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3.359 A GAMMA BAND SPECIFIC INVOLVEMENT OF THE SUBTHALAMIC NUCLEUS IN SWITCHING IN VERBAL FLUENCY IN PARKINSON'S DISEASE
Wednesday, 14 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S161–S234
3.356 STAGE-DEPENDENT DOPAMINERGIC CELL LOSS IN THE SUBSTANTIA NIGRA DURING PARKINSON’S DISEASE A.A. Dijkstra1,2 , P. Voorn1 , H.J. Groenewegen1 , P. Heutink2 , A.J. Rozemuller3 , W.D.J. van de Berg1 . 1 Anatomy and Neurosciences, 2 Medical Genomics, 3 Pathology, VU University Medical Center, Amsterdam, The Netherlands Alpha-synuclein pathology may spread in a predictive manner throughout the brain in six stages as defined by Braak and colleagues. Aged individuals with alpha-synuclein pathology in the brainstem (Braak stage 1–3) may represent the premotor stage of Parkinson’s disease. The present study aims to investigate dopaminergic cell loss in the substantia nigra (SN) in Braak stage 0–6 and correlate this with disease duration and alpha-synuclein pathology load in the SN. Lewy bodies and Lewy neurites were assessed in twelve brain regions in elderly without any clinical reference of neurological disorders and Parkinson patients. In total 56 donors were included of which the frozen or paraffin-embedded SN was available for histological processing. Dopaminergic cell density was determined in eight donors per Braak stage by counting neuromelanincontaining neurons in the entire SN using design-based stereology. No significant decrease in the dopaminergic nigral density was observed between the premotor stages. A 35% decrease in dopaminergic density was observed in Braak stage 4 compared to stage 3 (p = 0.031), and 50% in Braak stage 5 compared to stage 4 (p = 0.047). No significant difference in neuron density was observed between Braak stage 5 and 6. Preliminary results show no significant correlation between dopaminergic density and disease duration and alpha-synuclein load in the SN. Our results suggest profound loss in dopaminergic nigral density in Braak stage 4 and 5, but not in the premotor stages of PD. The alpha-synuclein pathology load and disease duration do not seem to be associated with dopaminergic loss in the SN. 3.357 REGULATION ROLE OF OVEREXPRESSION OF DFOSB TO THE SIGNAL PATHWAYS IN THE STRIATUM OF LEVODOPA-INDUCED DYSKINESIA OF HEMIPARKINSONIAN RATS X. Cao. Huazhong University of Science and Technology, Wuhan, China To explore the relationship of overexpression of DFosB in the striatum of hemiparkinsonian rats and levodopa-induced dyskinesia (LID). Hemiparkinsonian rat models were established by stereotaxical injection of 6-hydroxydopamine (6-OHDA) in the left medial forebrain bundle (MFB). The PD rats injected by DFosB and EGFP cDNA (rAAV2-DFosB-EGFP) in the lesioned striatum as the experimental group. The PD rats injected by recombinant adenoassociated virus vectors with EGFP cDNA (rAAV2-EGFP) in the lesioned striatum as the control group. They were divided into 3, 6, 9, 12-week groups at random respectively, the behavior changes and abnormal involuntary movement (AIM) rations to levodopa were observed. Immunohistochemistry staining technique and western blotting were used to detect the quantitive expression of FosB/DFosB in the striatum. Levels of prodynorphin, preproenkephalin and GAD67 mRNA were measured by in situ hybridization histochemistry. In rAAV2-DFosB-EGFP groups, the AIM scores increased gradually (P < 0.01), the expression of FosB/DFosB in the lesioned striatum increased as the weeks continue (P < 0.01). At the same time, the levels of PDyn, GAD67 mRNA in the lesioned striatum increased gradually (P < 0.01), but the preproenkephalin mRNA were not changed obviously (P > 0.05). In rAAV2-EGFP groups, the changes between different-week groups were not obvious compared with the rAAV2-DFosB-EGFP groups. There were significant changes in the lesioned striatum with the intact stiatum in every groups (P < 0.01). Those data showed that injection of overexpression of DFosB in the lesioned striatum of PD
S233
rats can induce LID and it may be involve in the occurrence of LID by regulation of the pathways of basal ganglia. 3.358 ESTABLISHMENT OF 2-DE OF CEREBROSPINAL FLUID AND PRIMARY STUDY OF CSF PROTEOME OF PARKINSON’S DISEASE H. Li1 , M. Shao2 . 1 The Third Affiliated Hospital of Nanfang Medical University Neurology, Guangzhou, 2 First Affiliated Hospital of Guangzhou Medical College, Guanghzou, China Objective: To identify disease-specific protein in cerebrospinal fluid of Parkinson’s disease (PD) and discuss the pathogenesis through the established the cerebrospinal fluid of proteomics technology system. Methods: To do the two-dimensional gel electrophoresis (2-DE) for the cerebrospinal fluid of patients with Parkinson’s disease, and then do the silver staining, image analysis to identify differences in protein, and mass spectrometry analysis to identify them. Results: There were 6 points of difference in two-dimensional gel electrophoresis map of two groups, and 4 points were identified by mass spectrometry. Conclusion: This study identified four kinds of protein of Parkinson’s disease, which might take part in the pathogenesis of Parkinson’s disease, but their actual mechanism and the degree in the pathogenesis in the PD must be studied further. The decreased proteins were CENP-E, the calcium-free form of the C-type lectinlike domain of tetranectin and the FLJ-38159 protein, and the increased protein was the KIAA-1640 protein. 