1038 deep brain stimulation in parkinson's disease. clinical utility six months later
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Poster Abstracts Wednesday, November 9, 2005 $363
Performance remained unchanged at follow-up for most measures even for patients with longer period of follow up. However the performance of Verbal Fluency and Stroup test was closer to the level of significance (p < 0,05). Conclusion: The results suggest that intrastriatal bilateral transplanta- tion of embryouic neurons producing dopamine is a safe procedure and does not induce cognitive impairment in patients with PD. The mild change on some cognitive tasks is in agreement with the decline observed in the natural evolution of idiopathic PD.
1035 Results froln a 2-year centralized Tolcapone liver et;zyme motfitoring program
Lew, M ~, Kricorian, G ~. 1Department of Neurology, University of Southern Calijbrnia/Keck School of Medicine, Los Angeles, CA, USA; 2Valeant Pharmaceuticals International, Costa ~fesa, CA, USA
Background: Tolcapone was the first COMT inhibitor approved to treat Parkinson's disease (PD). New liver monitoring guidelines were established by FDA in 1998. At that time, the manufacturer implemented a Liver Enzyme Monitoring Program whereby neurolo- gists sent their PD patient's blood samples to a central laboratory for analysis. Methods: We reviewed this central laboratory database in order to determine the frequency of liver function test (LFT) elevations in patients receiving tolcapone and undergoing every two-week LFT monitoring for up to 2 years from January 1999 to May 2001. Results: Of the 1725 PD patients who had at least one AST and ALT test performed, 67 patients (3.9%) had an elevation above the upper limit of normal (ULN). Only 15 patients (0.9"/0) had an LFT elevation greater than 2 times ULN. In most cases, LFTs returned to normal with continued tolcapone administration. Of the 472 patients who were monitored on tolcapone between 20 to 114 consecutive weeks, only 3 patients (10.6"/o) had an ALT or AST value greater titan 2 times ULN. The remaiuing 99.4% of patients did not have a significant LFT elevation, and would have achieved similar safety from a less demanding schedule of LFT monitoring. Conclusion: This review of up to 2 years of LFT monitoring suggests that the incidence of liver transanfinase elevations with tolcapone is rare. For most patients on chronic therapy, less fiequent monitoring with an action limit of 2-3 times the upper limit o f normal may be sufficient to ensure safety.
1036 Long-Term Treahnent of Parkh~son's Disease With a Novel MAO-B Inhibitor: Analysis of Safety and Efficacy
Lew, M 1, Kricorian, G 2. 1Department of Neurology, University of Southern California/Keek School of Medicine, Los Angeles, CA, United States of America; 2 Valeant Pharmaceuticals International, Costa Mesa, CA, United States of America
Backgrouml: Data from short-term studies in patients with Parkinson's disease (PD) suggest that selegiline orally disintegrating tablets (ODT), a selective monoanfine oxidase B inlfibitor, safely and effectively reduce "off-time". Method: The results of an open-label extension of two randomized, double-blind, placebo-controlled, parallel-group studies evaluating the long-term safety and efficacy of selegiline ODT in patients with PD being treated with levodopa, with or without a dopanfine agorfist, are reported. This extension study included 254 safety-evahiable and 248 efficacy-evahiable patients who were administered 2 dose levels of selegiline ODT (1.25 or 2.5 mg/day; 99.2% of the patients received 2.5 mg). Efficacy was based on percentage reduction in total daily "off-time" during waking hours as recorded in diary cards by the patient/caregiver. Safety and tolerability were assessed by recording adverse events (AEs) in addition to routine laboratory test, vital sign,
physical examination, electrocardiogram, and oropharyngeal exam- ination results. Results: Results from patients treated with selegiline ODT for >6 months, 1, 2, 3 and 4 years indicate long-term efficacy, with a mean reduction from baseline in daily off-time of 1.4 hours across all groups. Most reported AEs involved the central nervous system, and 23.2"/0 of patients discontinued treatment because of AEs. There were no treatment-related laboratory abnormalities and no significant changes from baseline in electrocardiographic or oropharyngeal findings. Conclusion: The results of this long-term open-label extension study indicate that selegiline ODT is safe and effective as an adjunctive maintenance therapy in patients with PD who experience a deteriora- tion of their response to levodopa.
