Ralf Reilmann

Coordination of Prehensile Forces during Precision Grip in Huntington's Disease

The present study examined the coordination of prehensile forces during precision grip in subjects with Huntingtons disease (HD). Fingertip forces were measured in 12 subjects with HD and 12 age-matched controls during the lifting of an instrumented object whose weight and surface texture were varied. The results indicate that subjects with HD have impaired initiation and delayed transitions between movement sequences and produce excessive and variable forces. However, subjects with HD demonstrated anticipatory scaling of force development based on the objects expected physical properties (planning) and adjustment of the force to the objects actual physical properties (sensorimotor integration). The observed findings generally were unrelated to the overall disease severity. However, the variability in forces was correlated with functional capacity and motor performance suggesting that variability is a key feature of the motor deficit. These results provide insights into the impaired hand function observed in individuals with HD.

Selective use of visual information signaling objects' center of mass for anticipatory control of manipulative fingertip forces

Abstract.The present study examines whether visual information indicating the center of mass (CM) of an object can be used for the appropriate scaling of fingertip forces at each digit during precision grip. In separate experiments subjects lifted an object with various types of visual cues concerning the CM location several times and then rotated and lifted it again to determine whether the visual cues signaling the new location of the CM could be used to appropriately scale the fingertip forces. Specifically, subjects had either no visual cues, visual instructional cues (i.e., an indicator) or visual geometric cues where the longer axis of the object indicated the CM. When no visual cues were provided, subjects were unable to appropriately scale the load forces at each digit following rotation despite their knowledge of the new weight distribution. When visual cues regarding the CM location were provided, the nature of the visual cues determined their effectiveness in retrieval of internal representations underlying the anticipatory scaling of fingertip forces. Specifically, when subjects were provided with visual instructional information, they were unable to appropriately scale the forces. More appropriate scaling of the load forces occurred when the visual cues were ecologically meaningful, i.e., when the shape of the object indicated the CM location. We suggest that visual instructional cues do not have access to the implicit processes underlying dynamic force control, whereas visual geometric cues can be used for the retrieval of the internal representation related to CM for appropriate partitioning of the forces in each digit.

Objective assessment of progression in Huntington’s disease: A 3-year follow-up study

Objective measures to assess progression of Huntington’s disease (HD) are desirable. The authors have previously found that patients with HD with higher Unified Huntington’s Disease Rating Scale (UHDRS) motor scores exhibited higher variability of isometric grip forces while grasping an object. Therefore, the authors assessed grip force variability during this task in 10 HD patients with a 3-year follow-up. Grip force variability increased in all patients at the follow-up. Thus, grip force variability during grasping might be an objective and quantitative measure to assess motor deficits associated with the progression of HD.

Altered movement trajectories and force control during object transport in Huntington's disease.

Individuals with Huntingtons Disease (HD) have difficulty grasping and transporting objects, however, the extent to which specific impairments affect their performance is unknown. The present study examined the kinematics and force coordination during transport of an object in 12 subjects with HD and 12 age‐matched controls. Subjects grasped an object between their thumb and index finger, transported it 25 cm forward, replaced and released it while their fingertip forces and the objects position were recorded. Five trials were performed with each of three weights (200 g, 400 g, and 800 g). While bradykinesia was evident in subjects with HD, this slowness was not consistently observed in all phases of the movement. The slowness of movement seen during the task appears to be due to impairments in sequencing and the movement strategies selected by the subjects. Compared to control subjects, subjects with HD produced highly curvilinear hand paths and more variable grip forces that were dependent on the weight of the object. Isometric force development and movement speed during transport were unaffected by the disease. The results suggest that prolonged task durations in subjects with HD are not necessarily due to slowness of movement, per se. These findings have clinical implications for understanding the task‐specific nature of movement impairments in HD and developing effective intervention strategies.

The impact of occipital lobe cortical thickness on cognitive task performance: An investigation in Huntington's Disease.

BACKGROUND The occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntingtons Disease (HD), we examined cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison. METHODS Cortical thickness was determined using FreeSurfer on T1-weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141). RESULTS Thickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally-specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region. CONCLUSIONS The heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD.

Behavioral phenotyping of minipigs transgenic for the Huntington gene.

