Total Functional Capacity Score Research Articles

High Levels of Mutant Huntingtin Protein in Tear Fluid From Huntington's Disease Gene Expansion Carriers.

Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before. We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington's Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer's strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology. The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, "estimated years to diagnosis," disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients. Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics.

Digital assessment of speech in Huntington disease.

Speech changes are an early symptom of Huntington disease (HD) and may occur prior to other motor and cognitive symptoms. Assessment of HD commonly uses clinician-rated outcome measures, which can be limited by observer variability and episodic administration. Speech symptoms are well suited for evaluation by digital measures which can enable sensitive, frequent, passive, and remote administration. We collected audio recordings using an external microphone of 36 (18 HD, 7 prodromal HD, and 11 control) participants completing passage reading, counting forward, and counting backwards speech tasks. Motor and cognitive assessments were also administered. Features including pausing, pitch, and accuracy were automatically extracted from recordings using the BioDigit Speech software and compared between the three groups. Speech features were also analyzed by the Unified Huntington Disease Rating Scale (UHDRS) dysarthria score. Random forest machine learning models were implemented to predict clinical status and clinical scores from speech features. Significant differences in pausing, intelligibility, and accuracy features were observed between HD, prodromal HD, and control groups for the passage reading task (e.g., p < 0.001 with Cohen'd = -2 between HD and control groups for pause ratio). A few parameters were significantly different between the HD and control groups for the counting forward and backwards speech tasks. A random forest classifier predicted clinical status from speech tasks with a balanced accuracy of 73% and an AUC of 0.92. Random forest regressors predicted clinical outcomes from speech features with mean absolute error ranging from 2.43-9.64 for UHDRS total functional capacity, motor and dysarthria scores, and explained variance ranging from 14 to 65%. Montreal Cognitive Assessment scores were predicted with mean absolute error of 2.3 and explained variance of 30%. Speech data have the potential to be a valuable digital measure of HD progression, and can also enable remote, frequent disease assessment in prodromal HD and HD. Clinical status and disease severity were predicted from extracted speech features using random forest machine learning models. Speech measurements could be leveraged as sensitive marker of clinical onset and disease progression in future clinical trials.

Factors Influencing the Total Functional Capacity Score as a Critical Endpoint in Huntington's Disease Research.

Background: The Total Functional Capacity (TFC) score is commonly used in Huntington's disease (HD) research. The classification separates each disease stage (1-5), e.g., as an inclusion criterion or endpoint in clinical trials accepted by the Food and Drug Administration (FDA). In addition to the quantification of age- and CAG-repeat-dependent effects as well as interacting effects of both on the TFC, we aimed to investigate factors influencing the TFC, such as neuropsychiatric, educational, and cognitive disease burden using data from the largest HD observational study to date. In addition, we analyzed data from pre-manifest stages to investigate the influence of the above-mentioned factors on the TFC in that stage. Methods: A moderated regression analysis was conducted to analyze the interaction effects of age and CAG-repeat length on the TFC in HD patients. A simple slope analysis was calculated to illustrate the effects. Depending on TFC results, motor-manifest patients were grouped into five stages. Data from pre-manifest participants were analyzed with regard to years to onset and CAP scores. Results: We identified N = 10,314 participants as manifest HD. A significant part of variance on the TFC was explained by age (R2 = 0.029, F (1;10,281) = 308.02, p < 0.001), CAG-repeat length (∆R2 = 0.132, ∆F (1;10,280) = 1611.22, p < 0.001), and their interaction (∆R2 = 0.049, ∆F (1;10,279) = 634.12, p < 0.001). The model explained altogether 20.9% of the TFC score's variance (F = 907.60, p < 0.001). Variance of psychiatric and cognitive symptoms significantly differed between stages. Exploratory analysis of median data in pre-manifest participants revealed the highest scores for neuropsychiatric changes between 5 to <20 years from the disease onset. Conclusions: TFC is mainly explained by the neurobiological factors, CAG-repeat length, and age, with subjects having more CAG-repeats showing a faster decline in function. Our study confirms TFC as a robust measure of progression in manifest HD.

