Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

A Phenotypic Atlas for Huntington Disease Based on Data From the Enroll-HD Cohort Study.

Background and Objectives: The variable CAG repeat expansion in the huntingtin gene and its inverse relationship to motor dysfunction onset are fundamental features of Huntington disease (HD). However, the wider phenotype (including non-motor features) at particular CAG lengths, ages, and functional levels is less well-characterized. The large number of participants in the Enroll-HD observational study enables the development of a phenotype atlas that summarizes the range and distribution of HD phenotypes, including outliers and possible clusters, with respect to various CAG repeat lengths, age ranges, and declining functional levels. Methods: Enroll-HD is an ongoing prospective longitudinal observational study that collects natural history data, releasing periodic data sets, in people with HD (PwHD) and controls. Core assessments at annual visits focus on behavioral, cognitive, motor, and functional status. Periodic data set 5, used for the development of the first iteration of the Enroll-HD Phenotype Atlas (EHDPA), included all eligible data collected through October 31, 2020. The atlas is based on subsets (cells) of descriptive data for all motor, cognitive, psychiatric, and functional measures that are routinely collected at most Enroll-HD sites, analyzed by single CAG lengths and 5-year age blocks. Results: Data from 42,840 visits from 15,982 unique PwHD were available for analysis. At baseline, participants had a mean ± SD age of 48.9 ± 13.9 years and CAG repeat length of 43.4 ± 3.6 and 54.1% were female. The EHDPA includes 223 age-by-CAG subsets for CAG repeats between 36 and 69 with five-year age brackets starting from 20-24 years up to 85-89 years. The atlas can be browsed at enroll-hd.org/for-researchers/atlas-of-hd-phenotype/. Discussion: The EHDPA summarizes the spectrum and distribution of HD phenotypes, including outliers and possible clusters, in all domains of disease involvement for the range of CAG repeat lengths, ages, and functional levels. Its availability in an easy-to-use online format will assist clinicians in tracking disease progression in PwHD by identifying phenotypic features most associated with loss of function and enabling conversations related to prognosis. The observable patterns in the EHDPA should also catalyze more formal multidomain characterization of motor, cognitive, and psychiatric progression and their relationships to functional decline and disease modifiers. Trial Registration Information: Enroll-HD is registered with clinicaltrials.gov: NCT01574053.

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease.

BACKGROUND: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). METHODS: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). RESULTS: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers. CONCLUSION: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.

Longitudinal Clinical and Biological Characteristics in Juvenile-Onset Huntington's Disease.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington's disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington's disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington's disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington's disease and their effect on brain structure.

Behavioral features in child and adolescent huntingtin gene-mutation carriers.

INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.

Standardizing the CAP Score in Huntington's Disease by Predicting Age-at-Onset.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant, neurological disease caused by an expanded CAG repeat near the N-terminus of the huntingtin (HTT) gene. A leading theory concerning the etiology of HD is that both onset and progression are driven by cumulative exposure to the effects of mutant (or CAG expanded) huntingtin (mHTT). The CAG-Age-Product (CAP) score (i.e., the product of excess CAG length and age) is a commonly used measure of this cumulative exposure. CAP score has been widely used as a predictor of a variety of disease state variables in HD. The utility of the CAP score has been somewhat diminished, however, by a lack of agreement on its precise definition. The most commonly used forms of the CAP score are highly correlated so that, for purposes of prediction, it makes little difference which is used. However, reported values of CAP scores, based on commonly used definitions, differ substantially in magnitude when applied to the same data. This complicates the process of inter-study comparison. OBJECTIVE: In this paper, we propose a standardized definition for the CAP score which will resolve this difficulty. Our standardization is chosen so that CAP = 100 at the expected age of diagnosis. METHODS: Statistical methods include novel survival analysis methodology applied to the 13 disease landmarks taken from the Enroll-HD database (PDS 5) and comparisons with the existing, gold standard, onset model. RESULTS: Useful by-products of our work include up-to-date, age-at-onset (AO) results and a refined AO model suitable for use in other contexts, a discussion of several useful properties of the CAP score that have not previously been noted in the literature and the introduction of the concept of a toxicity onset model. CONCLUSION: We suggest that taking L = 30 and K = 6.49 provides a useful standardization of the CAP score, suitable for use in the routine modeling of clinical data in HD.

Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Cortical Features in Child and Adolescent Carriers of Mutant Huntingtin (mHTT).

BACKGROUND: Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT. OBJECTIVE: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. METHODS: Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry. RESULTS: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. CONCLUSION: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.

Utility of the Huntington's Disease Prognostic Index Score for a Perimanifest Clinical Trial.

BACKGROUND: Subtle neurodegenerative motor and cognitive impairments accumulate over a prodromal period several years before clinical diagnosis of Huntington's disease (HD). The inclusion of prodromal individuals in therapeutic trials would facilitate testing of therapies early in the disease course and the development of treatments intended to prevent or delay disability. OBJECTIVES: We evaluate the normalized prognostic index (PIN) score as a tool to select participants for a perimanifest trial. We explore anticipated PIN-based inclusion rates from the preHD screening population and estimate sample-size requirements based on PIN threshold, trial duration, and outcome measure. METHODS: Individual participant data from ENROLL-HD were used to fit mixed effect linear models to assess longitudinal changes in clinical metrics for participants with early-manifest HD and PIN-stratified preHD subcohorts. RESULTS: A PIN threshold of 0.0 was met by 40% of the preHD participants in ENROLL-HD; 39.4% and 55.2% progressed to new diagnoses of early-manifest HD within 2 and 3 years, respectively. Various PIN thresholds also enabled the selection of specified ratios of prodromal preHD to early manifest HD participants for a perimanifest trial. Estimated sample sizes for a trial enrolling prodromal preHD (PIN > 0.0) and stage 1 and 2 motor-diagnosed participants varied depending on the composition of the screening pool, the length of follow-up (1, 2, or 3 years), and outcome measure. CONCLUSIONS: The composition of a perimanifest clinical trial population can be defined using preselected PIN thresholds, facilitating the assessment of potential disease-modifying therapies in HD. © 2022 Voyager Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease.

It is well known that the length of the CAG trinucleotide expansion of the huntingtin gene is associated with many aspects of Huntington disease progression. These include age of clinical onset and rate of initial progression of disease severity. The relationship between CAG length and survival in Huntington disease is less studied. To address this, we obtained the complete Registry HD database from the European Huntington Disease Network and reanalyzed the time from reported age of disease onset until death. We conducted semiparametric proportional hazards modeling of 8,422 participants who had experienced onset of clinical Huntington disease, either retrospectively or prospectively. Of these, 826 had a recorded age of death. To avoid biased model estimates, retrospective onset ages were represented by left truncation at study entry. After controlling for onset age, which tends to be younger in those with longer CAG repeat lengths, we found that CAG length had a substantial and highly significant influence upon survival time after disease onset. For a fixed age of onset, longer CAG expansions were predictive of shorter survival. This is consistent with other known relationships between CAG length and disease severity. We also show that older onset age predicts shorter lifespan after controlling for CAG length and that the influence of CAG on survival length is substantially greater in women. We demonstrate that apparent contradictions between these and previous analyses of the same data are primarily due to the question of whether to control for clinical onset age in the analysis of time until death.

Impact of binge drinking during college on resting state functional connectivity.

AIM: The current study examined the longitudinal effects of standard binge drinking (4+/5+ drinks for females/males in 2 hours) and extreme binge drinking (8+/10+ drinks for females/males in 2 hours) on resting-state functional connectivity. METHOD: 119 college students (61 males) were recruited in groups of distinct bingeing patterns at baseline: non-bingeing controls, standard and extreme bingers. Resting-state scans were first obtained when participants were freshmen/sophomores and again approximately two years later. Associations between longitudinal bingeing (reported during this two-year gap) and network connectivity were examined. Network connectivity was calculated by aggregating all edges affiliated with the same network (an edge is a functional connection between two brain regions). The relationship between longitudinal bingeing and connectivity edges was also studied using connectome-based predictive modeling (CPM). RESULTS: Greater standard bingeing was negatively associated with change in connectivity between Default Mode Network and Ventral Attention Network (DMN-VAN; False Discovery Rate corrected), controlling for initial binge groups, longitudinal network changes, motions, scanner, SES, sex, and age. The correlations between change in DMN-VAN connectivity and change in cognitive performance (Stroop, Digit Span, Letter Fluency, and Trail Making) were also tested, but the results were not significant. Lastly, CPM failed to identify a generalizable predictive model of longitudinal bingeing from change in connectivity edges. CONCLUSIONS: Binge drinking is associated with abnormality in networks implicated in attention and self-focused processes, which, in turn, have been implicated in rumination, craving, and relapse. More extensive alterations in functional connectivity might be observed with heavier or longer binge drinking pattern.

