Dystonie als Faktor der funktionellen, psychiatrischen und kognitiven Beeinträchtigung beim Morbus Huntington

Der Morbus Huntington zeichnet sich durch heterogene motorische, psychiatrische und kognitive Symptome aus. Neben choreatiformen können hypokinetische und dystone Bewegungsstörungen bestehen. Im Rahmen der ENROLL-HD Studie wurden die Dystonie und zusammenhängende kognitive, funktionelle und psychiatrische Aspekte der Krankheitsmanifestation in primär-dominanten motorischen Subgruppen klassifiziert. Von 7.512 Erkrankten ließen sich drei motorische Subgruppen mit choreatiformer (n=606), dystoner (n=402) und hypokinetisch-rigider (n=369) Symptomatik identifizieren. Dystone und hypokinetisch-rigide zeigten einen ähnlichen Symptombeginn, der im Vergleich zu choreatiformen Patienten früher auftrat (p<.001). Die Kognition stellte sich in der dystonen und choreatiformen im Vergleich zur hypokinetischen Subgruppe leistungsfähiger dar (p<.001). Funktionelle Parameter unterschieden sich in allen Gruppenvergleichen (p<.001)

Modelling the effect of age, semester of study and its interaction on self-reflection of competencies in medical students

$\bf Objectives:$ Accurate self-assessment and -reflection of competencies are crucial skills for all health professions. The National Competence-Based Learning Objectives Catalogue (NKLM) guiding medical faculties in Germany points out reflection as a non-technical skill and competency-based medical education (CBME) as important approaches. In this context, the role and structure of curricula and skills labs evolved. Especially in peer-assisted trainings, reflection of competencies is important to improve self-regulated learning. Traditionally, we assume self-reflection skills to evolve automatically with learners' experience. This approach aims to find empirical evidence for this assumption and implements self-reflection of competencies in clinical skills education. Here, we quantify the influence of age and semester of study and its interaction on the concordant self-reflection of students' own competencies. $\bf Methods:$ Investigation was based on a retrospective analysis of evaluation data from peer-assisted "first aid" and "physical examination" courses in the skills labs of the medical faculty at the Ruhr-University Bochum, Germany. Participants were asked for self-assessed competencies before $\it (pre)$ and after $\it (post)$ the course. Additionally, they were asked to retrospectively re-rate their "before" competencies after completing the course $\textit {(post-pre)}$. Differences between $\it pre$ and $\textit {post-pre}$ competencies were assessed as the concordant self-reflection in a moderated regression analysis. Group means and standard deviation were depicted using univariate analysis of variance (ANOVA) with post-hoc Tukey HSD testing in $\textit {IBM SPSS Statistics V.28}$. Moderated regression and simple slope analyses were conducted to calculate interaction effects of age and semester of study on the concordant self-reflection. $\bf Results:$ As expected, participants ($\it n$ = 168) showed significant progress in subjective self-assessment ($\it pre$ vs. $\it post$) in all 18 assessed domains in the course (all $\it p$ < 0.001). Additionally, participants self-assessed their previous competencies after the course $\textit {(post-pre)}$ differently than before the course $\it (pre)$ in 11 out of 18 domains. Hereby, the interaction of age and semester of study explained a significant part of variance in the first aid course ($\Delta R^{2}$ = 0.008, $\Delta F$ (1;1020) = 8.53, $\it p$ < 0.005) and in the physical examination course ($\Delta R^{2}$ = 0.03, $\Delta F$ (1;10,280) = 10.72, $\it p$ < 0.001). $\bf Conclusions:$ We quantified that interaction of age and semester has a significant influence on concordant self-reflection skills using a moderated regression analysis. Assumed as an indicator, we conclude that advanced and older students show less differences in $\it pre-$ vs. $\textit {post-pre-ratings}$. This has implications for curriculum development, postulating that an exposure to self-reflection as a metacognitive process should be introduced early in order to train competencies in health professionals. Prospective studies with competency-based assessments are necessary to validate findings