59 Preliminary Findings of Semantic Interference in Learning and Memory Processes in Manifest Huntington’s Disease

Objective:To explore the usefulness of the Lowenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) [Crocco et al, 2013], a novel memory-based cognitive stress test capitalizing on semantic interference, in Huntington’s Disease (HD).Participants and Methods:12 healthy adults (HA) and 14 individuals with manifest HD were administered the LASSI-L as part of an annual research visit with the UCSD Huntington’s Disease Clinical Research Center (HDCRC.) Participants in each group were well matched with regard to age and education. Individuals with manifest HD had an average MoCA score of 26, total functional capacity score of 10, and total motor score of 21 suggesting that they were in the early stages of HD. The LASSI-L examines different types of semantic interference that occur in the learning/encoding process. There are free and cued recall trials for two lists of semantically related words with certain trials specific to different aspects of semantic interference including proactive, retroactive, and failure to recover from proactive interference. T-tests for all recall trials and number of intrusions for each trial were conducted between HA and those with HD to examine whether HD renders one more prone to semantic interference in both encoding and retrieval memory processes.Results:Individuals with HD recalled fewer words on average than HA across all recall trials except for the initial free recall of the first word list. HD individuals recalled significantly fewer (∼1.5) words during the initial (t=-2.8, p=.005, Cohen’s d=2.7) and secondary (t=-2.9, p=.003, Cohen’s d=2.6) cued recall trials from the words on the first list. Individuals with HD also recalled significantly fewer words on initial free recall (t=-2.9, p=.003, Cohen’s d=2.6) and cued recall trials of the second list, with the initial cued recall (t=-2.8, p=.005, Cohen’s d=3.1) sensitive to proactive semantic interference and the second cued recall (t=-3.3, p=.001, Cohen’s d=2.6) sensitive to failure to recover from proactive semantic interference. In addition, individuals with HD also recalled significantly fewer (∼2.2) words on delayed cued recall of the first list, a measure of retroactive semantic interference, than HA (t=-4.8, p&lt;.001, Cohen’s d=2.4). Lastly, individuals with HD recalled fewer (∼4.1) words than HA on delayed free recall of both word lists (t=-3.5, p&lt;.001, Cohen’s d=5.9). The groups did not differ significantly with regard to number of total intrusions per trial.Conclusions:Overall, our study supports the usefulness of the LASSI-L for neuropsychological assessment of HD in clinical and research settings. In comparison to a demographically similar group of HA, individuals with manifest HD showed significant differences in frontally mediated retrieval processes as well as semantic interference processes that affect efficient encoding of novel information.

Disparities in Huntington Disease Severity: Analysis Using the ENROLL-HD Dataset.

Social and structural determinants of health (SDOH) have been associated with disability in neurologic diseases. However, the association between these factors and disability in Huntington disease (HD) has not been studied. This study aimed to evaluate the association of racial and sociodemographic factors with disease severity in patients with HD in North America. We conducted a cross-sectional study of genetically confirmed participants with HD (36+ CAG repeats) in the North American region using the ENROLL-HD 2020 periodic dataset. In this analysis, our exposure variable was the participant's race/ethnicity. The main outcome measure was disease severity, as measured by the Total Functional Capacity Score (TFC), which measures the level of disability of patients with HD. We used multivariate regression models to adjust for sociodemographic factors that may mediate or moderate a causal effect between race/ethnicity and disease severity. Among 4,717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TFC score was 10.22 (SD 3.22); 48% of participants completed either secondary education (including college) or a professional degree, and 55% lived in a city and not in a town, village, or rural location. In multivariate regression models, we found that Black participants and those with less than a high school degree entered the ENROLL-HD study with lower TFC scores than White participants. We also found that compared with those with at least a high school degree, those who completed some form of higher education or professional degree had higher TFC scores (p < 0.001). This multivariate analysis did not find an association between geographic location and TFC score. Our study found that Black participants in North America presented to ENROLL-HD with more advanced disease than White patients. We also found that higher education was associated with less advanced disease when entering the ENROLL-HD study. The role of race/ethnicity and education in HD symptom severity warrants further investigation. These findings underscore the importance of further studying the role of social and structural determinants of health in patients with HD, particularly those from historically marginalized communities.

Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington's disease: Korean cohort data

ObjectiveTo investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort. MethodsGenetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales. ResultsPlasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables. ConclusionsThis study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD.

