Thomas Klockgether

Parkinson’s disease: clinical aspects

Parkinsonism is a clinical syndrome characterized by akinesia, muscular rigidity, and resting tremor. The most frequent cause of parkinsonism is Parkinson’s disease (PD). Progressive loss of substantia nigra neurons together with the occurrence of Lewy bodies are considered essential neuropathological features of PD. Recent neuropathological studies suggest that nigral degeneration is only part of a more extended brain degeneration that starts in the medulla oblongata and then spreads to the mesencephalon and cerebral cortex. Correspondingly, the clinical symptoms occurring in PD go far beyond parkinsonism. Depending on the disease stage, autonomic dysfunction, olfactory disturbances, depression, and dementia are frequently encountered in PD. These neuropathological and clinical observations have major implications for future research in PD. In particular, the analysis of the properties that the neuronal cell types involved in PD have in common and that might make them susceptible to degeneration is essential.

Molecular Analysis of the PTEN, TP53 and CDKN2A Tumor Suppressor Genes in Long-term Survivors of Glioblastoma Multiforme

Despite multimodal therapy, glioblastoma multiforme (GBM) is associated with a poor prognosis with a median survival of less than 1 year. However, a small number of patients with GBM shows survival times of several years. Although clinical features like age and performance status at diagnosis are well known prognostic parameters, molecular markers for prognosis of overall survival are still lacking. Therefore, we compared 2 age- and gender-matched groups of GBM patients with different post-operative time to tumor progression (TTP), defined as short-term for TTP of less than 6 months (n=21), and long-term for TTP of more than 24 months (n=21) for genetic alterations of the PTEN, CDKN2A and TP53 genes as well as overexpression of the EGFR, p53 and Mdm2 proteins. For the GBMs with short-term TTP vs. long-term TTP, the studies revealed PTEN mutations in 4/21 vs. 2/21, TP53 mutations in 5/21 vs. 8/21, homozygous deletion of the CDKN2A gene in 5/21 vs. 6/21, overexpression of EGFR in 7/20 vs. 10/20, accumulation of p53 protein in 9/20 vs. 7/20 and of Mdm2 protein in 0/20 vs. 1/20 cases studied. Taken together, our data indicate that mutations of the PTEN and TP53 tumor suppressor genes, homozygous deletion of the CDKN2A gene as well as overexpression of the EGFR, p53 and Mdm2 proteins lack prognostic significance for overall survival time in patients with GBMs.

Cell death in polyglutamine diseases

Abstract An increasing number of inherited neurodegenerative diseases are known to be caused by trinucleotide repeat expansions in the respective genes. At least nine disorders result from a CAG trinucleotide repeat expansion which is translated into a polyglutamine stretch in the respective proteins: Huntingtons disease (HD), dentatorubral pallidolysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and several of the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 12). Although the molecular steps leading to the specific neuropathology of each disease are unknown and are still under intensive investigation, there is increasing evidence that some CAG repeat disorders involve the induction of apoptotic mechanisms. This review summarizes the clinical and genetic features of each CAG repeat disorder and focuses on the common mechanistic steps involved in the disease progression of these so-called polyglutamine diseases. Among the common molecular features the formation of intranuclear inclusions, the recruitment of interacting polyglutamine-containing proteins, the involvement of the proteasome and molecular chaperones, and the activation of caspases are discussed with regard to their potential implication for the induction of cell death.

The molecular biology of the autosomal-dominant cerebellar ataxias

Autosomal‐dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA‐1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA‐2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the α1A voltage‐dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3` translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.

Recent advances in degenerative ataxias.

Since the discovery of the first mutations that cause hereditary ataxias in the early 1990s, there has been continuous progress in deciphering the molecular pathogenesis of degenerative ataxias. Recent research in Friedreichs ataxia, the most frequent recessive ataxia, has provided further evidence that the clinical phenotype of this disorder is caused by abnormal oxidative phosphorylation due to mitochondrial dysfunction. The dominantly inherited spinocerebellar ataxias (SCAs) are genetically heterogeneous. Up to now, 11 distinct loci have been identified. The mutations that cause SCA1, SCA2, SCA3, SCA6 and SCA7 share the common feature of an expanded CAG sequence, encoding an abnormally long polyglutamine tract within the respective gene products. Recent pathogenetic research points to the importance of abnormal protein-protein interaction and altered gene transcription. The aetiology of many sporadic ataxias remains obscure. In some patients, association of ataxia with specific serum antibodies (antigliadin, antiglutamic acid decarboxylase) suggests an immune pathogenesis.

