Till Karsten Hauser

Comparing brain activation associated with isolated upper and lower limb movement across corresponding joints

It was shown recently that functional activation across brain motor areas during locomotion and foot movements are similar but differ substantially from activation related to upper extremity movement (Miyai [ 2001 ]: Neuroimage 14:1186–1192). The activation pattern may be a function of the behavioral context of the movement rather than of its mechanical properties. We compare motor system activation patterns associated with isolated single‐joint movement of corresponding joints in arm and leg carried out in equal frequency and range. Eleven healthy volunteers underwent BOLD‐weighted fMRI while performing repetitive elbow or knee extension/flexion. To relate elbow and knee activation to the well‐described patterns of finger movement, serial finger‐to‐thumb opposition was assessed in addition. After identifying task‐related voxels using statistical parametric mapping, activation was measured in five regions of interest (ROI; primary motor [M1] and somatosensory cortex [S1], premotor cortex, supplementary motor area [SMA] divided into preSMA and SMA‐proper, and cerebellum). Differences in the degree of activation across ROIs were found between elbow and knee movement. SMA‐proper activation was prominent for knee, but almost absent for elbow movement (P < 0.05); finger movement produced small but constant SMA‐proper activation. Ipsilateral M1 activation was detected during knee and finger movement, but was absent for the elbow task (P < 0.05). Knee movement showed less lateralization in M1 and S1 than other tasks (P < 0.05). The data demonstrate that central motor structures contribute differently to isolated elbow and knee movement. Activation during knee movement shows similarities to gait‐related activation patterns. Hum. Brain Mapping 17:131–140, 2002.

Overexpression of human wildtype torsinA and human ΔGAG torsinA in a transgenic mouse model causes phenotypic abnormalities

Primary torsion dystonia is an autosomal-dominant inherited movement disorder. Most cases are caused by an in-frame deletion (GAG) of the DYT1 gene encoding torsinA. Reduced penetrance and phenotypic variability suggest that alteration of torsinA amino acid sequence is necessary but not sufficient for development of clinical symptoms and that additional factors must contribute to the factual manifestation of the disease. We generated 4 independent transgenic mouse lines, two overexpressing human mutant torsinA and two overexpressing human wildtype torsinA using a strong murine prion protein promoter. Our data provide for the first time in vivo evidence that not only mutant torsinA is detrimental to neuronal cells but that also wildtype torsinA can lead to neuronal dysfunction when overexpressed at high levels. This hypothesis is supported by (i) neuropathological findings, (ii) neurochemistry, (iii) behavioral abnormalities and (iv) DTI-MRI analysis.

Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6.

BACKGROUND AND OBJECTIVE Biomarkers to monitor neurological dysfunction in autosomal dominant inherited spinocerebellar ataxias (SCA) are lacking. We therefore aimed to visualize, quantify and correlate localized brain atrophy with clinical symptoms in SCA1, SCA3, and SCA6. METHODS We compared patients suffering from SCA1 (n=48), SCA3 (n=24), and SCA6 (n=10) with 32 controls using magnetic resonance imaging (MRI) on four different scanners in eight centers followed by voxel-based morphometry (VBM) and quantitative three-dimensional (3D) volumetry. RESULTS SCA1 and SCA3 patients presented with severe atrophy in total brainstem (consisting of midbrain, pons, and medulla), pons, medulla, total cerebellum, cerebellar hemispheres and cerebellar vermis, putamen and caudate nucleus. Atrophy in the cerebellar hemispheres was less severe in SCA3 than in SCA1 and SCA6. Atrophy in SCA6 was restricted to the grey matter of the cerebellum (VBM and volumetry), total brainstem and pons (volumetry only). Overall, we did not observe substantial atrophy in the cerebral cortex. A discriminant analysis taking into account data from pons, cerebellar hemispheres, medulla, midbrain and putamen achieved a reclassification probability of 81.7% for SCA1, SCA3, and SCA6. The repeat length of the expanded allele showed a weak negative correlation with the volume of the brainstem, pons, caudate nucleus and putamen in SCA3, and a weak correlation with the pons in SCA1, whereas no such correlation was found in SCA6. Clinical dysfunction as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the Unified Huntingtons Disease Rating Scale functional assessment correlated best with the atrophy of pons in SCA1, with total brainstem atrophy in SCA3 and atrophy of total cerebellum in SCA6. CONCLUSIONS Our data provide strong evidence that MRI is an attractive surrogate marker for clinical studies of SCA. In each SCA genotype clinical dysfunction may be caused by different patho-anatomical processes.

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

Generation of a novel rodent model for DYT1 dystonia

A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (∆ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood. Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology. We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in ∆ETorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of ∆ETorA and to test for therapeutic approaches.

No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra.

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra.

A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability

Aim To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. Methods The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP=362, MSA=398), 627 had per protocol images (PSP=297, MSA=330). Intra-rater (n=60) and inter-rater (n=555) reliability were assessed through Cohens statistic, and scale structure through principal component analysis (PCA) (n=441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. Results Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75–0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1–F2; MSA: F2–F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity. Conclusions The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA. Clinical Trial Registration Number The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224.

SIADH following pituitary adenoma apoplexy.

The rare case of a patient with SIADH following pituitary adenoma apoplexy is reported. Since apoplexy did not exert any mass effect on surrounding structures, the patient was treated conservatively and the anterior pituitary gland insufficiency has been substituted adequately. Seven days after the apoplexy the patient again showed low serum–Na+ levels despite cortisol substitution. Diagnosis of SIADH was made. It is essential to be aware of this rare syndrome in patients with pituitary adenoma apoplexy.

Corrigendum to “Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6” [NeuroImage 49 (2010) 158–168]

a Department of Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, Göttingen, Germany b Center for Molecular Physiology of the Brain, University of Göttingen, Göttingen, Germany c Department of Neurology, University Medical Center, RWTH Aachen, Aachen, Germany d Department of Psychiatry, University of Bonn, Bonn, Germany e Department of Neurology, University of Bonn, Bonn, Germany f Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland g Department of Biochemistry and Genetics, Istituto Nazionale Neurologico C. Besta, Milan, Italy h Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany i Department of Neurology, University of Duisburg-Essen, Essen, Germany j Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands k INSERM U679, Neurology and Experimental Therapeutics, Paris, France l Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium m Department of Neurology, Johann Wolfgang Goethe University, Frankfurt, Germany n Department of Radiology, University Hospital Marqués de Valdecilla, CIBERMED, Santander, Spain o Department of Neuroradiology, University of Tübingen, Tübingen, Germany p Neuroradiology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy q Department of Radiology, Military Institute of Medicine, Warsaw, Poland r Department of Medical Genetics, University of Tübingen, Tübingen, Germany