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P119 Functional and molecular analysis of glycine receptors in human midbrain-derived neural progenitor cells
Abstract / Basal Ganglia 1 (2011) 13–45
P117 Atypical clinical presentation in postmortem validated PSP G. Respondek, S. Roeber, M. Apfelbacher, E. Gelpi, C. Gaig, C. Troakes, W. Chiu, J. van Swieten, A. Rajput, H. Kretzschmar, W.H. Oertel, G. Höglinger (Marburg, Munich, Würzburg; Barcelona, ES; London, UK; Rotterdam, NL; Saskatchewan, CA) Background: The commonly used NINDS-SPSP criteria (Litvan et al., 1996) for the clinical diagnosis of probable PSP show a sensitivity of 50% or lower. The low sensitivity might result from the heterogenic clinical presentation of PSP. The classical presentation of PSP is now referred to as Richardson’s syndrome. Atypical variants of PSP have been recently reported as PSP-parkinsonism (PSP-P), pure akinesia with gait freezing (PAGF), PSP with corticobasal syndrome (PSP-CBS), PSP with progressive non-fluent aphasia (PSP-PNFA), PSP with fronto-temporal dementia (PSP-FTD), PSP with Semantic Dementia (PSP-SD) and PSP with primary lateral sclerosis (PSPPLS). There are presently no accepted guidelines for the clinical diagnosis of these variants. Objective: Comprehensive and standardized description of the clinical features and their time course of onset in a large series of postmortem validated PSP in an attempt to identify core features encompassing Richardson’s syndrome as well as the atypical variants of PSP. Methods: Pathologically confirmed PSP cases based on the current criteria for the pathological diagnosis of PSP (Hauw et al., 1994) were selected from the research and clinical files from six medical centers in Germany, UK, the Netherland, Spain and Canada. Only neuropathologically verified cases of PSP were included. Retrospective chart review was performed. Clinical and demographic features were abstracted in a standardized manner by a neurologist. Each symptom was recorded with date of onset. Symptoms that could not be abstracted from the clinical files were recorded as ‘‘not available’’. Cases were classified into typical and atypical variants. Results and conclusions: Clinical characteristics of 110 cases were analysed. This retrospective study of the natural history cases showed a tremendous heterogeneity in clinical presentation of pathologically confirmed PSP. Vertical supranuclear gaze palsy was present at disease onset in only a few patients. Much more commonly, vertical supranuclear palsy occurred several years after disease onset, or developed never. Differences in the clinical presentation and the course of disease observed in our study show the need of guidelines for the clinical diagnosis of atypical PSP variants. Incorporation of clinical features for atypical PSP variants into diagnostic criteria could serve to improve sensitivity for diagnosing PSP clinically. doi:10.1016/j.baga.2011.01.037
P118 Health-related quality of life and disease-related costs in multiple system atrophy and progressive supranuclear palsy Y. Winter, A.E. Spottke, M. Stamelou, N. Cabanel, K. Eggert, G. Höglinger, F. Sixel-Döring, B. Herting, T. Klockgether, H. Reichmann, W.H. Oertel, R. Dodel (Marburg, Bonn, Kassel, Dresden) Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are neurodegenerative disorders causing severe disability and decreased life expectancy. Currently, no health-economic evaluations in those disorders are available. There are no studies investigating the health-related quality of life (HrQoL) in German patients with atypical parkinsonian syndromes. The objective of this study was to evaluate HrQoL and disease-related costs in German
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patients with MSA and PSP and to identify determinants of HrQoL and costs. Patients and methods: 101 consecutive patients with MSA (n = 54) and PSP (n = 47) were recruited in four German specialized movement disorder clinics. The HrQoL was evaluated using the EuroQol instrument (EQ-5D and EQ-VAS). The collection of the health-economic data was performed on the level of individuals (‘‘bottomup’’ approach) using comprehensive health-economic questionnaires. Costs were calculated from the societal perspective in 2010 Euros. Multiple regression analysis was used to identify independent determinants of HrQoL and costs. Results: The mean EQ-VAS score of patients with MSA and PSP was 33% lower than that reported for German patients with