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Association of α-synuclein gene expression with Parkinson’s disease is attenuated with higher serum urate in the PPMI cohort
Abstracts / Parkinsonism and Related Disorders 22 (2016) e87ee141
and their potential mode of actions. Results: Out of the four animals, two were severely affected by the MPTP lesions whereas the other two exhibited mild symptoms. Furthermore, the 18 F-dopa striatal uptake was reduced by about 80% in three of them. Six months following ANCE transplantations, all monkeys presented significant improvement of their motor impairments (spontaneous activity, manual dexterity, posture, etc.). This functional recovery was accompanied by an increase of 18F-dopa striatal uptake. Conclusions: Taken together these new data open new therapeutic perspectives for the ANCE approach regarding neurodegenerative disorders like Parkinson’s diseases. References: 1. Bloch J, Brunet, J.-F McEntire CRS, Redmond DE. Primate adult brain cell autotransplant-ation produces behavioral and biological recovery in 1methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced parkinsonian St. Kitts monkeys. J Comp Neurol 2014;522:2729e2740. 2. Brunet J-F, Pellerin L, Arsenijevic Y, Magistretti P, Villemure J-G. A novel method for in vitro production of human glial-like cells from neurosurgical resection tissue. Lab Invest 2002;82:809e812. 3. Schmidlin E, Kaeser M, Gindrat AD, et al. Behavioral Assessment of Manual Dexterity in Non-Human Primates. JoVE 2011;e3258ee3258. http://dx.doi.org/10.3791/3258
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end product of purine metabolism in humans, but also possesses potent antioxidant and neuroprotective properties. Lower serum urate is a reproducible risk factor both for developing PD and for a more rapid rate of its clinical progression. Methods: Data were analyzed from the Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI), which enrolled 218 people with early, untreated PD and 153 healthy control (HC) subjects for whom baseline blood levels of urate and a-synuclein gene (SNCA) transcript were available. Results: SNCA transcript counts are substantially reduced (p¼0.0001) in PD compared to HC among those with lower urate (below the median HC value of 5.4 mg/dL), but not appreciably different among those with higher urate (p¼0.5). In further analysis fully adjusting for relevant covariates, the odds of having PD were markedly lower among individuals with more SNCA transcripts only if they also had lower urate (OR ¼ 0.61 / 103 mRNA, p¼0.002), not higher urate (OR ¼ 0.91 / 103 mRNA, p¼0.6), with a significant interaction between urate and SNCA transcripts (p¼0.02). Conclusions: These preliminary data suggest that the impact of a-synuclein on PD is attenuated in the presence of higher concentrations of urate.
P 2.124. DIFFERENTIAL INDUCTION OF DYSKINESIA AND INFLAMMATORY RESPONSES BY INTERMITTENT VERSUS CONTINUOUS L-DOPA DELIVERY IN THE 6-OHDA MODEL OF PARKINSON'S DISEASE. Anna R. Carta 1, Giovanna Mulas 1, Saturnino Spiga 2, Daniela Lecca 1, Elisabetta Pillai 1. 1 Dept. of Biomedical Sciences, Univ. of Cagliari, Italy; 2 Dept. of Life and Environmental Sciences, Univ. of Cagliari, Italy Objectives: Neuroinflammation is a main component of PD neuropathology, and recent evidence suggests that may contribute to the development of L-DOPA-induced dyskinesia (LID). We investigated this issue by comparing a dyskinetic to a non-dyskinetic L-DOPA treatment in the 6OHDA rat model of PD. Methods: Emiparkinsonian rats were chronically treated with intermittent L-DOPA (DOPAi, 6 mg/kg/day s.c. for 15 days), or continuous L-DOPA via subcutaneous osmotic minipumps (DOPAc 12 mg/kg for 15 days). Moreover, one group of rats was challenged with a single peripheral dose of lipopolysaccharide (LPS, 2 mg/kg i.p.) 24 hrs before DOPAi treatment. Abnormal involuntary movements (AIMs) were evaluated on alternate days during L-DOPA treatments as a correlate of dyskinesia. Confocal analysis of OX-42, iNOS, GFAP and TNF-a immunoreactivity (IR) was performed in the dopamine-depleted dorsal striatum to assess microglia and astroglia reactivity. Results: Rats treated with DOPAi but not DOPAc developed AIMs. DOPAi induced an inflammatory response in the striatum as shown by increased OX-42-IR, iNOS-IR, GFAP-IR, TNF-a colocalization in microglia and neurons, as compared to vehicle. In contrast, DOPAc treatment did not produce any inflammatory response. The LPS challenge increased the amplitude of AIMs induced by DOPAi, and increased striatal levels of inflammatory markers as compared to DOPAi alone. Conclusions: Results suggest an involvement of neuroinflammation in the development of LID. P 2.125. ASSOCIATION OF a-SYNUCLEIN GENE EXPRESSION WITH PARKINSON’S DISEASE IS ATTENUATED WITH HIGHER SERUM URATE IN THE PPMI COHORT Michael Schwarzschild 1, Kathryn Fitzgerald 2, Rachit Bakshi 1, Eric Macklin 3, Clemens Scherzer 1, Alberto Ascherio 2. 1 Department of Neurology, Massachusetts General Hospital, Boston, United States; 2 Department of Nutrition, Harvard School of Public Health, Boston, United States; 3 Department of Medicine, Massachusetts General Hospital, Boston, United States Objective: To explore how urate may modulate Parkinson’s disease (PD)specific pathogenic mechanisms using clinical biomarker data. Urate is the
