Research

Spinocerebellar ataxia

The spinocerebellar ataxias type SCA1, SCA2, SCA3 and SCA6 are the most frequent subtypes in Germany and account for about 70% of dominant ataxias. In a research project sponsored by the European Community, EURO-SCA (http://www.eurosca.org/), we study the natural course of the disease by clinical rating scales, nerve conduction studies and magnetic resonance tomography. In a prospective study we generate data about the annual progression of the disease in terms of changes in a newly developed and evaluated rating scale (SARA) and functional tests. Furthermore, we aim to establish electrophysiological parameters and regional atrophy on MRI as progression markers for SCA. These data are essential for power calculation and planning of forthcoming therapeutical trials.
Special effort is put on the affection of basal ganglia in SCA. In cooperation with the Institute of Functional Anatomy in Frankfurt (Dr. Rüb) we study degenerative changes in the substantia nigra in SCA. Preliminary results show similar affection as in Parkinson’s disease but the patients do not necessarily develop Parkinsoninan symptoms. In a combined imaging approach sponsored by the Deutsche Forschungsgemeinschaft we assess basal ganglia structure and function in vivo using transcranial sonography, MRI and multiple PET tracers in SCA2 and SCA3 patients.

Figure1: Neuronal loss in the substantia nigra is similar in SCA2 (C) and SCA3 (D) as in Parkinson’s disease (B) in comparison to controls (A). Courtesy of Dr. U. Rüb, Institute of Clinical Neuroanatomy, Frankfurt

Basal ganglia dysfunction in SCA

The spinocerebellar ataxias (SCA) are characterised by an autosomal dominantly inherited progressive ataxia accompanied by variable extracerebellar symptoms. Neuropathological studies in SCA2 and SCA3, the most frequent SCA genotypes in Europe, regularly describe basal ganglia pathology to an extent resembling that in Parkinon´s disease (PD). Despite clear degeneration of the substantia nigra, clinical signs like akinesia, rigidity or tremor are not observed in most cases. Only a minority of SCA2 and SCA3 patients present with a parkinsonian phenotype showing predominantly extrapyramidal symptoms. Previous positron emission tomography (PET) studies point to affection of the dopaminergic system in vivo but are limited by the small number of patients and analysis of single tracers only. To enlight the discrepancy between neuropathological changes of basal ganglia and lack of clinical signs of Parkinsonism we perform a combined structural and functional imaging study using transcranial sonography (TCS), volumetry of basal ganglia by magnetic resonance imaging (MRI) and multitracer PET.

Contact: Christoph Globas
Supported by DFG grant Scho 754/3-1

Electrophysiology of cerebellar neurons

Purkinje cells are placed in decisive location within the motor system and are important for controlling execution of movement. They provide the only link between the cerebellar cortex and cerebellar nuclei. A novel mouse model for SCA3 shows shrinking of 50-80% of Purkinje cells characterized by an increase of electron density of the cytoplasm and the karyoplasms. We investigate the functional characteristics of these neuronsby means of patch-clamp recordings in cerebellar sclices of these transgenic animals. The functional characteristics of these Purkinje cells are an interplay between the intrinsic membrane properties and its synaptic interactions.

Contact: Christoph Linnemann

Friedreich’s ataxia

Figure 2: Assessment of left ventricular mass on cardiac MRI. Endocardiac and epicardiac boundaries of every slice are traced manually. Interobserver variability for left ventricular mass is less than 5%. A: Enddiastolic series. (B) Endsystolic series.

Friedreich’s ataxia (FA) is frequently associated with cardiomyopathy that is believed to be the most frequent cause of death in FA. FA associated cardiomyopathy is commonly regarded to be of hypertrophic type. Therapeutic trials of idebenone, coenzyme Q10 and vitamin E aim to reduce left ventricular mass. We assess the frequency and natural history of cardiac hypertrophy in FA by cardiac MRI in comparison to echocardiography and analyse which cardiac parameters have functional implications or prognostic relevance in Friedreich’s cardiomyopathy.
In cooperation with the Karolinska-Institute in Stockholm, the Institute for Human Nutrition in Jena and the Diabetes Center in Tübingen we study glucose metabolism and insulin oscillations in FA. About 18% of patients with FA develop diabetes mellitus and 80% of heterozygous mutation carriers show impaired insulin resistance.

Genetics of hereditary spastic paraplegia (HSP)

Although HSP is a rare disease with an prevalence of 0.5–1:100.000 it is highly heterogeneous with at least 32 genetically defined subtypes (s. Table "Molecular genetics of HSP"). For most families the responsible genetic defect is not yet identified. In families with autosomal dominant disease we perform haplotype analyses for all 11 so far characterized chromosomal loci. Appropriate pedigrees are analysed in a genome search using SNP chip technology. Recently we identified the first German SPG10 family with a novel mutation in KIF5a, an essential motor for anterograde axonal transport.
HSP with thin corpus callosum and autosomal recessive inheritance are hallmarks of SPG11. In cooperation with the Institute of Medical Genetics in Tübingen (Prof. Rieß) and the Department of Neurology in Regensburg (Prof. Winkler) we search for the gene responsible for SPG11 using a candidate gene approach.

Cranial MRI in SPG11: Midsagital plane shows severe thinning of the corpus callosum pronounced in its anterior parts.

Quantitative MRI

Spinal cord atrophy has been observed in patients with HSP. We try to elucidate the degree of axonal degeneration and subsequent spinal cord atrophy on MRI. Therefore HSP patients and healthy volunteers are scanned according to the GeNeMove MRI protocol, the recently developed standard protocol for MRI scans in HSP. For the quantitative assessment we use the 3D Slicer software, Surgical Planning Laboratory, Boston MA. Planimetry and volumetry is performed by a semi-automated segmentation on high contrast T2 weighted images. We want to establish subtype specific atrophy in HSP as well as in SCA. A longitudinal study with repetitive investigations aims to establish spinal cord atrophy as progression marker for intervention studies.
Funded by BMBF: German Network for hereditary Movement disorders

Contact: Tobias Lindig
Supported by BMBF: GeNEMove project, grant 01GM0304

Dopaminergic influence on executive function

Impaired executive function is observed in a variety of neuropsychiatric disorders with alterations in the dopaminergic system. For example, patients with schizophrenia have been shown to be impaired on set-shifting and working memory tasks. Other disorders include attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease. The facts that the dopaminergic system (a) seems to be directly involved in the etiology of these conditions and (b) many executive brain areas have rich dopaminergic innervation motivated studies trying to relate individual genetic differences in the dopaminergic system to aspects of executive functions.We screen polymorphisms of genes involved in dopaminergic function in a large cohort of students who underwent comprehensive psychometric assessment at the center in Barcelona (Prof. A. Rodriguez). Individuals homozygous for polymorphisms enhancing dopamine stimulation and for polymorphisms reducing dopamine function will be identified for all genes. These genetically defined subgroups will take part in brain potential experiments assessing executive function. The electrophysiological and behavioral markers (“endophenotypes”) of executive functions will be compared between the genetically defined subgroups. Moreover, high-resolution 3D structural MRI will be performed allowing anatomical comparison of brain structures implicated in executive control at the center in Magdeburg (Prof. T. Münte).

Contact: Ludger Schöls
Supported by Volkswagen foundation: Project I/80711