1037 ProteaSome Mediated Degradation of tile Parldn Co-Regulated Gene Protein (PACRG)
Lockhart, PJ~, Wilson, GR a, Farrer, MJ 2, Delatycki, M ~. 1Bruce Lefroy Centre, Murdooh Childrens Research Institute, Melbourne, Australia; ~Departrnent of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America
Background: Parkin Co-Regulated Gene or PACRG is a novel gene located on chromosome 6q25-27. PACRG shares a bi-directional promoter with Parldn, a gene that causes autosomal recessive juvenile Parkinsonism (AR-JP) when mutated. In addition, the protein product (PACRG) is present in Lewy bodies, the pathological hallmark of Parkinson's disease (PD). Although the exact function of PACRG is not known, it has been implicated in male infertility and neurodegen- eration. Method: To investigate the function of PACRG, we examined its expression and localisation in mammalian cells. Results: Western and innnunotfistochenfical analysis showed steady state levels of PACRG protein were practically undetectable in transfected cells. Similar results were observed with native and epitope tagged PACRG. Treatment of cells expressing P A C R G with inhibitors of the lysosomal protein degradation pathway did not significantly affect PACRG levels. In contrast, treatment with proteasomal intfibitors (lactacystin and MG-132) significantly increased the steady state levels of PACRG. To confirm PACRG levels were regulated by the ubiquitin proteasome system, we co-expressed ubiquitin and PACRG. Cell extracts were immunoprecipitated with an antibody directed against P A C R G and analysed by Western blot. Ubiquitin positive high molecular weight species were identified. Conclusion: Our results suggest P A C R G is regulated by the ubiquitin- proteasome system (UPS) and may play a role in the disease pathogenesis of neurodegenerative conditions, such as Parkinson's disease, which are characterised by disruption of the UPS.
1038 Deep Brain Stimulation in Parldnson's disease. Clinical Utility Six Months Later
Luengo, A ~, Heumndo, V 3, Pastor, 32, Pedrosa, M 2, Garcia de Sola, R a. 1Neurology University Hospital "La Prineesa", Madrid, Spain; ~Funetional Neurosurgery University Hospital "'La Prineesa", Madrid, Spain; 3Neurology, Functional Neurosurgery University Hospital "La Princesa", Madrid, Spain
Background: To evaluate the clinical utility of deep brain stimulation (DBS) of subthalamic nucleus (STN) in patients with Parkinson disease in ours series. Method: To analyze the evolution in the clinical changes of patients with Parkinson" disease treated with DBS of STN uni or bilaterally. Results: Twenty-four patients were analyzed, 18 with bilateral and 6 with uuilateral device. 16 males and 8 females; mean age 64,8 ± 8,5 years; evolution's time 14,0 ± 6,3 years. Initial: Hoehn Yahr OFF 4,0
$364 Wednesday, November 9, 2005 Poster Abstracts
ON 2,7; Schwab England OFF 50,5, ON 76,4. UPDRS I: 3 ,0± 3,0; II: 20,5±4,9; III OFF: 50,0±11,6, ON: 27,8±8,8; IV: 8,9±3,2. Six months later: Hoehn Yahr: OFF/OFF: 3,7; ON/ON 2,3; Schwab England OFF/OFF 61,3; ON/ON 84,7. UPDRS I: 2,1 ± 1,7; II: 16,0±5,5; III: OFF/OFF 44,5±16,3; OFF/ON: 34,5±10,2; ON/ OFF: 32,9 ± 11,7; ON/ON: 23,8 ± 7,3; IV: 4,7 ± 1,4. Antiparkinsonian medications were reduced in a mean of 38%. No important surgical complications occurred, only two surgical infections. Conclusion: In our series DBS of STN is a safety alternative for Parkinson's disease patients with poor clinical control in pharmaco- logical therapy. At the time of exposition, figures of one year of evolution will be available.
1039 Adult Stein Cells froin Persons wilh Parldnson's Disease are Therapeutic in a Rat Modal
WaTtle Murrell 1, Michael Domlellan 1, Andrew Wetzig 1, Tom Bume 1, Peter Silburn ~, Alan Mackay-Sim 1. 1Eskitis Institute For Cell And iVloleeular Therapies, Griffith University, Brisbane, Australia; 2Princess Alexandra Hospital, Brisbane, Australia
Background: Parkinson's disease is a complex disorder resulting primarily from degeneration of dopanffnergic neurons in the sub stantia nigra that project to the caudate-putamen. We recently demonstrated a multipotent adult stem cell in olfactory mucosa (Murrell et al., 2005). The aim of this study was to test whether these adult stem cells would be therapeutic in a rat model of Parkinson's disease. Methods: Olfactory adult stem cells were grown from biopsies of olfactory nlucosa of persons with Parkinson's disease, and from controls. Rats were unilaterally injected into the caudate-putamen with 6-hydroxydoparnine to destroy the dopaminergic input from the substantia nigra. Amphetamine-induced rotational behaviour was measured after the lesion and after transplantation of stem cells into the caudate putanlen on the lesioned side. All animals were immune- suppressed with daily injections of cyclosporine. Results: Transplantation of human adult olfactory stem cells reduced the amphetamine-induced rotational behaviour in six animals, three transplanted with cells from persons with Parkinson's disease and three with cells from controls. Tiffs therapeutic effect was evident at 3 weeks post-transplantation and persisted for 3 months. There was no change in rotational behaviour in three saline-injected control rats. The caudate putanlen of transplanted animals contained hunlan-derived cells that expressed both tyrosine hydroxylase and dopamine trans- porter. Conclusion: These results indicate that adult stem cells from human olfactory nlucosa are a potential source for autologous transplantation for the treatment of Parkinson's disease and other neurodegenerative disorders. Murrell W, et al. (2005) Multipotent stem cell in adult olfactory mucosa Developmental Dynamics (in press).