3.359 A GAMMA BAND SPECIFIC INVOLVEMENT OF THE SUBTHALAMIC NUCLEUS IN SWITCHING IN VERBAL FLUENCY IN PARKINSON’S DISEASE A. Anzak1,2 , L. Gaynor1 , M. Beigi1 , P. Limousin1 , M. Hariz1 , L. Zrinzo1 , T. Foltynie1 , P. Brown2 , M. Jahanshahi1 . 1 Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology & The National Hospital for Neurology & Neurosurgery, London, 2 Department of Clinical Neurology, University of Oxford, Oxford, UK Objective: Decline in verbal fluency is the most consistent and persistent cognitive impairment documented after deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. The mechanisms of this deficit are unclear. We aimed to identify and characterise verbal fluency related processing within the subthalamic nucleus through analysis of local field potentials. Methods: Local field potentials were recorded from deep brain stimulation electrodes implanted in the subthalamic nuclei of 8 patients (16 sides) with Parkinson’s disease, when patients were on medication. Patients performed phonemic and semantic verbal fluency tasks and a control word repetition task to control for the motor output involved in response generation. Results: Significant increases in local field potential Power (p ≤ 0.05) were seen across a broad gamma frequency band (30–95 Hz) during both verbal fluency tasks, after controlling for motor output. Increases in gamma local field potential Power of +7.5% ± 2.3% (SEM) in the semantic fluency task and +6.9% ± 2.0% in the phonemic fluency task were derived when averaging across all electrode contact pairs. Gamma changes recorded from contacts lying in the left hemisphere (dominant in verbal fluency) correlated with average number of correct responses generated (r = 0.81 p = 0.015) and measures of ‘switching’ (r = 0.79 p = 0.020) particularly strongly in the semantic fluency task. Conclusions: Gamma band specific power changes observed during task performance are consistent with involvement of the subthalamic nucleus in switching during verbal fluency. Antagonism of such task-related activity with high frequency stimulation of this nucleus may explain the impairments reported.
3.356 STAGE-DEPENDENT DOPAMINERGIC CELL LOSS IN THE SUBSTANTIA NIGRA DURING PARKINSON’S DISEASE A.A. Dijkstra1,2 , P. Voorn1 , H.J. Groenewegen1 , P. Heutink2 , A.J. Rozemuller3 , W.D.J. van de Berg1 . 1 Anatomy and Neurosciences, 2 Medical Genomics, 3 Pathology, VU University Medical Center, Amsterdam, The Netherlands Alpha-synuclein pathology may spread in a predictive manner throughout the brain in six stages as defined by Braak and colleagues. Aged individuals with alpha-synuclein pathology in the brainstem (Braak stage 1–3) may represent the premotor stage of Parkinson’s disease. The present study aims to investigate dopaminergic cell loss in the substantia nigra (SN) in Braak stage 0–6 and correlate this with disease duration and alpha-synuclein pathology load in the SN. Lewy bodies and Lewy neurites were assessed in twelve brain regions in elderly without any clinical reference of neurological disorders and Parkinson patients. In total 56 donors were included of which the frozen or paraffin-embedded SN was available for histological processing. Dopaminergic cell density was determined in eight donors per Braak stage by counting neuromelanincontaining neurons in the entire SN using design-based stereology. No significant decrease in the dopaminergic nigral density was observed between the premotor stages. A 35% decrease in dopaminergic density was observed in Braak stage 4 compared to stage 3 (p = 0.031), and 50% in Braak stage 5 compared to stage 4 (p = 0.047). No significant difference in neuron density was observed between Braak stage 5 and 6. Preliminary results show no significant correlation between dopaminergic density and disease duration and alpha-synuclein load in the SN. Our results suggest profound loss in dopaminergic nigral density in Braak stage 4 and 5, but not in the premotor stages of PD. The alpha-synuclein pathology load and disease duration do not seem to be associated with dopaminergic loss in the SN. 3.357 REGULATION ROLE OF OVEREXPRESSION OF DFOSB TO THE SIGNAL PATHWAYS IN THE STRIATUM OF LEVODOPA-INDUCED DYSKINESIA OF HEMIPARKINSONIAN RATS X. Cao. Huazhong University of Science and Technology, Wuhan, China To explore the relationship of overexpression of DFosB in the striatum of hemiparkinsonian rats and levodopa-induced dyskinesia (LID). Hemiparkinsonian rat models were established by stereotaxical injection of 