Stefan Bohlen

Grasping Premanifest Huntington's Disease - Shaping New Endpoints for New Trials

Future clinical trials in subjects with premanifest Huntingtons disease (preHD) may depend on the availability of biomarkers. It was previously shown in symptomatic HD that, the grip force variability coefficient‐of‐variation (GFV‐C) in a grasping paradigm was correlated to the Unified‐Huntingtons‐Disease‐Rating‐Scale‐Total‐Motor‐Score (UHDRS‐TMS) and increased in a 3 year follow‐up study. To further elucidate its potential as a biomarker, we investigated whether GFV‐C is able to detect a motor phenotype in preHD and is correlated to the genotype assessed by a disease‐burden‐score. The ability of preHD (n = 15) and symptomatic HD subjects (n = 20) to maintain stable grip forces, while holding an object (250 g and 500 g), was measured and compared with the controls (n = 19). GFV‐C was increased in preHD at 500 g, in symptomatic subjects at both weights and was correlated to the disease‐burden‐score and UHDRS‐TMS. GFV‐C may be a useful objective and quantitative marker of motor dysfunction across genetically diagnosed premanifest and symptomatic HD subjects.

Assessment of involuntary choreatic movements in Huntington's disease--toward objective and quantitative measures.

Objective measures of motor impairment may improve the sensitivity and reliability of motor end points in clinical trials. In Huntingtons disease, involuntary choreatic movements are one of the hallmarks of motor dysfunction. Chorea is commonly assessed by subitems of the Unified‐Huntingtons Disease Rating Scale. However, clinical rating scales are limited by inter‐ and intrarater variability, subjective error, and categorical design. We hypothesized that assessment of position and orientation changes interfering with a static upper extremity holding task may provide objective and quantitative measures of involuntary movements in patients with Huntingtons disease. Subjects with symptomatic Huntingtons disease (n = 19), premanifest gene carriers (n = 15; Unified‐Huntingtons Disease Rating Scale total motor score ≤ 3), and matched controls (n = 19) were asked to grasp and lift a device (250 and 500 g) equipped with an electromagnetic sensor. While subjects were instructed to hold the device as stable as possible, changes in position (x, y, z) and orientation (roll, pitch, yaw) were recorded. These were used to calculate a position index and an orientation index, both depicting the amount of choreatic movement interfering with task performance. Both indices were increased in patients with symptomatic Huntingtons disease compared with controls and premanifest gene carriers for both weights, whereas only the position index with 500 g was increased in premanifest gene carriers compared with controls. Correlations were observed with the Disease Burden Score based on CAG‐repeat length and age and with the Unified‐Huntingtons Disease Rating Scale. We conclude that quantitative assessment of chorea is feasible in Huntingtons disease. The method is safe, noninvasive, and easily applicable and can be used repeatedly in outpatient settings. A use in clinical trials should be further explored in larger cohorts and follow‐up studies.

Tongue Force Analysis Assesses Motor Phenotype in Premanifest and Symptomatic Huntington's Disease

Motor symptoms in Huntingtons Disease (HD) are commonly assessed by the Unified Huntingtons Disease Rating Scale‐Total Motor Score (UHDRS‐TMS). However, the UHDRS‐TMS is limited by interrater variability, its categorical nature, and insensitivity in premanifest subjects. More objective and quantitative measures of motor phenotype may complement the use of the UHDRS‐TMS as outcome measure and increase the power and sensitivity of clinical trials. Deficits in tongue protrusion are well acknowledged in HD and constitute a subitem of the UHDRS‐TMS. We, therefore, investigated whether objective and quantitative assessment of tongue protrusion forces (TPF) provides measures that (1) correlate to the severity of motor phenotype detected in the UHDRS‐TMS in symptomatic HD, (2) detect a motor phenotype in premanifest HD gene‐carriers, and (3) exhibit a correlation to the genotype as assessed by a disease burden score (based on CAG‐repeat length and age). Using a precalibrated force transducer, the ability of premanifest gene carriers (n = 15) and subjects with symptomatic HD (n = 20) to generate and maintain isometric TPF at three target force levels (0.25, 0.5, and 1.0 N) was assessed and compared with age‐matched controls (n = 20) in a cross‐sectional study. Measures of variability of TPF and tongue contact time distinguished controls, premanifest, and symptomatic HD groups and correlated to the UHDRS‐TMS and disease burden score, suggesting a strong genotype‐phenotype correlation. Group distinction was most reliable at the lowest target force level. We conclude that assessment of TPF may be a useful objective and quantitative marker of motor dysfunction in premanifest and symptomatic HD.