1040 ~rUllt Oxidative and Anti-oxidative Agenls Assodaled with Parldnson's Disease: Electron Spine Resonance (ESR) Study
Makita, y1, Aizawa, H ~, Enomoto, S a, Kimura, T ~, Yahara, 02 1Asahikawa Medical College, Asahikawa, Japan; 2National Organiza- tion Doh&u Hospital, Asahikawa, Japan
Background: Oxidative stress is strongly associated with Parkinson's disease (PD). Anti-Parkinson's disease agents may make another effect of systemic changes in vivo. Method: We measured 30 PD samples and 15 normal controls serum level of hydoxyradical scavenge potential with Hydroxy Radical Scavenge Assay (HRSA) using ESR system. Common anti-Parkinson's disease drug was measured as same method. Drug samples consisted of levodopa, amantadine, dopanffne-agonists, selegiline, zonisanffde. We received letters with all patient's consents.
Results: In PD group, hydroxy radical scavenge level was declined (iJ < 0.005). Selegiline had best potential ofhydroxy radical scavenge. Contusion: We suggested PD in systemic had declined radical scavenge level. We may chose selegiline as a first selection of PD therapy.
1041 Parkin gene therapy for Alpha Synucleinopathy: A rat model of Parkinson's disease
Mochizuld, H, Yamada, M, Mizuno, Y. Department of Neurology, ,,~untendo University School of Medicine
Background: Parkin is known to mitigate ~-sylmclein-induced neuronal cell death, suggesting that parkin gene therapy could be suitable for Parkinson's disease (PD). However, there are no studies on the inhibitory effects of parkin on ~-synudeinopathy in rat or mice brains. Method: In the present study, a recombinant adeno-associated viral (rAAV) vector system was used for human ~ sytruclein gene transfer to rat substantia nigra (SN). This transfection induced ~-synudeinopathy and the model appeared to more closely resemble the human disease. The effect of parkin was examined by co-infection of rAAV-parkin with rAAV-c~ sytruclein into dopanfinergic neurons in SN. Result anti Conclusions: At 13 weeks post-rAAV infection, c~ sytmclein overexpression induced dopaminergic neuron loss. However, co- expression of parkin mitigated ~-synuclein toxidty with neither decrease in the amount of cz-synudein protein nor formation of inclusions remJrfiscent of Lewy bodies (LB). Moreover, c~-sytruclein- induced dopaminergic neuron loss consequently resulted in motor dysfunction, which was also mitigated by parkin. Our results indicate that parkin gene therapy is effective against ~-synudein, suggesting its potential suitability for patients with PD.
1042 Spike Characterization in The Human Subthalainus and Substantia Nigra
Mrakic-Sposta, S 1, Marceglia, S 1 , Egidi, M ~ , Tamma, F ~, Caputo, E ~, Carrabba, G ~, Bmrbieri, S ~, Bertolasi, L ~, Priori, A ~. 1Fondazione IRCCS Ospedale Polielinieo, Milano; 2Cliniea Neurologiea, Azienda Ospedaliera San Paolo, ~filano, Italy; 3Dipartimento di Scienze Neurologicke e della l/Tsione, Universitfi di Verona, Verona, Italy
Background: Intraoperative microrecordings are determinant for a precise localization of the subthalamic nucleus (STN) during stereo- tactic, neurosurgery for the deep brain stimulation (DBS). However, the spike descriptors in the STN have been poorly characterized. Tiffs study aimed to evaluate the spike descriptors in the STN and in the substantia nigra pars reticulata (SNr) in 11 patients (21 sides of the brain) undergoing DBS surgery. Methods: Signals were captured through bipolar microelectrodes (Inomed mod. 230760, tip impedance 1.5-2.5 Mr2 at 1KHz), band- passed 300Hz-5KHz and differentially amplified. The STN and the SNr were identified through a the TC-MRI fusion-based neuroimaging technique and data matching with a digitized stereotactic atlas. Results: In the core of the STN the spikes were mainly biphasic with an initial upward (negative) deflection with a total frequency of 70 ± 4,04 Hz [mean± SEM], duration of 1,4 ± 0,05ms, rise time of 0,7 ± 0,07ms, amplitude of 35,5± 2,22~aV and area 25,8 ± 1,91~aVms; the 75% of the spikes analyzed were assamnetric. In the core of the SNr the spikes were mostly monophasic with upward deflection or biphasic with an initial upward (negative) deflection. The total frequency was 79 ± 6,81Hz, the duration 2,1 ± 0,13ms, the rise time 1 ± 0,07ms, the amplitude 46,7±3,88 pV and the area 37,9±2,67pVms; the 60% of the spikes analyzed were symmetric.. Contusions: In conclusion, besides the firing pattern, only spike morphology can help in differentiating between the STN and the SNr during stereotactic neurosurgery.