Another perspective on Huntington’s Disease: Disease burden in family members and pre-manifest HD when compared to genotype-negative participants from ENROLL-HD

Background: In addition to the effects on patients suffering from motor-manifest Hunting-ton’s disease (HD), this fatal disease is devasting to people who are at risk, premanifest mutation-carriers, and especially to whole families. There is a huge burden on people in the environment of affected HD patients, and a need for further research to identify at-risk caregivers. The aim of our research was to investigate a large cohort of family members, in comparison with genotype negative and premanifest HD in order to evaluate particular cohorts more closely. Methods: We used the ENROLL-HD global registry study to compare motoric, cognitive, functional, and psychiatric manifestation in family members, premanifest HD, and genotype negative participant as controls. Cross-sectional data were analyzed using ANCOVA-analyses in IBM SPSS Statistics V.28. Results: Of $\it N$ = 21,116 participants from the global registry study, $\it n$ = 5174 participants had a premanifest motor-phenotype, $\it n$ = 2358 were identified as family controls, and $\it n$ = 2640 with a negative HD genotype. Analysis of variance revealed more motoric, cognitive, and psychiatric impairments in premanifest HD (all $\it p$ < 0.001). Self-reported psychiatric assessments revealed a significantly higher score for depression in family controls ($\it p$ < 0.001) when compared to genotype negative ($\it p$ < 0.001) and premanifest HD patients ($\it p$ < 0.05). Family controls had significantly less cognitive capacities within the cognitive test battery when compared to genotype negative participants. Conclusions: Within the largest cohort of HD patients and families, several impairments of motoric, functional, cognitive, and psychiatric components can be confirmed in a large cohort of premanifest HD, po-tentially due to prodromal HD pathology. HD family controls suffered from higher self-reported depression and less cognitive capacities, which were potentially due to loaded or stressful situations. This research aims to sensitize investigators to be aware of caregiver burdens caused by HD and encourage support with socio-medical care and targeted psychological interventions. In particular, further surveys and variables are necessary in order to implement them within the database so as to identify at-risk caregiver

Differential diagnosis of chorea

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of $\it n$ = 21,116 participants in ENROLL-HD, we identified $\it n$ = 10,125 motor-manifest HD patients. $\it n$ = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to $\it n$ = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger ($\it p$ < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD ($\it p$ < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all $\it p$ < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all $\it p$ < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care

Factors influencing the total functional capacity score as a critical endpoint in Huntington’s disease research

$\bf Background:$ 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. $\bf Methods:$ 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. $\bf Results:$ We identified $\it N$ = 10,314 participants as manifest HD. A significant part of variance on the TFC was explained by age ($\it {R}^{2}$ = 0.029, $\it F$ (1;10,281) = 308.02, $\it p$ < 0.001), CAG-repeat length (∆$\it {R}^{2}$ = 0.132, $\Delta$$\it F$ (1;10,280) = 1611.22, $\it p$ < 0.001), and their interaction ($\Delta$$\it {R}^{2}$ = 0.049, $\Delta$$\it F$ (1;10,279) = 634.12, $\it p$ < 0.001). The model explained altogether 20.9% of the TFC score’s variance ($\it F$ = 907.60, $\it p$ < 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. $\bf Conclusions:$ 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

Longitudinal evaluation of the effect of tricyclic antidepressants and neuroleptics on the course of Huntington's disease