Ă
P 3.001. CLINICAL AND NEUROPATHOLOGICAL FEATURES PROGRESSIVE DEMENTIA WITH LEWY BODIES
OF
RAPID
A.J. Geut 1, D.H. Hepp 1, A.M.T. Ingrassia 1, Y. Galis 1, E.M.J. Foncke 2, A.W. Lemstra 2, A.J.M. Rozemuller 2, W.D.J. van de Berg 1. 1 Dept. Anatomy and Neurosciences, VU University Medical Center, Amsterdam, Netherlands; 2 Dept. of Neurology, VU University Medical Center, Amsterdam, Netherlands Objectives: Dementia with Lewy Bodies (DLB) can follow a very rapid progressive disease course, resembling Creutzfeldt-Jakob’s Disease (CJD)1. This is the first study to describe the neuropathological findings in a cohort of rapid progressive DLB patients. Our aim is to test whether the presence and load of Lewy Bodies and concomitant pathology differs between rapid progressive DLB and classical DLB. Methods: All cases suspected of CJD in the Netherlands from 1998-2014 that had alpha-synuclein pathology but not CJD upon autopsy were collected. Fourteen patients with clinically probable DLB and a disease duration of less than four years were included. All 38 probable DLB patients that were collected from 1996 to 2013 in the Netherlands Brain Bank with a disease duration of five years or more were included as a classical DLB group. Results: In rapid progressive DLB, symptoms of CJD such as myoclonus (71%), pyramidal (21%) and cerebellar symptoms (29%) frequently occur, but not in classical DLB. There was no difference between groups in presence and load of Lewy Bodies or concomitant pathology throughout the brain. 21% of the rapid progressive DLB and 29% of classical DLB cases showed severe spongiosis. Conclusions: Patients with rapid progressive DLB frequently have clinical symptoms not classically described in DLB, but show the same neuropathological features as slow progressive DLB patients. Spongiosis is present in a substantial number of all DLB patients.
and their potential mode of actions. Results: Out of the four animals, two were severely affected by the MPTP lesions whereas the other two exhibited mild symptoms. Furthermore, the 18 F-dopa striatal uptake was reduced by about 80% in three of them. Six months following ANCE transplantations, all monkeys presented significant improvement of their motor impairments (spontaneous activity, manual dexterity, posture, etc.). This functional recovery was accompanied by an increase of 18F-dopa striatal uptake. Conclusions: Taken together these new data open new therapeutic perspectives for the ANCE approach regarding neurodegenerative disorders like Parkinson’s diseases. References: 1. Bloch J, Brunet, J.-F McEntire CRS, Redmond DE. Primate adult brain cell autotransplant-ation produces behavioral and biological recovery in 1methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced parkinsonian St. Kitts monkeys. J Comp Neurol 2014;522:2729e2740. 2. Brunet J-F, Pellerin L, Arsenijevic Y, Magistretti P, Villemure J-G. A novel method for in vitro production of human glial-like cells from neurosurgical resection tissue. Lab Invest 2002;82:809e812. 3. Schmidlin E, Kaeser M, Gindrat AD, et al. Behavioral Assessment of Manual Dexterity in Non-Human Primates. JoVE 2011;e3258ee3258. http://dx.doi.org/10.3791/3258
e115
end product of purine metabolism in humans, but also possesses potent antioxidant and neuroprotective properties. Lower serum urate is a reproducible risk factor both for developing PD and for a more rapid rate of its clinical progression. Methods: Data were analyzed from the Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI), which enrolled 218 people with early, untreated PD and 153 healthy control (HC) subjects for whom baseline blood levels of urate and a-synuclein gene (SNCA) transcript were available. Results: SNCA transcript counts are substantially reduced (p¼0.0001) in PD compared to HC among those with lower urate (below the median HC value of 5.4 mg/dL), but not appreciably different among those with higher urate (p¼0.5). In further analysis fully adjusting for relevant covariates, the odds of having PD were markedly lower among individuals with more SNCA transcripts only if they also had lower urate (OR ¼ 0.61 / 103 mRNA, p¼0.002), not higher urate (OR ¼ 0.91 / 103 mRNA, p¼0.6), with a significant interaction between urate and SNCA transcripts (p¼0.02). Conclusions: These preliminary data suggest that the impact of a-synuclein on PD is attenuated in the presence of higher concentrations of urate.