6-hydroxydopamine (6-OHDA) in the left medial forebrain bundle (MFB). The PD rats injected by DFosB and EGFP cDNA (rAAV2-DFosB-EGFP) in the lesioned striatum as the experimental group. The PD rats injected by recombinant adenoassociated virus vectors with EGFP cDNA (rAAV2-EGFP) in the lesioned striatum as the control group. They were divided into 3, 6, 9, 12-week groups at random respectively, the behavior changes and abnormal involuntary movement (AIM) rations to levodopa were observed. Immunohistochemistry staining technique and western blotting were used to detect the quantitive expression of FosB/DFosB in the striatum. Levels of prodynorphin, preproenkephalin and GAD67 mRNA were measured by in situ hybridization histochemistry. In rAAV2-DFosB-EGFP groups, the AIM scores increased gradually (P < 0.01), the expression of FosB/DFosB in the lesioned striatum increased as the weeks continue (P < 0.01). At the same time, the levels of PDyn, GAD67 mRNA in the lesioned striatum increased gradually (P < 0.01), but the preproenkephalin mRNA were not changed obviously (P > 0.05). In rAAV2-EGFP groups, the changes between different-week groups were not obvious compared with the rAAV2-DFosB-EGFP groups. There were significant changes in the lesioned striatum with the intact stiatum in every groups (P < 0.01). Those data showed that injection of overexpression of DFosB in the lesioned striatum of PD
S233
rats can induce LID and it may be involve in the occurrence of LID by regulation of the pathways of basal ganglia. 3.358 ESTABLISHMENT OF 2-DE OF CEREBROSPINAL FLUID AND PRIMARY STUDY OF CSF PROTEOME OF PARKINSON’S DISEASE H. Li1 , M. Shao2 . 1 The Third Affiliated Hospital of Nanfang Medical University Neurology, Guangzhou, 2 First Affiliated Hospital of Guangzhou Medical College, Guanghzou, China Objective: To identify disease-specific protein in cerebrospinal fluid of Parkinson’s disease (PD) and discuss the pathogenesis through the established the cerebrospinal fluid of proteomics technology system. Methods: To do the two-dimensional gel electrophoresis (2-DE) for the cerebrospinal fluid of patients with Parkinson’s disease, and then do the silver staining, image analysis to identify differences in protein, and mass spectrometry analysis to identify them. Results: There were 6 points of difference in two-dimensional gel electrophoresis map of two groups, and 4 points were identified by mass spectrometry. Conclusion: This study identified four kinds of protein of Parkinson’s disease, which might take part in the pathogenesis of Parkinson’s disease, but their actual mechanism and the degree in the pathogenesis in the PD must be studied further. The decreased proteins were CENP-E, the calcium-free form of the C-type lectinlike domain of tetranectin and the FLJ-38159 protein, and the increased protein was the KIAA-1640 protein. 3.359 A GAMMA BAND SPECIFIC INVOLVEMENT OF THE SUBTHALAMIC NUCLEUS IN SWITCHING IN VERBAL FLUENCY IN PARKINSON’S DISEASE A. Anzak1,2 , L. Gaynor1 , M. Beigi1 , P. Limousin1 , M. Hariz1 , L. Zrinzo1 , T. Foltynie1 , P. Brown2 , M. Jahanshahi1 . 1 Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology & The National Hospital for Neurology & Neurosurgery, London, 2 Department of Clinical Neurology, University of Oxford, Oxford, UK Objective: Decline in verbal fluency is the most consistent and persistent cognitive impairment documented after deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. The mechanisms of this deficit are unclear. We aimed to identify and characterise verbal fluency related processing within the subthalamic nucleus through analysis of local field potentials. Methods: Local field potentials were recorded from deep brain stimulation electrodes implanted in the subthalamic nuclei of 8 patients (16 sides) with Parkinson’s disease, when patients were on medication. Patients performed phonemic and semantic verbal fluency tasks and a control word repetition task to control for the motor output involved in response generation. Results: Significant increases in local field potential Power (p ≤ 0.05) were seen across a broad gamma frequency band (30–95 Hz) during both verbal fluency tasks, after controlling for motor output. Increases in gamma local field potential Power of +7.5% ± 2.3% (SEM) in the semantic fluency task and +6.9% ± 2.0% in the phonemic fluency task were derived when averaging across all electrode contact pairs. Gamma changes recorded from contacts lying in the left hemisphere (dominant in verbal fluency) correlated with average number of correct responses generated (r = 0.81 p = 0.015) and measures of ‘switching’ (r = 0.79 p = 0.020) particularly strongly in the semantic fluency task. Conclusions: Gamma band specific power changes observed during task performance are consistent with involvement of the subthalamic nucleus in switching during verbal fluency. Antagonism of such task-related activity with high frequency stimulation of this nucleus may explain the impairments reported.