Cognitive training in MS: effects and relation to brain atrophy.

PURPOSE: Cognitive disorders are common in MS patients without any generally recommended treatment. Recent brain imaging studies show considerable neuroplasticity for cognitive tasks in MS patients, but also brain atrophy already early in the disease progression. We explored the benefits of a home-based cognitive training program for memory and working memory functions in relapsing-remitting MS patients controlling for whole brain and central brain atrophy as covariates. METHODS: Using a single-blinded controlled study design, 42 patients were randomised into a treatment group and a control group. Home based computer training focusing on memory and working memory was started at least 4 weeks after the discontinuation of methylprednisolone treatment and lasted for 6 weeks. Two weeks later the patients were re-investigated for their clinical and cognitive performance. We assessed also quality of life (QoL), depression and fatigue using self-rating scales. RESULTS: Training had no effect on the neurological status and on QoL or fatigue. However, the treatment group showed better verbal learning, long-delay verbal memory performance, and working memory performance. The impact of treatment on long-delay verbal memory performance was independent from the extent of brain atrophy, whereas for the other findings brain atrophy played a significant role. CONCLUSIONS: An intensive home-based cognitive training program is suitable to improve the cognitive performance of MS patients. The impact of brain atrophy on rehabilitation outcome may differ for cognitive functions.

Discriminant analysis of the cognitive performance profile of MS patients differentiates their clinical course.

OBJECTIVE: To compare the neuropsychological deficits of primary progressive multiple sclerosis with those of relapsing-remitting and secondary progressive multiple sclerosis. METHODS: Sixty-five patients with different clinical courses of MS were neuropsychologically tested for language, attention, memory and executive functions. Discriminant analysis was used to predict the type of clinical course either by clinical variables (age, EDSS and duration of illness) or neuropsychological test results. RESULTS: For single neuropsychological tests, group differences were rare between the progressive courses and the relapsing-remitting course of MS or absent between the progressive courses of MS. However, discriminant analysis correctly identified 87.7 percent of the patients' courses in general, and about 90 percent of the patients with chronic progressive MS. CONCLUSION: Using discriminant analysis, this study found neuropsychological impairment characteristic for relapsing remitting, secondary progressive and primary progressive patients.

Cognitive performance and magnetic resonance imaging findings after high-dose systemic and intraventricular chemotherapy for primary central nervous system lymphoma.

BACKGROUND: Long-term neurotoxicity is a frequent complication of combined radiotherapy and chemotherapy in patients with primary central nervous system lymphoma. Treatment protocols without radiotherapy have been implemented to avoid this; however, little detailed neuropsychologic and neuroradiologic data exist to assess the frequency of long-term treatment sequelae in this patient group. OBJECTIVE: To determine whether a polychemotherapy regimen based on high-dose methotrexate results in cognitive impairment and/or changes detectable by magnetic resonance imaging of the brain during long-term follow-up. PATIENTS AND METHODS: Twenty patients with histologically proven primary central nervous system lymphoma were treated with a novel chemotherapy protocol that included systemic and intraventricular administration of methotrexate and cytarabine (ara-C). Standardized neuropsychologic testing and magnetic resonance imaging investigations were performed prior to therapy and prospectively during a median follow-up period of 36 months (range, 21-69 months). RESULTS: Ten patients achieved durable remissions without relapse for more than 1 year after completion of chemotherapy. There was no gross cognitive decline in any of these patients during the follow-up period. In contrast, magnetic resonance imaging revealed therapy-induced white matter changes in 5 of these patients. CONCLUSIONS: We conclude that chemotherapy alone is associated with a low risk of long-term neurotoxicity in primary central nervous system lymphoma. Methotrexate-induced white matter lesions detectable on magnetic resonance imaging are not inevitably associated with significant cognitive decline.

Intensified PCV-chemotherapy with optional stem cell support in recurrent malignant oligodendroglioma.