Age-Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin.

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040.

Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease.

BACKGROUND: The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies. OBJECTIVE: Evaluating volumetric and structural connectivity correlates of the cUHDRS. METHODS: One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics. RESULTS: Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline. CONCLUSION: The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society.

Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington's disease.

Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington's disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington's disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington's disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the supplementary motor area, and another receiving neurofeedback based on the correlation of supplementary motor area and left striatum activity (connectivity neurofeedback training), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during neurofeedback training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants' ability to upregulate neurofeedback training target levels without feedback (near transfer), as well as by examining change in objective, a priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher neurofeedback training target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two neurofeedback training methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and learning success. We conclude that although there is evidence that neurofeedback training can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust.

Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington's Disease: Effect of mHTT on Growth.

BACKGROUND: The gene (Huntingtin or HTT) causing Huntington's disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development. OBJECTIVE: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. METHODS: Children ages 6-18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. RESULTS: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. CONCLUSION: Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology.

Clinical Outcomes and Selection Criteria for Prodromal Huntington's Disease Trials.

BACKGROUND: Huntington's disease (HD) develops in individuals with extended cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability. OBJECTIVES: The present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures. METHODS: Individual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN-stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts. RESULTS: Longitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and >0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD. CONCLUSIONS: These analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Behavioral inhibition and reward processing in college binge drinkers with and without marijuana use.

AIM: Binge drinking is common during college, and studies have shown that many college students drink in quantities that far exceed the standard binge drinking threshold. Previous research has noted personality differences in individuals who engage in binge drinking, but few studies have examined neurobiological differences in both standard bingers (4/5 drinks in two hours for females/males; sBinge) and extreme binge drinkers (8+/10+ drinks in two hours for females/males; eBinge). METHOD: The current study of 221 college students used functional magnetic resonance imaging (fMRI) to study neural activation on a stop signal task (SST) to assess behavioral inhibition and a monetary incentive delay (MID) task to assess activation to rewards and losses. Non-bingeing controls, sBinge, and eBinge freshmen and sophomores were recruited. In addition, because binge/extreme binge drinking is often associated with marijuana (MJ) use, MJ + sBinge and MJ + eBinge groups were also included. RESULTS: All five groups showed strong activation in expected key cortical and striatal regions on both the SST and the MID. However, there were no significant differences between groups either at the whole-brain level or in specific regions of interest. Behavioral performance on the fMRI tasks also did not differ between groups. CONCLUSIONS: These results suggest that our sample of individuals who engage in binge or extreme binge drinking with or without MJ co-use do not differ in brain activity on reward and inhibitory tasks. Neural differences may be present on other cognitive tasks or may emerge later after more sustained use of alcohol, MJ, and other drugs.

Huntington's Disease Progression: A Population Modeling Approach to Characterization Using Clinical Rating Scales.

Development of effective therapeutics that slow Huntington's disease progression is a research priority that requires an understanding of natural disease progression. We applied a population-modeling approach to describe the progression of 2 routinely used rating scales - the total motor score and the total functional capacity score. Models were fitted to data from research participants aged ≥ 18 years with Huntington's disease stage I or II at study entry (total functional capacity score ≥ 7), from a controlled clinical trial (CARE-HD) and 2 observational studies (COHORT and Registry). A logistic model without shape factors was selected as the base model based on placebo data from CARE-HD and validated using data from the CARE-HD active-treatment arms. Albeit with a smaller progression rate constant than was found in CARE-HD, the proposed models provided reasonable predictions for both rating scales in the pooled data from COHORT and Registry and were considered suitable for use in clinical trial simulations. Results also showed that disease burden score (a product of age and expanded CAG length) is a significant covariate on both the progression rate constant and the baseline score in the total motor score model. These findings suggest that total motor score and total functional capacity progress fastest near their half-maximal score, implying that the efficiency of clinical trials evaluating disease-modifying therapeutics for Huntington's disease could be enhanced by enrolling patients with faster disease progression or evaluating treatment effect near their half-maximal score, provided that the evaluated therapy is expected to be efficacious at this disease stage.