Neurologic complications in immune-mediated heparin-induced thrombocytopenia

Objective: To evaluate neurologic complications in patients with immune-mediated heparin-induced thrombocytopenia (HIT) with respect to incidence, clinical characteristics, outcome, and therapy. Methods: One hundred and twenty consecutive patients with immune-mediated HIT were recruited over a period of 11 years and studied retrospectively for the occurrence of neurologic complications. Diagnosis of HIT was based on established clinical criteria and confirmed by detection of heparin-induced antibodies using functional and immunologic tests. Results: Eleven of the 120 patients (9.2%) presented with neurologic complications; 7 suffered from ischemic cerebrovascular events, 3 from cerebral venous thrombosis, and 1 had a transient confusional state during high-dose heparin administration. Primary intracerebral hemorrhage was not observed. The relative mortality was much higher (Chi-square test, p < 0.01) in HIT patients with neurologic complications (55%) as compared to patients without neurologic complications (11%). The mean platelet count nadir in neurologic patients was 38 ± 25 × 109/l on average, and was lower in patients with fatal outcome compared to those who survived (21 ± 13 × 109/l versus 58 ± 21 × 109/l; p < 0.05, Wilcoxon test). In three patients neurologic complications preceded thrombocytopenia. There was a high coincidence of HIT-associated neurologic complications with other HIT-associated arterial or venous thrombotic manifestations. Conclusion: Neurologic complications in HIT are relatively rare, but associated with a high comorbidity and mortality. HIT-associated neurologic complications include cerebrovascular ischemia and cerebral venous thrombosis. They may occur at a normal platelet count.

Temporal, regional, and cell-specific changes of iNOS expression after intrastriatal microinjection of interferon gamma and bacterial lipopolysaccharide.

Here we study expression of the inducible isoform of nitric oxide synthases after intrastriatal microinjection of interferon-gamma and bacterial lipopolysaccharide in the rat at different time points to detect time- and localisation-dependent changes of iNOS expression. Three different areas in the striatum and the corpus callosum were evaluated. Antibodies against the glial fibrillary acidic protein and the microglia/brain macrophage epitope ED1 were used to detect colocalization of inducible nitric oxide synthase with astrocytes or activated microglia/brain macrophages, respectively. Inducible nitric oxide synthase-positive cells occurred first in intravascular and perivascular cells at 4 h. Perivascular and parenchymal inducible nitric oxide synthase expression increased up to 24 h in the striatum, whereas in the corpus callosum inducible nitric oxide synthase expression was maximal after 16 h. Inducible nitric oxide synthase was still present in perivascular cells 7 days after immunostimulation. At all time points, inducible nitric oxide synthase was predominantly detected in ED1-positive microglia/brain. Nitrotyrosine immunohistochemistry was performed to detect NO-mediated nitration of proteins at all time points. Nitrotyrosine-positive neurons and microglial cells were detected from 24 h until 7 days after immunostimulation and were absent in controls. Detailed knowledge of the changes in the time course and cellular source of inducible nitric oxide synthase expression following brain immunostimulation provide a basis for establishing treatment strategies and windows of therapeutic intervention during neuroinflammation.

Significantly increased prevalence of factor V Leiden in patients with dural arteriovenous fistulas

Abstract Resistance to activated protein C (APCR) is the most common genetic risk factor for venous thrombosis and is generally caused by a mutation in the factor V (FV) gene leading to FV Leiden. The recent finding of FV Leiden in three of seven patients with dural arteriovenous fistulas (DAVFs) prompted us to evaluate systematically the role of APCR due to FV Leiden in the pathogenesis of DAVFs in 22 patients and age- and sex-matched controls. We found a significantly higher frequency of APCR and FV Leiden in the patient group than among controls (5/22 vs. 0/22, P=0.048, Fishers exact test). We conclude that APCR due to FV Leiden is of pathogenetic significance in a subgroup of DAVFs.

Primary non-Hodgkin's lymphoma of the spinal cord

Study Design Case report. Objective To report a rare case of primary lymphoma of the spinal cord and to discuss therapeutic options. Summary of Background Data Only few cases of primary spinal cord lymphomas are reported. Prognosis is often poor, and therapy is not yet established. Methods A primary lymphoplasmacytoid lymphoma of the thoracic cord in a 75-year-old woman was treated with focal radiotherapy (30 Gy) and three cycles of chemotherapy consisting of procarbazine, lomustine, and vincristine. Results Complete tumor response and partial recovery of neurologic symptoms were achieved. The patient was in complete remission at last follow-up (11 months after diagnosis). Conclusions Primary spinal cord lymphomas should be considered in the differential diagnosis of spinal cord tumors, especially in older patients. Combination therapy with radiotherapy and chemotherapy may be superior to radiotherapy alone in these tumors. Rapid initiation of treatment is essential to achieve recovery of neurologic function.

Altered expression of calcium- and apoptosis-regulating proteins in multiple system atrophy Purkinje cells.

The expression patterns of the calcium binding proteins calbindin and parvalbumin and of the apoptosis modulating proteins Bcl‐2, Bax, and Bcl‐x were studied in the cerebellum of patients with multiple system atrophy (MSA). Calbindin and parvalbumin immunoreactivity was markedly decreased in MSA Purkinje cells whereas Bax and Bcl‐x protein expression was increased. Bcl‐2 expression was restricted to a subpopulation of granule neurons, but no decrease of Bcl‐2 was evident in MSA. Additional DNA end‐labeling (ISEL) studies revealed only one possible apoptotic Purkinje cell nucleus, but nuclei in the cerebellar white matter, probably oligodendrocytes, in the cerebellum of patients with MSA. The present results suggest that a diminished calcium binding capacity of MSA Purkinje cells might lead to a change in the regulation of proteins of the bcl‐2 family that could favor the pathologic initiation of apoptosis.