 0.66) than in controls (0.08, 0.03). Pearson correlation with predicted years to disease onset in pre-HD was 0.65 for loading time and 0.69 for loading time variability. Conclusions Temporal delay in coordination between grip and load force, and increased motor variability are seen well before diagnosis of HD and may serve as good biomarkers of disease onset and progression.

Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease

BackgroundCognition is affected early in Huntington disease (HD), and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. The authors investigated whether there is any evidence...

Keynote Address—The Pathway Forward for Development of New Treatments for Manifest and Premanifest Huntington Disease

Keynote Address—The Pathway Forward for Development of New Treatments for Manifest and Premanifest Huntington Disease

Evaluation of psychological symptoms among presymptomatic HD gene carriers as measured by selected MMPI scales

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) ( n=363), presymptomatic gene carriers (PSGC) ( n=149), and those with manifest HD (MHD) ( n=26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P=0.005; MHD vs. NGC, P=0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P=0.0005; MHD vs. NGC, P=0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms.