Functional and cognitive capacity differ in dystonic motor subtypes when compared to choreatic and hypokinetic‐rigid motor subtypes in Huntington's disease

Abstract Background Motor phenotypes in Huntington's disease vary manifold. Phenotype classification is essential to adapt treatment. The aim of this study was to classify a dystonic subtype closer. Methods A total of 7,512 manifest ENROLL‐HD participants were subdivided into mainly choreatic (N = 606), dystonic (N = 402), and hypokinetic‐rigid (N = 369) subjects. Cognitive (verbal fluency, symbol digit, stroop color, trail making, Mini‐Mental State Examination), functional (total functional capacity, Independence Scale), and psychiatric (problem behaviors assessment, Hospital Anxiety and Depression Scale) performance was evaluated at baseline visit. Results Symptoms onset for dystonic were similar to hypokinetic‐rigid, but earlier compared to choreatic subjects (p < .001). Cognition was better in both groups compared to hypokinetic rigid (all p < .001). Functionality differed between all groups (all p < .001). Differences remained (all p < .001) after controlling for CAP score, CAG, age, disease duration, and education. Conclusions Motor subtypes differ in functional and cognitive capacities but less in psychiatric. We identified better cognitive and functional capacities and similar onsets in predominant dystonic compared to hypokinetic‐rigid patients.

. More recently, Hart et al. (2013) focused on aspects of predominant choreatic versus hypokinetic-rigid motor phenotypes and described a better capacity for global and cognitive functioning of their choreatic group.
So far only a few smaller studies investigated the role of dystonia in HD (Mahant et al., 2003;Zande et al., 2017). Zande et al. (2017) described a high prevalence of dystonia as being a late symptom correlating with increasing HD stage and disease duration. In addition, a strong relationship with functional status of dystonia and rigidity was described (Carlozzi et al., 2019). To our knowledge, no study compared three different phenotypes with predominant dystonia, chorea, and hypokinetic-rigidity which are essential for symptomatic treatments (Saft, von Hein, & Lucke, 2018;Wojtecki, Groiss, & Ferrea, 2015;Zittel et al., 2018). For a better understanding, we investigated whether there are collectives in the European Huntington's Disease Network ENROLL-HD study classified as predominant choreatic, dystonic, and hypokinetic-rigid in order to compare cognitive, functional, and psychiatric performance data (Landwehrmeyer, Fitzer-Attas, & Giuliano, 2017). We hypothesize a better cognitive functioning of a choreatic and dystonic group when compared to a hypokinetic-rigid group and possibly more depression due to pain in our dystonic subgroup.
Enroll-HD is a global clinical research platform designed to facilitate clinical research in Huntington's disease. Core datasets are collected annually from all research participants as part of this multicentre longitudinal observational study. Data are monitored for quality and accuracy using a risk-based monitoring approach. All sites are required to obtain and maintain local ethical approval.
For subdividing predominant motor phenotypes, sum scores were calculated according to Hart et al. (2013) Scores had to differ by at least one standard deviation compared to the entire cohort.
Classification of predominant choreatic (N = 606) due to chorea scale and hypokinetic-rigid (N = 369) due to hypokinetic-rigidity with finger taps, pronate-supinate hands, bradykinesia, and rigidity, phenotypes were identified in UHDRS motor assessment (Hart et al., 2013). Equally onset and classification of dystonia were evaluated due to items for dystonia in trunk, right, and left upper and lower extremities as part of the UHDRS motor score, and (N = 402) subjects were classified as predominant dystonic. Interference with predominant hypokinetic-rigidity and dystonia (n = 661) or smaller deviations were regarded as mixed phenotypes (n = 6,135) and excluded.
Differences among group means were assessed using ANOVA with post hoc Tukey's HSD tests in IBM SPSS Statistics V.25.
Afterward, one-way ANCOVAs were conducted determining differences between subtypes on functional and cognitive assessments controlling for CAP score (Zhang et al., 2011), CAG, age, disease duration, and education.

| RE SULTS
Significant mean differences were detected between choreatic, dystonic, and hypokinetic-rigid groups regarding all demographic parameters (all p < .001) ( Table 1). Post hoc comparisons indicated CAP score was higher, education level lower, and disease duration longer in hypokinetic compared to dystonic and choreatic group (all p < .001). The CAG mean was lower in the choreatic versus dyston and hypokinetic group (all p < .001). Comparison of age indicated that the dystonic group was younger than choreatic and hypokinetic-rigid (all p < .001).
Analysis of motoric manifestation verified a higher UHDRS-TMS for hypokinetic subjects when compared to other groups (all p < .001). The dystonic group had earlier motoric onset when compared to choreatic (p < .001) but not to hypokinetic-rigid subjects (p = .216). Comparisons of choreatic versus hypokinetic did not differ in means (p = .072). Timed onsets for the rater's estimation date of HD diagnosis and symptoms noticed by participant and family differed in same manner as described for motoric manifestation.
Differences regarding cognitive capacity revealed lower performance of hypokinetic if compared to choreatic or dystonic participants (all p < .001). Differences of the choreatic versus dystonic group were not significant except for better performance in SDMT (p < .001) and verbal fluency (180 s; p < .005).
Functional capacities differed for the UHDRS-total functional capacity (TFC) score and Independence Scale (IS) (all p < .001) detecting choreatic with better capacities compared to dystonic (all p < .005) and hypokinetic (all p < .001). Post hoc tests indicated better functionality for the dystonic versus the hypokinetic group (all p < .001).
One-way ANCOVAs determined effects in cognitive and functional scores remained significant (all p < .001) after controlling for covariates (Table 2). Controlling for the covariate CAP score indicated highest effect-changes (in partial η 2 ) compared to other covariates.

| D ISCUSS I ON
To our knowledge, this is the first study comprising data coming from a large cohort of manifest HD patients analyzing subjects with motor symptoms in terms of predominantly dystonia compared to choreatic and hypokinetic-rigid regarding their cognitive, functional, and psychiatric performance.
If compared to hypokinetic-rigids, no differences regarding onsets were observed in the dystonic group except for earlier apathy. TA B L E 1 Analysis of demographics, motoric, cognitive, functional, and psychiatric capacities in different motor subtypes Apart from an increased apathy sum score in the hypokinetic-rigid group versus the dystonic and choreatic group, we did not observe any differences in the severity of psychiatric symptoms between groups. Besides, less executive function was observed in the hypokinetic versus the choreatic group (PBA score). This is remarkable because patients with focal dystonia complained about increased psychiatric symptoms with depression, anxiety, and obsessive-compulsive disorders (Jahanshahi, 2017). We therefore initially hypothesize that dystonia may lead to more depression in HD which is however not supported by our data. Hereby, unawareness in HD patients might be a possible explanation (Hergert, Haaland, & Cimino, 2019;Hergert, Sanchez-Ramos, & Cimino, 2019;McCusker & Loy, 2014;Sitek, Thompson, Craufurd, & Snowden, 2014).
According to our data, functional status and cognition seem not primary influenced by psychiatric status.

ACK N OWLED G M ENTS
Enroll-HD is a clinical research platform and longitudinal observational study for Huntington's disease families intended to accelerate progress toward therapeutics; it is sponsored by the CHDI Foundation, a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics for HD.
Enroll-HD would not be possible without the vital contribution of the research participants and their families. We acknowledge the individuals (https://www.enrol l-hd.org/ackno wledg ments /) who contributed to the collection of the Enroll-HD data. We acknowledge support by the DFG Open Access Publication Funds of the Ruhr-Universität Bochum.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon request.