P.018 Oculomotor learning as a biomarker in Huntington’s Disease (HD) patients

Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder associated with cognitive, psychiatric, and motor dysfunction. As a potential behavioural biomarker, experimental tasks assessing motor learning may thus provide a reasonable assay of HD onset and progression. The saccadic adaptation paradigm is a non-invasive, accessible method of assessing rapid learning in the oculomotor system. Evidence demonstrates that the thalamus and basal ganglia are important loci for saccadic adaptation, also known to exhibit neurodegenerative pathology before the onset of clinically observable symptoms in HD. Methods: 26 early symptomatic HD patients (Total Functional Capacity Score ≥ 10/13) and sex/age-matched controls were tested on a standard saccadic adaptation task. Eye movements were measured using infrared oculography. Learning dynamics of how quickly the participants adapted their saccade metrics were analysed using state learning models. Results: Initial findings demonstrate that the learning dynamics of HD patients are slower and more variable with respect to saccade amplitude compared to controls. Conclusions: These results demonstrate that motor learning dynamics as captured by a saccadic adaptation task reveal early motor dysfunction in HD, thus providing a discriminating tool to detect early pathological changes in HD patients. Further work is needed regarding applications as a biomarker for disease progression.

Racial and Ethnic Disparities in Access to Huntington’s Disease (HD) care in North America: Analysis using the ENROLL-HD dataset (P1-11.009)

<h3>Objective:</h3> To evaluate racial and ethnic disparities in time to HD diagnosis and level of disability at the time of enrollment in ENROLL HD. <h3>Background:</h3> Given well-documented racial and ethnic disparities in access to care for neurological conditions, we were interested in evaluating disparities in access to HD care among minoritized communities in North America. <h3>Design/Methods:</h3> We used multivariate linear regression models to evaluate differences in the time from the age of symptom onset to the age of HD diagnosis. Multivariate models adjusted for age, sex, CAG repeat length, type of symptom at disease onset, education, employment status, and geographic location. To evaluate the level of disability, we analyzed racial and ethnic differences in the total functional capacity score (TFC) during the baseline visit. Multivariate linear regression models included age, sex, CAG repeat length, level of education, and geographic location. <h3>Results:</h3> Of 4717 patients in the North America region with genetically confirmed HD, 10% identified as an ethnicity other than white. The average time to HD diagnosis was 3.78 years, and the average TFC score was 10.22, consistent with Early Manifest HD Stage II. The relationship between race and ethnicity and delays in diagnosis was mostly mediated by the type of symptom at disease onset, with patients with psychiatric symptoms being diagnosed 2.43-years later than those with motor symptoms (p&lt;0.001). Black patients received an HD diagnosis 4.94 years after symptom onset, 1 year later than White Non-Hispanic patients (p=0.018). Black and Asian patients had higher disability at the time of enrollment, with TFC scores of 9.22 (p&lt;0.001) and 9.39 (p=0.067), respectively. <h3>Conclusions:</h3> Black patients with HD experience delays in HD diagnosis and enter ENROLL-HD with higher disability than other racial/ethnic groups. Additional HD studies are needed to understand the causes for delays in HD diagnosis and higher disability, and to develop interventions to reduce disparities. <b>Disclosure:</b> Dr. Mendizabal has received research support from Huntington’s Disease Society of America. Dr. Perlman has nothing to disclose. Dr. Bordelon has nothing to disclose.

The Risk of Depression in a Large Huntington Disease Population Compared With Controls: Analysis of the Enroll-HD Registry Data (P1-11.012)