P 2.124. DIFFERENTIAL INDUCTION OF DYSKINESIA AND INFLAMMATORY RESPONSES BY INTERMITTENT VERSUS CONTINUOUS L-DOPA DELIVERY IN THE 6-OHDA MODEL OF PARKINSON'S DISEASE. Anna R. Carta 1, Giovanna Mulas 1, Saturnino Spiga 2, Daniela Lecca 1, Elisabetta Pillai 1. 1 Dept. of Biomedical Sciences, Univ. of Cagliari, Italy; 2 Dept. of Life and Environmental Sciences, Univ. of Cagliari, Italy Objectives: Neuroinflammation is a main component of PD neuropathology, and recent evidence suggests that may contribute to the development of L-DOPA-induced dyskinesia (LID). We investigated this issue by comparing a dyskinetic to a non-dyskinetic L-DOPA treatment in the 6OHDA rat model of PD. Methods: Emiparkinsonian rats were chronically treated with intermittent L-DOPA (DOPAi, 6 mg/kg/day s.c. for 15 days), or continuous L-DOPA via subcutaneous osmotic minipumps (DOPAc 12 mg/kg for 15 days). Moreover, one group of rats was challenged with a single peripheral dose of lipopolysaccharide (LPS, 2 mg/kg i.p.) 24 hrs before DOPAi treatment. Abnormal involuntary movements (AIMs) were evaluated on alternate days during L-DOPA treatments as a correlate of dyskinesia. Confocal analysis of OX-42, iNOS, GFAP and TNF-a immunoreactivity (IR) was performed in the dopamine-depleted dorsal striatum to assess microglia and astroglia reactivity. Results: Rats treated with DOPAi but not DOPAc developed AIMs. DOPAi induced an inflammatory response in the striatum as shown by increased OX-42-IR, iNOS-IR, GFAP-IR, TNF-a colocalization in microglia and neurons, as compared to vehicle. In contrast, DOPAc treatment did not produce any inflammatory response. The LPS challenge increased the amplitude of AIMs induced by DOPAi, and increased striatal levels of inflammatory markers as compared to DOPAi alone. Conclusions: Results suggest an involvement of neuroinflammation in the development of LID. P 2.125. ASSOCIATION OF a-SYNUCLEIN GENE EXPRESSION WITH PARKINSON’S DISEASE IS ATTENUATED WITH HIGHER SERUM URATE IN THE PPMI COHORT Michael Schwarzschild 1, Kathryn Fitzgerald 2, Rachit Bakshi 1, Eric Macklin 3, Clemens Scherzer 1, Alberto Ascherio 2. 1 Department of Neurology, Massachusetts General Hospital, Boston, United States; 2 Department of Nutrition, Harvard School of Public Health, Boston, United States; 3 Department of Medicine, Massachusetts General Hospital, Boston, United States Objective: To explore how urate may modulate Parkinson’s disease (PD)specific pathogenic mechanisms using clinical biomarker data. Urate is the
Ă
P 3.001. CLINICAL AND NEUROPATHOLOGICAL FEATURES PROGRESSIVE DEMENTIA WITH LEWY BODIES
OF
RAPID
A.J. Geut 1, D.H. Hepp 1, A.M.T. Ingrassia 1, Y. Galis 1, E.M.J. Foncke 2, A.W. Lemstra 2, A.J.M. Rozemuller 2, W.D.J. van de Berg 1. 1 Dept. Anatomy and Neurosciences, VU University Medical Center, Amsterdam, Netherlands; 2 Dept. of Neurology, VU University Medical Center, Amsterdam, Netherlands Objectives: Dementia with Lewy Bodies (DLB) can follow a very rapid progressive disease course, resembling Creutzfeldt-Jakob’s Disease (CJD)1. This is the first study to describe the neuropathological findings in a cohort of rapid progressive DLB patients. Our aim is to test whether the presence and load of Lewy Bodies and concomitant pathology differs between rapid progressive DLB and classical DLB. Methods: All cases suspected of CJD in the Netherlands from 1998-2014 that had alpha-synuclein pathology but not CJD upon autopsy were collected. Fourteen patients with clinically probable DLB and a disease duration of less than four years were included. All 38 probable DLB patients that were collected from 1996 to 2013 in the Netherlands Brain Bank with a disease duration of five years or more were included as a classical DLB group. Results: In rapid progressive DLB, symptoms of CJD such as myoclonus (71%), pyramidal (21%) and cerebellar symptoms (29%) frequently occur, but not in classical DLB. There was no difference between groups in presence and load of Lewy Bodies or concomitant pathology throughout the brain. 21% of the rapid progressive DLB and 29% of classical DLB cases showed severe spongiosis. Conclusions: Patients with rapid progressive DLB frequently have clinical symptoms not classically described in DLB, but show the same neuropathological features as slow progressive DLB patients. Spongiosis is present in a substantial number of all DLB patients.