BACKGROUND While several novel therapeutic approaches for HD are in development, resources to conduct clinical trials are limited. Large animal models have been proposed to improve assessment of safety, tolerability and especially to increase translational reliability of efficacy signals obtained in preclinical studies. They may thus help to select candidates for translation to human studies. We here introduce a battery of novel tests designed to assess the motor, cognitive and behavioral phenotype of a transgenic (tg) HD minipig model. NEW METHODS A group of tgHD and wildtype (wt) Libechov minipigs (n=36) was available for assessment with (1) a gait test using the GAITRite(®) automated acquisition system, (2) a hurdle-test, (3) a tongue coordination test, (4) a color discrimination test, (5) a startbox back and forth test and (6) a dominance test. Performance of all tests and definition of measures obtained is presented. RESULTS Minipigs were able to learn performance of all tests. All tests were safe, well tolerated and feasible. Exploratory between group comparisons showed no differences between groups of tgHD and wt minipigs assessed, but low variability within and between groups. COMPARISON WITH EXISTING METHOD(S) So far there are no established or validated assessments to test minipigs in the domains described. CONCLUSIONS The data shows that the tests presented are safe, well tolerated and all measures defined can be assessed. Prospective longitudinal application of these tests is warranted to determine their test-retest reliability, sensitivity and validity in assessing motor, cognitive and behavioral features of tg and wt minipigs.

Neuroimaging of a minipig model of Huntington's disease: Feasibility of volumetric, diffusion-weighted and spectroscopic assessments

BACKGROUND As novel treatment approaches for Huntingtons disease (HD) evolve, the use of transgenic (tg) large animal models has been considered for preclinical safety and efficacy assessments. It is hoped that large animal models may provide higher reliability in translating preclinical findings to humans, e.g., by using similar endpoints and biomarkers. NEW METHOD We here investigated the feasibility to conduct MRI assessments in a recently developed tgHD model in the Libechov minipig. The model is characterized by high genetic homology to humans and a similar body mass and compartments. The minipig brain provides anatomical features that are attractive for imaging studies and could be used as endpoints for disease modifying preclinical studies similar to human HD. RESULTS We demonstrate that complex MRI protocols can be successfully acquired with tgHD and wild type (wt) Libechov minipigs. We show that acquisition of anatomical images applicable for volumetric assessments is feasible and outline the development of a segmented MRI brain atlas. Similarly diffusion-weighted imaging (DWI) including fiber tractography is presented. We also demonstrate the feasibility to conduct in vivo metabolic assessments using MR spectroscopy. COMPARISON WITH EXISTING METHODS In human HD, these MRI methods are already validated and used as reliable biomarker of disease progression even before the onset of a clinical motor phenotype. CONCLUSIONS The results show that the minipig brain is well suited for MRI assessments in preclinical studies. We conclude that further characterization of phenotypical differences between tg and wt animals in sufficiently powered cross-sectional and longitudinal studies is warranted.

Coordination of fingertip forces during precision grasping in multiple system atrophy.

While the pathology and autonomic nervous system components of multiple system atrophy (MSA) have been well described, little is known about the associated motor dysfunction. One prominent feature of MSA is parkinsonism, although ataxias and pyramidal tract signs are frequently present. To investigate the nature of motor deficits in MSA, a natural grip-lift movement requiring a precision grasp was used to examine force coordination. Subjects were asked to grasp an instrumented object using the fingertips of the thumb and index finger and lift it 10 cm above the table surface. Subjects with MSA demonstrated a prolonged duration between object contact and initiation of the lifting drive that increased with the weight of the object. During this period these subjects produced large grasping forces generating a significant portion of the eventual grip force employed to hold the object. In contrast, control subjects generated grip and load forces in parallel after establishing contact with the object. Therefore, subjects with MSA showed a disrupted performance on both the sequential (grasp, then lift) and simultaneous (grip and load force development) portions of this task. Only after initiation of the vertical lifting drive did subjects with MSA generate forces in a similar manner to control subjects. These findings demonstrate that subjects with MSA exhibit a disrupted coordination of grasp and could suggest a general deficit in motor control resulting from multi-focal neural degeneration.

Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease

While the HTT CAG‐repeat expansion mutation causing Huntingtons disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age‐at‐onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory‐motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory‐motor structural MRI, tractography, resting‐state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory‐motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory‐motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory‐motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non‐CAG‐driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory‐motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non‐CAG‐driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615–4628, 2016.

Does arterial hypertension influence the onset of Huntington's disease?

Huntington’s disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington’s Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5–8 years later than normotensive patients in the most frequent CAGexp range (40–44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management.