<h3>Objective:</h3> To describe the risk of depression among individuals with Huntington disease (HD; manifest) versus non-HD registry controls utilizing Enroll-HD data. <h3>Background:</h3> While high rates of depression have been reported in HD, real-world data on depression risk and risk factors in individuals with versus without HD by disease stage are incomplete. <h3>Design/Methods:</h3> Enroll-HD is a global observational registry for individuals with or at risk for HD, and their relatives. Data were collected annually (2013–31 October 2020; manifest, n=10,917; non-HD, n=4996). HD stage was estimated via Total Functional Capacity (TFC) score and Shoulson-Fahn staging: TFC 7–13/stage 1–2 (early), TFC 3–6/stage 3 (middle), TFC 0–2/stage 4–5 (late). Chorea severity was measured by Total Maximal Chorea (TMC) score (TMC 0–7/mild; TMC 8–28/moderate-to-severe), and depression by the Problem Behavioral Assessment binary scale. Odds ratios (ORs) were estimated via a logistic regression model controlling for multiple risk factors. <h3>Results:</h3> Early (OR, 1.84) and middle (1.45) TFC groups were associated with significantly higher risk of depression relative to the non-HD group (both <i>P</i>&lt;.001), but not the late group (1.10; <i>P</i>&gt;.25). Depression risk was lower in moderate-to-severe versus mild chorea (0.81, <i>P</i>&lt;.001), and for higher versus lower education (0.84, <i>P</i>&lt;.001). Depression risk was higher for the following (all <i>P</i>&lt;.01): ages 31–60 versus ≤30 years (1.18), females (1.53), overweight versus normal weight (1.13), obese versus normal weight (1.19), antipsychotic agents use (1.27), antidepressant agents use (1.58), smoking (1.18), alcohol problems (1.26), and drug abuse (1.32). <h3>Conclusions:</h3> Depression risk was higher in participants with versus without HD, with an increased risk during early HD stages, even after controlling for relevant risk factors for depression. These findings emphasize the need for attention to depression in early HD. <b>Disclosure:</b> Dr. Reshef has received personal compensation for serving as an employee of Teva. The institution of Mr. Smith has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Cytel Inc.. The institution of Dr. Harari has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Cytel Inc.. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Rinat Ribalov has received personal compensation for serving as an employee of TEVA. Dr. Lengil has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Leo has received personal compensation for serving as an employee of Teva Pharmaceutical Industries. Ms. Willock has received personal compensation for serving as an employee of HCD Economics. Dr. Robles-Zurita has received personal compensation for serving as an employee of HCD Economics. Dr. Robles-Zurita has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for HCD Economics. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Michael J. Fox Foundation. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Furr-Stimming has received research support from Cures within Reach. The institution of Dr. Furr-Stimming has received research support from Huntington’s Disease Society of America. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from Sage Therapeutics. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech.

Chorea Severity Change Over Time in Huntington Disease and by Huntington Disease Stage (P1-11.010)

<h3>Objective:</h3> To describe chorea severity over time in individuals with Huntington disease (HD) stratified by Total Functional Capacity (TFC). <h3>Background:</h3> Chorea, the most common motor symptom in HD, negatively affects quality of life and TFC. Addressing chorea is crucial to reduce the burden of motor symptomatology in HD. Chorea has been reported to increase initially, plateau, and potentially decrease over time; however, longitudinal data assessing chorea severity by disease stage are limited. <h3>Design/Methods:</h3> Participants were adults from Enroll-HD, a global, longitudinal, observational registry for individuals with or at risk for HD (data cut 2013–31 October 2020). The manifest population was stratified by baseline TFC score as a proxy for HD stage (TFC 7–13/stage 1–2 [early], 3–6/stage 3 [middle], 0–2/stage 4–5 [late]). Chorea severity was assessed by Total Maximal Chorea (TMC) score at baseline and at annual visits. Patients with ≥4 years of follow-up were selected for estimating chorea progression over time. <h3>Results:</h3> The manifest population was grouped by HD stage: early, n=7441; middle, n=2330; late, n=1120. Baseline TMC scores (mean [SD]) increased as HD stage progressed (early, 8.0 [4.7]; middle, 10.4 [5.8]; late, 10.6 [6.9]). For participants with ≥4 years of follow-up (n=1271), TMC scores increased over time in early-stage HD (n=963; years 1–2, 8.5 [5.0]; years 2–3, 9.1 [5.3]; years 3–4, 9.5 [5.6]), but plateaued at high levels in middle- (n=222; 10.6 [5.3]; 10.6 [6.0]; 10.1 [5.7], respectively) and late-stage HD (n=86; 10.4 [6.6]; 9.8 [6.9]; 9.7 [6.2]). <h3>Conclusions:</h3> Chorea severity increased in early-stage HD, and plateaued in middle- and late-stage HD. Chorea severity did not decrease longitudinally in any stage; however, the limited sample size for the follow-up period should be considered. These results support the need for increased awareness about the potential for persistent chorea in late-stage HD. <b>Disclosure:</b> Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Michael J. Fox Foundation. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Furr-Stimming has received research support from Cures within Reach. The institution of Dr. Furr-Stimming has received research support from Huntington’s Disease Society of America. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from Sage Therapeutics. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Reshef has received personal compensation for serving as an employee of Teva. Ms. Willock has received personal compensation for serving as an employee of HCD Economics. Rinat Ribalov has received personal compensation for serving as an employee of TEVA. Miss Brighton has nothing to disclose. Dr. Leo has received personal compensation for serving as an employee of Teva Pharmaceutical Industries.

Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases.

Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases.

The effects of antidepressants on depressive symptoms in manifest Huntington's disease

ObjectiveCurrently there is little evidence to guide the treatment of depression in Huntington's disease (HD). The primary objective was to determine the effectiveness of antidepressant medications on lowering depressive symptom scores in patients with manifest HD. The secondary objective was to determine the effect of antidepressant use on measures of disease progression. MethodsAfter retrospectively identifying motor-manifest HD participants with at least borderline depressive symptoms from the Enroll-HD database, 86 new users of antidepressant medication were exact matched with non-users on depression score, and matched on propensity scores developed using age, sex, CAG repeat length, anxiety scores, and disease progression measures. Linear mixed effect models were used to assess the change in depression scores, anxiety scores, and disease progression measures based on antidepressant use between two visits approximately one-year apart. ResultsThere was no significant difference in the change in depression score between antidepressant users and non-users (p = 0.46). There were also no significant differences in the change in total motor score (p = 0.88), total functional capacity score (p = 0.16), number correct on the symbol digit modality test (p = 0.49), or anxiety score (p = 0.68). ConclusionsInitiation of antidepressant medication was not associated with a greater reduction in depressive symptoms or changes in other symptoms when compared to non-use. The findings of this study support further research on the effectiveness of antidepressants in Huntington's disease patients. Clinical trials or studies with a larger sample of new antidepressant users should be used to assess the causal effects of antidepressant medications on depressive symptoms.

The Huntington’s Disease Health Index: Initial Evaluation of a Disease-Specific Patient Reported Outcome Measure

When developed properly, disease-specific patient reported outcome measures have the potential to measure relevant changes in how a patient feels and functions in the context of a therapeutic trial. The Huntington's Disease Health Index (HD-HI) is a multifaceted disease-specific patient reported outcome measure (PROM) designed specifically to satisfy previously published FDA guidance for developing PROMs for product development and labeling claims. In preparation for clinical trials, we examine the validity, reliability, clinical relevance, and patient understanding of the Huntington's Disease Health Index (HD-HI). We partnered with 389 people with Huntington's disease (HD) and caregivers to identify the most relevant questions for the HD-HI. We subsequently utilized two rounds of factor analysis, cognitive interviews with fifteen individuals with HD, and test-retest reliability assessments with 25 individuals with HD to refine, evaluate, and optimize the HD-HI. Lastly, we determined the capability of the HD-HI to differentiate between groups of HD participants with high versus low total functional capacity score, prodromal versus manifest HD, and normal ambulation versus mobility impairment. HD participants identified 13 relevant and unique symptomatic domains to be included as subscales in the HD-HI. All HD-HI subscales had a high level of internal consistency and reliability and were found by participants to have acceptable content, relevance, and usability. The total HD-HI score and each subscale score statistically differentiated between groups of HD participants with high versus low disease burden. Initial evaluation of the HD-HI supports its validity and reliability as a PROM for assessing how individuals with HD feel and function.

Negative symptoms in Huntington's disease.