A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers

Putaminal metabolites examined using cross‐sectional magnetic resonance spectroscopy (MRS) can distinguish pre‐manifest and early Huntingtons Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty‐four participants (30 controls, 25 pre‐manifest HD, 29 early HD) recruited as part of TRACK‐HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK‐HD motor assessment. Statistical analyses included linear regression and one‐way analysis of variance (ANOVA). At all time‐points N‐acetyl aspartate and total N‐acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre‐manifest HD than in controls, whereas the gliosis marker myo‐inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross‐sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD‐affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi‐site assessments in large, pathologically diverse cohorts.

On the rise: Quantitative measures in Huntington's disease: Quantitative Measures In HD

On the Rise: Quantitative Measures in Huntington’s Disease We read with interest the article by Casula and colleagues titled “Motor Cortex Synchronization Influences the Rhythm of Motor Performance in Premanifest Huntington’s Disease.” We are pleased to see that the sensitivity provided by raterindependent objective and quantitative-motor (Q-Motor) measures helps to shed light on the functional relevance of transcranial magnetic stimulation (TMS) in Huntington’s disease (HD). However, the way the authors make reference to “grip force” in different ways, for example, “grip force task,” “grip force assessment,” “grip force composite,” “grip force score,” or “grip force index” needs clarification to ensure correct interpretation and consistent terminology across studies. Both the “orientation-index” and “position-index,” which were used by the authors to create the “composite score,” are measures of involuntary choreatic movements assessed in the “choreomotography” task as reported previously. Both measures are recorded using precalibrated 3-dimensional position and orientation sensors. They do not represent “grip force.” In contrast, the assessment of “grip force” represents a different modality of motor disability in HD and is assessed in the “manumotography” task. It also tracks HD progression even in small cohorts of patients. It is recorded using force transducers and assesses isometric normal forces in the precision grip between the thumb and index finger. It is thought to serve as measure of fine motor control and coordination. We noted with interest that the Q-Motor speeded tapping measures recorded in the “digitomotography” assessment provided a sensitive measure for correlations with cortical oscillations in the theta frequency band. Casula and colleagues conclude: “participants who showed better timed motor performance also showed stronger oscillatory synchronization”—see their figure 4 showing the “Inter-TapInterval-Standard-Deviation.” This is consistent with correlations seen between speeded tapping intervals and their variability and caudate volumes, white matter volumes, cortical thickness, diffusion tensor imaging, magnetization transfer imaging, and magnetic resonance spectroscopy in HD. Tapping is thought to represent fine motor control and coordination with a strong link to voluntary motor function. In contrast, it is misleading that the authors concluded the following: “However, there were no correlations of any of the TMS/EEG measures with composite grip force.” As outlined previously, the authors created a composite chorea and not grip force score. Although the creation of this composite has limitations in itself, for example, because the dynamics of these measures may not always be aligned and dimensions are different, chorea may involve other brain circuits than grip force control. In fact, it would be interesting to correlate the TMS/EEG measures to “grip force variability,” which should show a correlation if the conclusions about variability drawn from the tapping observations are robust and more generalizable. In any case, this study supports a link between TMS and Q-Motor measures in HD. Because Q-Motor data in this project was analyzed in our institute blinded without access to patient characteristics, this further supports the validity of the observations and conclusions. Interestingly, Q-Motor speeded tapping detected changes in HD mutation carriers years before clinical diagnosis in cross sectional and longitudinal settings, which in this context should encourage the exploration of TMS in premanifest mutation carriers.

