Herwig W. Lange

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.

Huntington's Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem

Huntingtons disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer‐specific neuronal loss in the cerebral neo‐and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post‐mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well‐understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.

Huntington's disease: Objective assessment of posture—A link between motor and functional deficits†‡

Postural deficits in Huntingtons disease are linked to functional impairment. We investigated whether assessment of center‐of‐mass variability using posturography provides objective and quantitative measures that correlate to the severity of motor phenotype, functional measures, and genotype as assessed by a disease burden score (based on repeat length and age). In addition, we investigated whether withdrawing visual feedback facilitates the detection of postural deficits.

Huntington's Disease (HD): Neurodegeneration of Brodmann's Primary Visual Area 17 (BA17)

Huntingtons disease (HD), an autosomal dominantly inherited polyglutamine or CAG repeat disease along with somatomotor, oculomotor, psychiatric and cognitive symptoms, presents clinically with impairments of elementary and complex visual functions as well as altered visual‐evoked potentials (VEPs). Previous volumetric and pathoanatomical post‐mortem investigations pointed to an involvement of Brodmanns primary visual area 17 (BA17) in HD. Because the involvement of BA17 could be interpreted as an early onset brain neurodegeneration, we further characterized this potential primary cortical site of HD‐related neurodegeneration neuropathologically and performed an unbiased estimation of the absolute nerve cell number in thick gallocyanin‐stained frontoparallel tissue sections through the striate area of seven control individuals and seven HD patients using Cavalieris principle for volume and the optical disector for nerve and glial cell density estimations. This investigation showed a reduction of the estimated absolute nerve cell number of BA17 in the HD patients (71 044 037 ± 12 740 515 nerve cells) of 32% in comparison with the control individuals (104 075 067 ± 9 424 491 nerve cells) (Mann–Whitney U‐test; P < 0.001). Additional pathoanatomical studies showed that nerve cell loss was most prominent in the outer pyramidal layer III, the inner granular layers IVa and IVc as well as in the multiform layer VI of BA17 of the HD patients. Our neuropathological results in BA17 confirm and extend previous post‐mortem, biochemical and in vivo neuroradiological HD findings and offer suitable explanations for the elementary and complex visual dysfunctions, as well as for the altered VEP observed in HD patients.

Huntington's Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem: The Brainstem in Huntington's Disease

Huntingtons disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer‐specific neuronal loss in the cerebral neo‐and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post‐mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well‐understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.

Huntington's Disease (HD)

Huntingtons disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer‐specific neuronal loss in the cerebral neo‐and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post‐mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well‐understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.

I07 Impaired isometric force coordination in Huntington's disease

Background Assessment of motor phenotype and diagnosis of Huntingtons Disease (HD) are based on the Unified HD Rating Scale-Total Motor Score, a categorical scale. We have previously shown that impairments in tongue protrusion forces can be seen in premanifest and manifest HD and correlate with clinical severity as assessed by the Unified HD Rating Scale-Total Motor Score and the disease burden score (Reilmann et al. 2010). In this study we aimed to investigate whether similar impairments of force coordination can be found in different force matching tasks. Objective To assess whether impairments in isometric force coordination of the upper and lower extremities can be detected in manifest HD gene carriers compared to controls. Methods Using a precalibrated force transducer, the ability of subjects with symptomatic HD (n=31) to generate and maintain isometric TPF at different target force levels (1.5, and 5.0 N for thumb, 1.0, 5.0 and 10.0 N for big toe) was assessed and compared with age-matched controls (n=22) in a cross-sectional pilot study. Results All paradigms distinguish controls from symptomatic subjects. The static coefficient of variability (%), assessing the degree of deviation from the target force normalised to the mean force, was the most robust measure in all matching trials. Comparisons between tasks and correlations with clinical measures such as the TMS, DBS and TFC will be presented. Conclusions Assessment of force matching tasks by hand and feet may provide quantitative objective measures for severity of motor phenotype in symptomatic HD.

F15 Balance control in Huntington's disease: is the berg balance scale a useful test for clinical and quantitative motor assessment?

Background Patients with Huntingtons disease (HD) develop a progressive impairment of stability of stance and walking (Rumpf et al. 2007), frequently resulting in falls and injuries. Objective assessment of postural control in HD may be helpful to assess the risk of injury and may serve as a surrogate marker for motor phenotype dysfunction. Objective To investigate whether HD patients exhibit impairments in balance control that can be assessed by the BBS and whether the BBS correlates to the severity of disease as assessed by the UHDRS-TMS and quantitative measures of balance recorded by a force plate (posturography). Methods HD patients (n=48: 11 premanifest, 37 symptomatic HD) and age-and-sex-matched controls (n=20) were assessed by the Berg Balance Scale (BBS), the UHDRS-TMS and a force plate (standing still with eyes open and closed for 25 s). Stability of center of mass (COM) location was assessed by the variables SURFACE, VELOCITY and DISTANCE. Non-parametric statistics were performed to compare patients and controls (Mann-Whitney-Test) and to assess dependent variables (Wilcoxon-Test) using SAS 9.2. Correlation analysis was performed using non-parametric Spearman correlations. Results The BBS correlated in all HD gene-carriers to the UHDRS-TMS with r=−0.786 in symptomatic patients the correlation was r=−0.826. In symptomatic patients BBS correlated with force plate measures SURFACE (r≥−0.665), VELOCITY (r≥−0.453) and DISTANCE (r≥−0.465). However, BBS was insensitive to impairments of balance in patients with UHDRS-TMS ≤20. Force plate measures were significantly increased in HD compared to controls (p<0.001). All variables correlated to the severity of the disease as assessed in the UHDRS-TMS (r≥0.705). Conclusions Assessment of balance with the BBS is limited to patients with UHDRS-TMS scores ≥20. In contrast, objective and quantitative force plate measures are more sensitive covering a wider range of disease.