Apathy is the commonest psychiatric manifestation in Huntington's disease (HD). We investigated negative psychiatric symptoms-as determined by the Scale for the Assessment of Negative Psychiatric Symptoms (SANS)-in early and intermediate HD patients, hypothesizing that such symptoms would be prominent and constitute a more comprehensive and clinically relevant assessment than apathy alone. We also assessed relations between negative symptoms and disease stage, mood, motor, and cognitive disturbances. Thirty-five stage 1 and twenty-nine stage 2 consecutive adult HD outpatients were administered SANS; the Scale for the Assessment of Positive Psychiatric Symptoms (SAPS); the motor section of the Unified Huntington's Disease Rating Scale (UHDRS); Total Functional Capacity (TFC); and instruments to assess cognition, anxiety, and depression. The groups had similar age, education, and CAG length. Scores on the Hamilton depression and anxiety scales, and SAPS were similar. Negative symptoms were pervasive in the entire series. Illness duration, UHDRS, TFC, cognition, and SANS scores were significantly worse in stage 2. Mini Mental State Examination (MMSE) and SAPS scores were significantly (multiple regression) associated with SANS score, while Hamilton depression and UHDRS scores were not. SANS score was also associated with stage after removing the cognition-related domains of alogia and attention. Negative symptoms are pervasive in HD but more severe in stage 2. The associations of SANS with MMSE and SAPS suggest impaired cognition and thinking as important in generating negative symptoms. SANS appears useful for revealing a wide range of negative symptoms in HD.

Cognitive Reserve in Early Manifest Huntington Disease Patients: Leisure Time Is Associated with Lower Cognitive and Functional Impairment.

We focused on Cognitive Reserve (CR) in patients with early Huntington Disease (HD) and investigated whether clinical outcomes might be influenced by lifetime intellectual enrichment over time. CR was evaluated by means of the Cognitive Reserve Index questionnaire (CRIq), an internationally validated scale which includes three sections: education, working activity, and leisure time. The clinical HD variables were quantified at three different time points (baseline-t0, 1 year follow up-t1 and 2 years follow up-t2) as per the Unified Huntington’s Disease Rating Scale (UHDRS), an internationally standardized and validated scale including motor, cognitive, functional and behavioral assays. Our sample consisted of 75 early manifest patients, withclinical stage scored according to the Total Functional Capacity (TFC) scale. Our correlational analysis highlighted a significant inverse association between CRIq leisure time (CRIq_LA) and longitudinal functional impairment (namely, the differential TFC score between t2 and t0 or ΔTFC) (p < 0.05), and the multidimensional progression of HD as measured by the composite UHDRS (cUHDRS, p < 0.01). CRIq_LA was significantly and positively associated with better cognitive performances at all time points (p < 0.05). Our results suggest that higher is the CRIq_LA, milder is the progression of HD in terms of functional, multidimensional and cognitive outcome.

Sleep disturbances by disease type and stage in Huntington's disease

IntroductionSleep disturbances are a common symptom in patients with Huntington's disease (HD). However, it is unclear when in the disease course of HD sleep disturbances become more frequent compared to the general population. This study investigated the frequency and odds of developing sleep disturbances between adults with HD or at-risk for HD and non-HD controls. MethodsParticipants from the Enroll-HD study were split by both disease type and disease severity using CAG length, diagnostic confidence level, and total functional capacity score. Multivariate logistic regression was used to calculate odds ratios adjusted for age, sex, tobacco and alcohol use, depression and psychosis scores, and cognition to compare HD groups to non-HD controls. Cox proportional hazards models and Kaplan Meier curves were used to determine differences in probabilities of developing sleep disturbances and how sleep disturbances are related to age at motor onset. ResultsThere were significant differences between HD participants and non-HD controls in both the disease type and disease stage analyses (p < 0.001). The odds of a sleep disturbance increased with worsening disease stage and was highest in those with juvenile HD. The development of a sleep disorder in manifest HD participants was observed to be around the time of disease onset. ConclusionsSleep disturbances are more frequent in HD patients than those without HD. There are also differences based on disease type and stage. This is supplemented by the finding that the onset of sleep disturbances occurs near the time of motor onset of HD.

High Frequency of Concomitant Bladder, Bowel, and Sexual Symptoms in Huntington's Disease: A Self-Reported Questionnaire Study.