idiopathic Parkinson’s disease (PD) (36.9 ± 18.3 versus 59.9 ± 18.0). Of the study participants, 63% reported severe problems in at least one dimension of the EQ-5D. The dimensions most affected were ‘‘mobility’’, ‘‘self-care’’ and ‘‘usual activities’’. Independent determinants of reduced HrQoL were female gender, <12 years of education, disease severity, a decreased number of persons in the household and depression. The total semiannual costs were EUR 16,670 (95% CI: 13,470–21,850) per patient. Direct costs accounted for 73% (inpatient care 31%, special equipment 24%, copayments of patients 21%, others 24%) of total costs. Independent cost-driving factors were younger age, disease severity, living without a partner and depression. Conclusion: MSA and PSP have considerably reduced HrQoL and higher disease-related costs in comparison to idiopathic PD. While therapeutic options in the treatment of motor symptoms remain restricted, greater attention should be paid to the treatment of non-motor symptoms, such as depression, which was identified among independent determinants of HrQoL and costs. Independent determinants of HrQoL and cost-driving factors should be considered when developing national healthcare programs aimed at improving the health-care in atypical parkinsonian syndromes. doi:10.1016/j.baga.2011.01.038
P119 Functional and molecular analysis of glycine receptors in human midbrain-derived neural progenitor cells F. Wegner, R. Kraft, K. Busse, W. Härtig, J. Schwarz (Hannover, Leipzig) Human fetal midbrain-derived neural progenitor cells (NPCs) may serve as a continuous source of dopaminergic neurons for the development of novel regenerative therapies in Parkinson’s disease. However, the molecular and functional characteristics of the important glycine receptors in human NPCs are largely unknown. Here, we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of many NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular characterisations indicate a predominance of glycine receptor heteromers containing subunits a2 and b. Intracellular calcium measurements and the expression profile of the Na–K– Cl-co-transporter 1 (NKCC1) and the K–Cl-co-transporter 2 (KCC2) in differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors. These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation in vitro. doi:10.1016/j.baga.2011.01.039
P117 Atypical clinical presentation in postmortem validated PSP G. Respondek, S. Roeber, M. Apfelbacher, E. Gelpi, C. Gaig, C. Troakes, W. Chiu, J. van Swieten, A. Rajput, H. Kretzschmar, W.H. Oertel, G. Höglinger (Marburg, Munich, Würzburg; Barcelona, ES; London, UK; Rotterdam, NL; Saskatchewan, CA) Background: The commonly used NINDS-SPSP criteria (Litvan et al., 1996) for the clinical diagnosis of probable PSP show a sensitivity of 50% or lower. The low sensitivity might result from the heterogenic clinical presentation of PSP. The classical presentation of PSP is now referred to as Richardson’s syndrome. Atypical variants of PSP have been recently reported as PSP-parkinsonism (PSP-P), pure akinesia with gait freezing (PAGF), PSP with corticobasal syndrome (PSP-CBS), PSP with progressive non-fluent aphasia (PSP-PNFA), PSP with fronto-temporal dementia (PSP-FTD), PSP with Semantic Dementia (PSP-SD) and PSP with primary lateral sclerosis (PSPPLS). There are presently no accepted guidelines for the clinical diagnosis of these variants. Objective: Comprehensive and standardized description of the clinical features and their time course of onset in a large series of postmortem validated PSP in an attempt to identify core features encompassing Richardson’s syndrome as well as the atypical variants of PSP. Methods: Pathologically confirmed PSP cases based on the current criteria for the pathological diagnosis of PSP (Hauw et al., 1994) were selected from the research and clinical files from six medical centers in Germany, UK, the Netherland, Spain and Canada. Only neuropathologically verified cases of PSP were included. Retrospective chart review was performed. Clinical and demographic features were abstracted in a standardized manner by a neurologist. Each symptom was recorded with date of onset. Symptoms that could not be abstracted from the clinical files were recorded as ‘‘not available’’. Cases were classified into typical and atypical variants. Results and conclusions: Clinical characteristics of 110 cases were analysed. This retrospective study of the natural history cases showed a tremendous heterogeneity in clinical presentation of pathologically confirmed PSP. Vertical supranuclear gaze palsy was present at disease onset in only a few patients. Much more commonly, vertical supranuclear palsy occurred several years after disease onset, or developed never. Differences in the clinical presentation and the course of disease observed in our study show the need of guidelines for the clinical diagnosis of atypical PSP variants. Incorporation of clinical features for atypical PSP variants into diagnostic criteria could serve to improve sensitivity for diagnosing PSP clinically. doi:10.1016/j.baga.2011.01.037