Six patients with recurrent or progressive anaplastic oligodendroglial tumors after surgical treatment and irradiation were treated with six/seven cycles of intensified PCV: Vincristine (1 mg/m(2)), CCNU (50 mg/m(2)) d.1,15 and procarbazine (75 mg/m(2)) d.2 to 29. If leukocytopenia (< 2.500/microl) or thrombocytopenia (< 75.000/microl) developed, 1 x 10(6) CD34(+) autologous stem cells/ kg body weight were reinfused three days after completion of subsequent cycles. Complete response was seen in 2/6 and partial response in 4/6 patients. Median follow up from time of recurrence was 35 months, progression free survival was 18 to > 39 months and overall survival 23 to > 39 months. We conclude that intensified PCV with stem cell support is feasable in recurrent/progressive anaplastic oligodendroglial tumors and appears to be sufficiently well tolerated to allow further study.

Molecular analysis of thrombophilic risk factors in patients with dural arteriovenous fistulas.

Dural arteriovenous fistulas (DAVFs) are direct artery-to-cerebral venous sinus shunts. Our recent finding of a significantly increased prevalence of factor V (FV) Leiden in patients with DAVFs prompted us to evaluate prothrombinG20210A, MTHFRC677T, beta-fibrinogenG455A, PAI-14G/5G and FXIIIVal34Leu as additional risk factors for thrombophilia in 26 patients with DAVFs and a group of age- and gender-matched controls. There was no significantly increased prevalence of these risk factors in DAVF patients. We conclude that FV Leiden is of pathogenetic significance in the aetiology of a subgroup of DAVFs whereas the other thrombophilic risk factors are not likely to be involved.

Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma.

Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARgamma can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARgamma agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARgamma agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARalpha agonist WY14643, inhibited proliferation and induced cell death. PPARgamma agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARgamma agonist treatment. The apoptotic death in the glioma cell lines treated with PPARgamma agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARgamma-mediated apoptosis, indicating an essential role of Bax in PPARgamma-induced apoptosis. However, PPARgamma agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARgamma agonists. Taken together, treatment of glioma cells with PPARgamma agonists may hold therapeutic potential for the treatment of gliomas.

Prognostic impact of molecular genetic alterations in hepatoblastoma.

BACKGROUND: During recent years, we identified characteristic genetic alterations in sporadic hepatoblastoma (HB). These include loss of heterozygosity (LOH) at the chromosomal region 11p15.5, LOH on chromosome arms 1p and 1q, activating mutations in exon 3 of the beta-catenin gene, as well as overexpression of the c-met oncogene, which encodes the hepatocyte growth factor receptor. We now wanted to evaluate the prognostic relevance of these abnormalities concerning the outcome in a large group of patients. PROCEDURE: All but 7 of 56 patients with HB were treated either with primary resection for small tumors, or neo-adjuvant chemotherapy with ifosfamide, cisplatin and doxorubicin (IPA) before delayed surgery in case of extended disease and additional adjuvant IPA therapy in all cases. Seven tumors were primarily resected and adjuvantly treated with different cytotoxic drugs. LOH 11p15.5, LOH 1p, and LOH 1q were detected in tumor tissue in comparison to normal liver and/or peripheral blood leukocytes by PCR based microsatellite analysis. Beta-catenin mutations were analysed with SSCP, deletion screening and direct sequencing. RT-PCR was used for identification of c-met mRNA overexpression. The results were correlated with the tumors' stage, histological type and epithelial differentiation, as well as with the patients' outcome. RESULTS: Overall disease-free survival after median follow-up of 5 years was 43/56 patients (77%). LOH 11p15.5 was found in 15/56, LOH1p in 11/53, LOH1q in 7/53 and beta-catenin mutations in 25/55 HB. 13/23 HB had a c-met overexpression. LOH 11p15.5 and LOH 1p were significantly more often found in embryonal HB, while there was no correlation of other genetic alterations with histological type or differentiation. Furthermore, statistical analysis revealed no correlation of any of these disorders with initial tumor stage, nor with the patients' outcome. CONCLUSION: None of the investigated molecular genetic alterations are suited to serve as a prognostic indicator in HB. Further investigations, especially genetic screening of tumor tissue may reveal prognostic markers for this neoplasm.