F06 When and how does manifest hd begin? a comparison of age at onset of motor and non-motor symptoms

Background In his classical paper, George Huntington described movement disorder and psychiatric symptoms. In 1915, Davenport described ‘a biotype in which the tremors are absent but mental deterioration present’. In 1921, Entres used the term ‘chorea sine chorea’ to depict onset of HD without motor symptoms. Until today diagnosis of HD without overt motor symptoms is an unmet need. Aims Present corroborated data on age at onset and onset of clinical symptoms (motor, cognitive, behavioral) as available form charts of patient seen at the GHI out-patient clinic. Methods/techniques SPSS analysis of age at onset of symptoms of 260 symptomatic HD patients (DCL=4) available for analysis at GHI before December 2017. Results/outcome In those 260 patients both age at diagnosis and at onset of motor symptoms was documented. In 10 patients of this group, HD was diagnosed in an external center before documented motor onset. In 9 of these cases, diagnosis was established within 1 year after motor onset. Depression was documented in 196 of the 260 patients. Depression was present in 32% before the onset of motor symptoms and was the symptom that appeared more frequently before motor symptoms than any other symptom. Cognitive problems were documented in 211 cases, but occurred in only 15% before the onset of motor symptoms. Conclusion New guidelines are needed to enable clinicians to provide adequate care early and establish a reliable diagnosis of HD in the absence of overt motor symptoms, permitting access to health care support.

F65 Mobile sensor-based gait analysis provides objective motor assessments in huntington’s disease

Background Gait disturbance plays an important role for quality of life in patients with Huntington’s disease (HD). Measuring gait parameters in patients with HD is essential for the objective assessment of motor impairments and potential beneficial effects of future treatments. Aims A mobile sensor-based gait analysis system was used to objectively assess specific features of gait in HD patients compared to healthy controls. Moreover, these measures were correlated to the clinical scores UDHRS Total Motor Score (TMS) and Total Functional Capacity (TFC). Methods 50 HD patients at two German sites were included in the study and received standardized clinical assessments during their annual ENROLL-HD visit. In addition, HD patients and a cohort of age- and gender matched healthy controls performed defined gait tests consisting of a 4 × 10 m walk, the 2-Minute-Walk-Test, and the Timed Up and Go Test (TUG). The mobile gait analysis system utilized inertial sensors attached to both shoes. Spatio-temporal gait parameters were calculated by machine learning algorithms. Results Specific gait parameters such as stride length and gait velocity were severely reduced, stride and stance time were significantly increased in patients with HD compared to healthy controls. Parameters describing gait variability were significantly altered in HD subjects and showed strong correlations to TMS and TFC. The objective gait measurements reflected disease stage according to TFC. In contrast, correlations of functional measures (e.g. TUG) were notably weaker. Conclusions Mobile gait analysis objectively supports the identification of specific features of motor impairment in HD for future clinical trials.

Objective assessment of gait and posture in premanifest and manifest Huntington disease — A multi-center study

BACKGROUND Deficits in posture and gait are known to contribute to the complex motor phenotype of Huntington disease (HD). Objective and quantitative measures of posture and gait provided by posturography and GAITRite® assessments may supplement categorical rating scales such as the UHDRS-TMS and increase power and sensitivity of clinical trials. OBJECTIVES To investigate whether posturography and GAITRite® measures reveal (1) changes in manifest or premanifest HD mutation-carriers, (2) a correlation to the UHDRS-TMS and functional measures in manifest HD, and (3) a correlation to the disease-burden-score (based on CAG-repeat-length and age). METHODS Posturography and GAITRite® were applied in premanifest (n = 26) and manifest HD gene-mutation-carriers (n = 40) in different paradigms compared to age-matched controls (n = 30) in a cross-sectional multi-site study conducted in three centers. Subjects were assessed clinically with the UHDRS Total-Motor-Score, Total-Functional-Capacity and Functional-Assessment-Scale. RESULTS Several posturography measures were able to discriminate between controls, premanifest, and manifest mutation-carriers in both conditions assessed. Only one GAITRite® measure separated controls and premanifest participants, while discrimination between controls and manifest same as between premanifest and manifest participants was possible in several measures. Correlation with all clinical measures was seen in only one measure per device while correlations to the disease-burden-score seen in posturography only. CONCLUSION Overall the results suggests that posturography detects alterations in premanifest and manifest mutation-carriers more reliably than GAITRite® measures. Correlations with clinical assessment scores are limited; correlation with disease-burden-score is seen in posturography only. Data acquisition and analysis was easier with posturography than GAITRite® assessments in out-patient settings.

