Gb Landwehrmeyer

Tapping linked to function and structure in premanifest and symptomatic Huntington disease

Objective: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntingtons Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. Methods: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. Results: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. Conclusion: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

Cortical dysfunction in patients with Huntington's disease during working memory performance

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntingtons disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event‐related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy‐related activation confounds. Voxel‐based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso‐ and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM‐related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy. Hum Brain Mapp, 2009.

Myopathy as a first symptom of Huntington's disease in a Marathon runner

A semi professional marathon runner at risk for Huntingtons disease (HD) (43 CAG repeats) developed signs of a slowly progressive myopathy with exercise‐induced muscle fatigue, pain, elevated creatine kinase level, and worsening of his running performance many years before first signs of chorea were detected. Muscle biopsy displayed a mild myopathy with mitochondrial pathology including a complex IV deficiency and analysis of the patients fibroblast culture demonstrated deficits in mitochondrial function. Challenging skeletal muscle by excessive training might have disclosed myopathy in HD even years before the appearance of other neurological symptoms.

Neurofilament heavy-chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfHSMI35 in the laboratory‐supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinsons disease (PD; n = 22), multiple‐system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age‐matched controls (n = 45) were included. CSF levels of NfHSMI35 were measured using ELISA. Levels of CSF NfHSMI35 were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfHSMI35 differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfHSMI35 is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfHSMI35 may therefore be of some value for the laboratory‐supported differential diagnosis of atypical parkinsonian syndromes.

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease

This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntingtons disease (HD).

Visual system integrity and cognition in early Huntington's disease

Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntingtons disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel‐based morphometry was employed to assess regional brain atrophy, and ‘biological parametric mapping’ analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients.

Data Analytics from Enroll-HD, a Global Clinical Research Platform for Huntington's Disease

The study of complex neurodegenerative diseases is moving away from hypothesis‐driven biological methods toward large scale multimodal approaches, requiring standardized collaborative efforts. Enroll‐HD exemplifies such an integrated clinical research platform, designed and implemented to meet the research and clinical needs of Huntingtons disease (HD). The aim of this study was to describe the unique organization of Enroll‐HD and report baseline data analyses of its core study.

Stability effects on results of diffusion tensor imaging analysis by reduction of the number of gradient directions due to motion artifacts: an application to presymptomatic Huntington's disease.

In diffusion tensor imaging (DTI), an improvement in the signal-to-noise ratio (SNR) of the fractional anisotropy (FA) maps can be obtained when the number of recorded gradient directions (GD) is increased. Vice versa, elimination of motion-corrupted or noisy GD leads to a more accurate characterization of the diffusion tensor. We previously suggest a slice-wise method for artifact detection in FA maps. This current study applies this approach to a cohort of 18 premanifest Huntington’s disease (pHD) subjects and 23 controls. By 2-D voxelwise statistical comparison of original FA-maps and FA-maps with a reduced number of GD, the effect of eliminating GD that were affected by motion was demonstrated. We present an evaluation metric that allows to test if the computed FA-maps (with a reduced number of GD) still reflect a “true” FA-map, as defined by simulations in the control sample. Furthermore, we investigated if omitting data volumes affected by motion in the pHD cohort could lead to an increased SNR in the resulting FA-maps. A high agreement between original FA maps (with all GD) and corrected FA maps (i.e. without GD corrupted by motion) were observed even for numbers of eliminated GD up to 13. Even in one data set in which 46 GD had to be eliminated, the results showed a moderate agreement.

Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntingtons disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Motor network structure and function are associated with motor performance in Huntington's disease.

In Huntington’s disease, the relationship of brain structure, brain function and clinical measures remains incompletely understood. We asked how sensory-motor network brain structure and neural activity relate to each other and to motor performance. Thirty-four early stage HD and 32 age- and sex-matched healthy control participants underwent structural magnetic resonance imaging (MRI), diffusion tensor, and intrinsic functional connectivity MRI. Diffusivity patterns were assessed in the cortico-spinal tract and the thalamus–somatosensory cortex tract. For the motor network connectivity analyses the dominant M1 motor cortex region and for the basal ganglia-thalamic network the thalamus were used as seeds. Region to region structural and functional connectivity was examined between thalamus and somatosensory cortex. Fractional anisotropy (FA) was higher in HD than controls in the basal ganglia, and lower in the external and internal capsule, in the thalamus, and in subcortical white matter. Between-group axial and radial diffusivity differences were more prominent than differences in FA, and correlated with motor performance. Within the motor network, the insula was less connected in HD than in controls, with the degree of connection correlating with motor scores. The basal ganglia-thalamic network’s connectivity differed in the insula and basal ganglia. Tract specific white matter diffusivity and functional connectivity were not correlated. In HD sensory-motor white matter organization and functional connectivity in a motor network were independently associated with motor performance. The lack of tract-specific association of structure and function suggests that functional adaptation to structural loss differs between participants.