$\textbf {Background:}$ Reducing the progress of neurodegeneration is a key goal in Huntington's disease (HD). A previously performed systematic screening for medications with neuroprotective features identified tricyclic antidepressants and neuroleptics as neuroprotective and mitochondrioprotective agents. Here, we analyzed the characteristics of disease manifestation, progression and potential beneficial effects in HD patients treated with afore-mentioned medications compared to un- and otherwise treated motor-manifest patients in a large real-world cohort over two years. $\textbf {Methods:}$ We analyzed cross-sectional data of the largest cohort worldwide of motor-manifest HD patients using the ENROLL-HD database, including demographic, moleculargenetic, clinical-motoric, cognitive and functional data. Longitudinal data of up to two years were obtained to analyze potential effects on disease progression between groups with different medications used. Data were analyzed using repeated ANOVA-analyses while controlling for the co-variates age and CAG-repeat length. $\textbf {Results:}$ We identified $\it n$ = 7397 motor-manifest HD patients using no or different medication (HD-ctrl) and subgroups treated with clomipramine ($\it n$ = 56), clozapine ($\it n$ = 66), chlorpromazine ($\it n$ = 17), doxepine ($\it n$ = 34) and desi-, imi- or trimipramine ($\it n$ = 19). Demographic parameters, disease onset and CAP-score did not differ. Total motor scores (TMS) at baseline were higher in patients treated with clozapine ($\it p$ < 0.001), chlorpromazine and clomipramine ($\it p$ < 0.05) compared to HD-ctrl with higher sub scores for bradykinesia (all $\it p$ < 0.01) and dystonia in clozapine treated patients ($\it p$ < 0.001). Functional and cognitive capacities were worse in medication groups in comparison to HD-ctrl at baseline ($\it p$ < 0.001). Repeated measures analysis of variance documented no differences regarding motoric, functional and cognitive disease progressions between groups. $\bf Conclusions:$ We identified group differences, potentially caused by side effects or potential selection bias in terms of bradykinetic motoric symptoms, more dystonia and lower functional and cognitive performance in some treatment groups at baseline, which were not entirely explained because of underlying fundamental characteristics. Disease progression regarding clinical, functional and cognitive outcomes over two years was not affected by any of the treatment groups compared to HD-ctrl. Our data do not support our hypothesis of a potential neuroprotective effect of these drugs on disease progression

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

$\bf Background$ 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. $\bf Methods$ A total of 7,512 manifest ENROLL‐HD participants were subdivided into mainly choreatic ($\it N$ = 606), dystonic ($\it N$ = 402), and hypokinetic‐rigid ($\it N$ = 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. $\bf Results$ Symptoms onset for dystonic were similar to hypokinetic‐rigid, but earlier compared to choreatic subjects ($\it p$ < .001). Cognition was better in both groups compared to hypokinetic rigid (all $\it p$ < .001). Functionality differed between all groups (all $\it p$ < .001). Differences remained (all $\it p$ < .001) after controlling for CAP score, CAG, age, disease duration, and education. $\bf Conclusions$ 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

Divergent effects of the nonselective adenosine receptor antagonist caffeine in pre-manifest and motor-manifest Huntington's disease

There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within $\it n$ = 21,045 participants, we identified $\it n$ = 1901 premanifest and $\it n$ = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. $\it n$ = 841 premanifest and $\it n$ = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all $\it p$ < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all $\it p$ < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all $\it p$ < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all $\it p$ < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects

Quality assessment and modulating factors on self-regulatory behavior in peer-assisted medical learning