Huntington’s disease (HD) can be associated with pathologic involvement beyond the striatum including the autonomic nervous system. Bladder, bowel, and sexual dysfunction have been reported independently in HD, but little is known about their concomitant occurrence. To document this concomitant phenomena, forty-eight subjects (54% male, ages 28–74 years, CAG repeat 38–61) with manifest/symptomatic HD completed detailed questionnaires regarding bladder, bowel, and sexual function. In total, 45 subjects (93.8%) reported symptoms in at least one organ system (bladder, bowel, or sexual), 13 (27.1%) reported symptoms in two systems, and 19 (39.6%) reported concomitant symptoms in all three systems. Urinary problems were most frequent in 42 subjects (87.5%) followed by lower bowel (60.4%) and sexual dysfunction (56.2%). Participants reporting concomitant symptoms were more likely to have longer duration of disease and lower Total Functional Capacity (TFC) scores. This study documents the high frequency of bladder, bowel, and sexual dysfunction in HD and the common occurrence of concomitance of these pelvic organ problems.

The Effect of Education on Symptom Onset and Severity of Huntington's Disease.

Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Little is known about the effects of environmental factors on HD symptom onset and severity. To evaluate the relationship between education level and age of diagnosis, symptom onset, and symptom severity in HD. This study evaluated 4537 adult-onset, motor-manifest HD participants from the Enroll-HD global registry. Education level was assessed using International Standard Classification of Education categories, stratified into three education groups corresponding to pre-secondary, secondary, and post-secondary educational attainment. Motor and behavioral symptoms of HD, cognition, and functional capacity were measured using baseline Unified Huntington's Disease Rating Scale (UHDRS), Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), verbal fluency, and Stroop assessments. After adjusting for CAG repeats, higher level of education predicted lower age of onset of motor symptoms, depression, irritability, and cognitive impairment (all P-values < 0.001). After adjusting for age of enrollment and CAG repeats, the highest education level predicted the lowest UHDRS motor scores, higher UHDRS total functional capacity and functional assessment scores, and higher SDMT, MMSE, verbal fluency, and Stroop assessment scores (all P-values < 0.001). HD participants with higher education levels have earlier age of diagnosis and age of symptom onset, but lower motor exam scores and higher functional assessment scores. Earlier recognition of symptoms in more highly educated participants may explain earlier symptom onset and diagnosis. Better performance on motor and functional assessments may be explained by higher cognitive reserve in those with greater education.

Association of CAG Repeat Length in the Huntington Gene With Cognitive Performance in Young Adults.

To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington disease (HD), we performed a cross-sectional analysis of the Enroll-HD database. We analyzed data from young, developing adults (≤30 years of age) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene expansion (CAG ≥36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, and a total motor score of <10 and had to be >28.6 years from their predicted motor onset. We performed regression analyses to investigate the nonlinear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level. There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference test scores. There were significant negative relationships between CAG repeat length and scores on Parts A and B of the Trails Making Test (p < 0.05), indicating that longer CAG repeat lengths were associated with better performance. An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathologic CAG ranges were associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development. This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.

Altered Gut Microbiota Related to Inflammatory Responses in Patients With Huntington's Disease.

Emerging evidence indicates that gut dysbiosis may play a regulatory role in the onset and progression of Huntington’s disease (HD). However, any alterations in the fecal microbiome of HD patients and its relation to the host cytokine response remain unknown. The present study investigated alterations and host cytokine responses in patients with HD. We enrolled 33 HD patients and 33 sex- and age- matched healthy controls. Fecal microbiota communities were determined through 16S ribosomal DNA gene sequencing, from which we analyzed fecal microbial richness, evenness, structure, and differential abundance of individual taxa between HD patients and healthy controls. HD patients were evaluated for their clinical characteristics, and the relationships of fecal microbiota with these clinical characteristics were analyzed. Plasma concentrations of interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were measured by Meso Scale Discovery (MSD) assays, and relationships between microbiota and cytokine levels were analyzed in the HD group. HD patients showed increased α-diversity (richness), β-diversity (structure), and altered relative abundances of several taxa compared to those in healthy controls. HD-associated clinical characteristics correlated with the abundances of components of fecal microbiota at the genus level. Genus Intestinimonas was correlated with total functional capacity scores and IL-4 levels. Our present study also revealed that genus Bilophila were negatively correlated with proinflammatory IL-6 levels. Taken together, our present study represents the first to demonstrate alterations in fecal microbiota and inflammatory cytokine responses in HD patients. Further elucidation of interactions between microbial and host immune responses may help to better understand the pathogenesis of HD.