P118 Health-related quality of life and disease-related costs in multiple system atrophy and progressive supranuclear palsy Y. Winter, A.E. Spottke, M. Stamelou, N. Cabanel, K. Eggert, G. Höglinger, F. Sixel-Döring, B. Herting, T. Klockgether, H. Reichmann, W.H. Oertel, R. Dodel (Marburg, Bonn, Kassel, Dresden) Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are neurodegenerative disorders causing severe disability and decreased life expectancy. Currently, no health-economic evaluations in those disorders are available. There are no studies investigating the health-related quality of life (HrQoL) in German patients with atypical parkinsonian syndromes. The objective of this study was to evaluate HrQoL and disease-related costs in German
25
patients with MSA and PSP and to identify determinants of HrQoL and costs. Patients and methods: 101 consecutive patients with MSA (n = 54) and PSP (n = 47) were recruited in four German specialized movement disorder clinics. The HrQoL was evaluated using the EuroQol instrument (EQ-5D and EQ-VAS). The collection of the health-economic data was performed on the level of individuals (‘‘bottomup’’ approach) using comprehensive health-economic questionnaires. Costs were calculated from the societal perspective in 2010 Euros. Multiple regression analysis was used to identify independent determinants of HrQoL and costs. Results: The mean EQ-VAS score of patients with MSA and PSP was 33% lower than that reported for German patients with idiopathic Parkinson’s disease (PD) (36.9 ± 18.3 versus 59.9 ± 18.0). Of the study participants, 63% reported severe problems in at least one dimension of the EQ-5D. The dimensions most affected were ‘‘mobility’’, ‘‘self-care’’ and ‘‘usual activities’’. Independent determinants of reduced HrQoL were female gender, <12 years of education, disease severity, a decreased number of persons in the household and depression. The total semiannual costs were EUR 16,670 (95% CI: 13,470–21,850) per patient. Direct costs accounted for 73% (inpatient care 31%, special equipment 24%, copayments of patients 21%, others 24%) of total costs. Independent cost-driving factors were younger age, disease severity, living without a partner and depression. Conclusion: MSA and PSP have considerably reduced HrQoL and higher disease-related costs in comparison to idiopathic PD. While therapeutic options in the treatment of motor symptoms remain restricted, greater attention should be paid to the treatment of non-motor symptoms, such as depression, which was identified among independent determinants of HrQoL and costs. Independent determinants of HrQoL and cost-driving factors should be considered when developing national healthcare programs aimed at improving the health-care in atypical parkinsonian syndromes. doi:10.1016/j.baga.2011.01.038
P119 Functional and molecular analysis of glycine receptors in human midbrain-derived neural progenitor cells F. Wegner, R. Kraft, K. Busse, W. Härtig, J. Schwarz (Hannover, Leipzig) Human fetal midbrain-derived neural progenitor cells (NPCs) may serve as a continuous source of dopaminergic neurons for the development of novel regenerative therapies in Parkinson’s disease. However, the molecular and functional characteristics of the important glycine receptors in human NPCs are largely unknown. Here, we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of many NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular characterisations indicate a predominance of glycine receptor heteromers containing subunits a2 and b. Intracellular calcium measurements and the expression profile of the Na–K– Cl-co-transporter 1 (NKCC1) and the K–Cl-co-transporter 2 (KCC2) in differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors. These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation in vitro. doi:10.1016/j.baga.2011.01.039