M4 Safety and tolerability of BN82451B in huntington’s disease

Background BN82451B is a small, orally active molecule with good CNS penetration. Preclinical studies in tgHD R6/2 mice suggested improved motor function and prolonged survival. In addition antidyskinetic activity was observed in other models. The proposed mechanisms of action (MOA) are (1) antiexcytotoxic due to a sodium channel blocking potential, (2) antioxidant, (3) anti-inflammatory due to a cyclooxygenase (COX) inhibitory potential and (4) mitochondrial protective. Aims The primary objective of this phase 2a study (NCT02231580) is to investigate the safety and tolerability of BN82451B bid versus placebo for 28 days in male HD subjects. Secondary objectives include assessment of pharmacokinetics and of pharmacodynamics via the effects on quantitative motor (Q-Motor) measures. UHDRS subscales are implemented as exploratory measures. Methods Subjects: We intend to recruit 30 male HD subjects. 24 receive BN82451B and 6 placebo. The study is conducted in an inpatient setting at a single phase I unit in Germany. Design A sequential design was chosen to enable dose escalation starting with 40 mg bid with a potential maximum dose of 80 mg bid. Three subsequent cohorts of 10 patients each are randomised with different starting doses. Subjects in group one are treated with 40 mg bid for 14 days and may be increased to 60 mg bid the subsequent 14 days. In group 2, subjects may first receive 60 mg bid with possible increase to 80 mg bid. Group 3 subjects may receive 80 mg bid for 28 days. Dose increases in the consecutive groups are subject to approval by a Data Review Committee (DRC). The decision to increase the dose in individual patient will be based on the investigator’s judgement. Results Results of the study are expected for Q4/2016. Conclusions Recruitment in this trial is difficult as in-patient periods of nearly one month are logistically challenging. Safety data will be available soon and pharmacodynamics readouts such as Q-motor measures may help to guide decisions on the further path of development of BN82451B.

FDG μPET Fails to Detect a Disease-Specific Phenotype in Rats Transgenic for Huntington's Disease – A 15 Months Follow-up Study

BACKGROUND FDG-PET detects hypometabolism in premanifest and symptomatic Huntingtons disease (HD). A cross-sectional study suggested that whole-brain FDG-PET is capable to detect a phenotype in transgenic (tg) HD rats. Recently, a longitudinal follow-up study showed no FDG-PET changes in tgHD rats. Both studies applied small sample sizes and analysis was limited to whole-brain or striatum. OBJECTIVE We therefore performed a follow-up study in a larger cohort of tgHD and wild-type (wt) rats encompassing several pre-defined regions of interest (ROIs) and hypothesis free voxel-by-voxel SPM analysis to clarify whether FDG-PET can detect a phenotype in tgHD rats and to determine onset …and effect sizes of changes over time. METHODS N = 19 tgHD- and n = 20 wt-rats, mixed gender, were included. Repeated small animal FDG-μPET and MRI were performed at 5,10,15, and 20 months of age. ROIs encompassing entire brain, cortex, striatum, thalamus, subventricular-zone, and cerebellum were placed manually on the MRI and transferred to the co-registered μPET. Mean and maximal FDG-PET activities within ROIs were calculated and normalized to cerebellar FDG uptake. Activity and spatially normalized FDG-μPET were compared between groups on a hypothesis-free voxel-by-voxel basis using SPM. RESULTS FDG uptake showed changes over time in both tgHD- and wt-rats, however, there was no consistent difference between tgHD- and wt-rats in both the manual ROI and SPM analysis. CONCLUSIONS In this transgenic rat model of HD FDG-μPET imaging does not detect significant alterations at the ages investigated. Further investigations are warranted employing other age groups and alternative imaging biomarkers for neuronal degeneration, respectively.