Insufficient evidence exists to guide the long-term pharmacological management of Huntington’s disease (HD) although most current interventions rely on symptomatic management. The effect of many frontline treatments on potential endpoints for HD clinical trials remains unknown. Our objective was to investigate how therapies widely used to manage HD affect the symptom for which they are prescribed and other endpoints using data from TRACK-HD. We used longitudinal models to estimate effects of medication use on performance on tests of motor, cognitive and neuropsychiatric function using data from 123 TRACK-HD stage 1/2 participants across four study visits. Adjustment for confounding by prior medication use, prior clinical performance, concomitant use of other medications, and baseline variables (sex, disease group, age, CAG, study site, education) enabled a closer-to-causal interpretation of the associations. Adjusting for baseline variables only, medication use was typically associated with worse clinical performance, reflecting greater medication use in more advanced patients. After additional adjustment for longitudinal confounders such “inverse” associations were generally eliminated and in the expected directions: participants taking neuroleptics tended to have better motor performance, improved affect and poorer cognitive performance, and those taking SSRI/SNRIs had less apathy, less affect and better total behaviour scores. However, we uncovered few statistically significant associations. Limitations include sample size and unmeasured confounding. In conclusion, adjustment for confounding by prior measurements largely eliminated associations between medication use and poorer clinical performance from simple analyses. However, there was little convincing evidence of causal effects of medication on clinical performance and larger cohorts or trials are needed.
Background: Recently a profound depletion of cystathionine γ-lyase (CSE), the principal enzyme involved in the generation of cysteine from cystathionine, was shown in Huntington disease (HD) patients and several transgenic HD mouse models. We therefore hypothesized that blood and urine cystathionine levels may be increased in HD patients and that this increase might correlate with disease progression. Methods: We measured concentrations of cystathionine as well as 22 other amino acids in fasting plasma and 24-h urine samples of nine early-stage HD patients and nine age, sex, and body mass index matched controls. Results: There were no significant differences in the plasma or urine concentrations of cystathionine or any other amino acid between HD patients and controls. Conclusion: We found no evidence for changes in plasma or urine concentrations of cystathionine in early-stage HD patients. Therefore, cystathionine levels are unlikely to be useful as a state biomarker in HD.
Huntington’s disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by choreatic and hypokinetic movements, disturbed behaviour, and cognitive decline. Pneumonia is the most common cause of death, followed by cardiovasculair diseases. It has been suggested that choking is the causative underlying factor for pneumonia in HD. As a detailed specification of the type of pneumonia has never been performed, we analyzed the records of our Brain Bank containing 224 cases to determine the exact cause of death and type of pneumonia. The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.
Detecting subtle clinical abnormalities in the ‘premanifest’ phase of Huntington’s disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington’s Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.
Several candidate modifier genes which, in addition to the pathogenic CAG repeat expansion, influence the age at onset (AO) in Huntington disease (HD) have already been described. The aim of this study was to replicate association of variations in the N-methyl D-aspartate receptor subtype genes GRIN2A and GRIN2B in the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). The analyses did replicate the association reported between the GRIN2A rs2650427 variation and AO in the entire cohort. Yet, when subjects were stratified by AO subtypes, we found nominally significant evidence for an association of the GRIN2A rs1969060 variation and the GRIN2B rs1806201 variation. These findings further implicate the N-methyl D-aspartate receptor subtype genes as loci containing variation associated with AO in HD.
Increased iron levels have been demonstrated in the basal ganglia of manifest Huntington’s disease (HD). An excess in iron accumulation correlates with MRI T2-weighted hypointensity. Determination of the amount of hypointensities in the basal ganglia in the premanifest phase of HD may give more insight in the role of iron in the pathogenesis of HD. Therefore, the present study assessed whether the degree of hypointensities on T2-w MRI in the basal ganglia of premanifest gene carriers differs from non-carriers. Seventeen HD gene carriers without clinical motor signs and 15 non-carriers underwent clinical evaluation and MRI scanning. The amount of T2-w hypointensities was determined using a computer-assisted quantitative method that classified each pixel in the basal ganglia as hypointense or not, resulting in a total of hypointense pixels for each individual. Carriers showed an increased amount of hypointensities in the basal ganglia compared to non-carriers. More hypointensities were furthermore associated with a higher UHDRS total motor score, a longer CAG repeat length and a greater probability of developing symptoms within 5 years. We concluded that the increased amount of hypointensities in the basal ganglia of premanifest carriers of the HD gene may reflect excessive iron deposition and a role for iron in the neuropathology of HD. Furthermore, this phenomenon is associated with clinical and biological disease characteristics. An increased amount of hypointensities on T2-w MRI in the basal ganglia may be considered a biomarker for HD.