Objectives: Standardized extracurricular skills labs courses have been developed in recent decades and are important approaches in peer-assisted medical learning (PAL). To provide high quality training and achieve effective learning strategies, continuous evaluations and quality assessments are essential. This research aims to evaluate quality data from medical students participating in extracurricular skills labs courses at Ruhr-University Bochum to prospectively optimize concepts and didactical training and standardize processes. Additionally, we set out to assess and quantify drivers that are influencing factors of the self-reflection of competencies. Methods: The analysis was based on a routine assessment of $\it n$ = 503 attendees of the PAL courses in the skills labs in three consecutive semesters, who voluntarily participated in the evaluation. We analyzed the effects of age, semester and their interaction on the self-reflection of competencies in technical skills courses using moderated regression and simple slope analyses, as previously published. A univariate analysis of variance (ANOVA) with post hoc Tukey HSD testing was used to analyze group means in estimated competencies using $\textit {IBM SPSS Statistics V.28}$. Results: An analysis of variance revealed a significant increase in self-assessed competencies when comparing $\it pre-$ vs. $\it post$-course evaluation data in all 35 depicted items $\textit {(all p < 0.001)}$. A total of 65.5% of the items were adjusted significantly differently, revealing modified self-reflected pre-course levels compared to those stated before. A moderated regression analysis revealed that age \textit {(\(R^{2} = 0.001, F(1;2347) = 1.88, p < 0.665)}\), semester of study \textit {(\(\Delta$R^{2}$ = 0.001, $\Delta$F (1;2346) = 0.012, p < 0.912)}\) and their interaction \textit {(\(\Delta$R^{2}$ = 0.001, $\Delta$F (1;2345) = 10.72, p < 0.227)}\) did not explain a significant amount of the variance in self-reflection variance. A simple slope analysis of earlier $\textit {(b = 0.07, t = 0.29, p < 0.773)}$ and later semesters of study $\textit {(b = 0.06, t = 0.07, p < 0.941)}$ did not differentiate from zero. Conclusions: The presented evaluation paradigm proved to be a useful tool to encourage students to initiate self-regulatory and self-reflective behavior. The cohesive evaluation of the large cohort of attendees in extracurricular, facultative skills labs courses was helpful in terms of quality assessments and future adaptations. Further evaluation paradigms should be implemented to assess other influencing factors, such as gender, on self-reflection, since age and semester did not explain significant differences in the model

Positive effect of immunomodulatory therapies on disease progression in Huntington’s disease?

$\bf Background:$ The role of neuroinflammation and autoimmune processes in neurodegenerative diseases is not fully understood. Activation of microglia with expression of proinflammatory cytokines supports the hypothesis that immune processes may play an important role in the pathophysiology of Huntington’s disease (HD) and thus, immunomodulating therapies might have potential neuroprotective properties. Until now, no disease-modifying therapy (DMT) is available for HD. $\bf Objective:$ The aim of this research was to characterize a cohort of patients suffering from both HD and autoimmune demyelinating diseases of the central nervous system (classified as G35-37 in ICD-10; ADD-CNS) in comparison to HD cases without ADD-CNS. In particular, we were interested to investigate potential modulating effects on disease manifestation and progression of HD over time of prescribed immunomodulating medications (DMT). $\bf Methods:$ We analyzed the course of HD regarding motoric, functional, and cognitive aspects, using longitudinal data of up to 2 years from the worldwide registry study ENROLL-HD. Additional cross-sectional data in the largest cohort worldwide of HD patients was analyzed using demographic and molecular genetic parameters. Data were analyzed using analysis of variance (ANOVA) for cross-sectional and repeated-measures ANOVA for longitudinal parameters in IBM SPSS Statistics V.27. $\bf Results:$ Within the ENROLL-HD database, we investigated $\it N$ = 21,116 participants and identified $\it n$ = 60 participants suffering from ADD-CNS. Molecular, genetic, and demographic data did not differ between groups. The subgroup of $\it n$ = 32 participants with motor-manifest HD revealed better cognitive performance in five out of eight cognitive tests at baseline with less progression over time in two tests (all $\it p$ < 0.05). Differentiation between DMT-treated and untreated patients revealed better cognitive and motor performance in the DMT group; those patients, however, tended to be younger. Pre-manifest HD patients simultaneously diagnosed with ADD-CNS ($\it n$ = 12) showed lower functional scores and more decline over time when compared with other pre-manifest HD ($\it p$ < 0.05). $\bf Conclusion:$ Patients suffering from motor-manifest HD and simultaneously from ADD-CNS have better cognitive capacities compared with other motor-manifest HD patients. Moreover, DMTs might have beneficial effects on progression of neurodegeneration including the motor phenotype. However, this effect might have been biased by younger age in DMT-treated patients. Pre-manifest HD patients showed more functional impairment as expected due to their additional ADD-CNS disease