- Email: [email protected]
PT021 Etiopathogenesis - Environmental toxins
Guided Pester Tours
178
Results: Acute SIN-1 or MPP+ treatments caused dose-dependent protein nitration reaching a maximum of 8-fold by 10 mM SIN-1 or 2-fold by 10 ~tM MPP+. Chronic MPP+ or rotenone treatments caused maximum protein nitration by 1 pM (2-fold) or 50 nM (4-fold) respectivdy. Cotreatment with L-NAME (300 [xM) prevented protein nitration by acute MPP+. Conclusion: Protein nitration and dopamine depletion by MPP+ or rotenone treatments are closely related, but inhibition o f protein nitration did not prevent dopamine depletion in tile acute MPP+ model. Whether protein nitration plays a role in dopamine depletion and neuronal cell loss under chronic conditions remains to be investigated.
consistent autephagy is observed using lysesome markers and electronic microscopy. Conclusion: Similarly to tile results found in a neuroblastoma cell line, dopamine may trigger a death program when accumulated in the cellular cytosol. This could happen in duparninergic neurons when the equilibrium between vesicle storage, intramitochondrial metabolism and plasmatic dupamine re-uptake is disrupted and tile depamine concentration increases in the cell cytosol
Tuesday, 7 June 2005, 12.30 13.30, Hall 15.1 PT021
~ l n
quest for the molecular brain: New models of Parkinson's disease
R. Constantinescu*, B. Janetzky, H. Reichmann
*Dresden, Germar~y Objective: The project aims to set up two new cell culture models of Par!dnson's disease (PD) and employ them for investigating mitochondrial oxidative stress, apparently a major cause of idiopathic PD. Furthermore, the potency of coenzyme Q10 (a bieenergetic agent and antioxidant) for neureprotection will be assessed. Method: The human neuroblastema cell line SH-SY5Y (which possesses many of the qualities of human neurons) was differentiated into dopaminergic neurons using a long-term perfusion culture system, retinoic acid and mitotic inhibitors. Using these cells, we established two models: The pharmacological model of PD involves usage of rotenone as a potent neuretoxin that inhibits the Complex I of the mitochendrial respiratory chain. The RNAi model aims at disrupting the mitochondrial free radical scavenging system (by knocking down the nuclear-encoded, mitechondrial MnSOD gene). JC-1, a fluorescent mitochendrial membrane potential sensor, will give indications on the extent of mitochondrial depolarization. Results: The treatment with retenene increased, as expected, the oxidative stress in neurons, as measured using JC-1. The simultaneous treatment with retenene and ceenzyme Q10 produced a far smaller depolarization, leading to recovery ofintexicated neurons. Optimization of the RNAi model is underway and tile results are very promising. Conclusion: Our findings indicate that the pharmacological model gencrated PD-like molecular symptoms. The coenzyme Q10 exhibited a good rescuing efficiency in this model. Further experiments have to be performed to finalize the RNAi model and to test the coenzyme Q10 in this model.
•
Mechanisms of cell damage by dopamine in SH-SY5Y cells
X. Pol Gimenez*, C. G6mez, M. Barrachina, I. Ferrer, S. Ambrosio
*L'Hespitalet de LLobregat, Spa#~ Objective: Doparnine (DA) could play a central role in neuronal dopaminergic degeneration in Parkinson's disease and other neurodegenerative disorders. Tile rnechaniarns leading to neuronal damage and death are not yet fully understood Method: We have used human neuroblastoma SH-SY5Y cells, that are sensitive to dopamine, with the aim to deep in the molecular mechanisms through which dopamine may damage tile cell Results: DA enters the cell in a dose-dependent and saturating way. DA triggers a redox cycle that causes a slight increase in peroxidation (DCFH) and a decrease in the reductive power of the cell, that could be assessed by MTT, NADH concentration and GSH/GSSG relationship. Such an effect is reflected in: decrease of cell viability, decrease of oxygen consumption, increase in cytosolic calcium concentration. Calpain, p38 and JNK are transiently activated. The transcription factors C/EBPj3 and GADD153/CHOP increase their expression, o~-Synuclein, but not parkin or UCHL-1, increases also its expression, probably triggered by C/EBP[3. Parameters of endoplasmic reticulum stress (grp78) are activated and a
Etlopathogenesis
-
Environmental
toxins
Chair: Coral Gartner, Forest Lake, Brisbane, Australia Co-Chair: ©le Koldkjce~ Sonderborg, Denmark
~ R i s k of Parkinson's disease and environmental exposures C. Gartner*, D. Battistutta, M. Dunne, P. Silburn, G. Mellick
*Forest Lake, Brisbane, Australia Objective: Environmental exposures have been implicated in tile aetiology of Parkinson's Disease (PD), although findings have been inconsistent. Few report on the reliability of the exposure measurement methods employed, one potential source of inconsistency. This study aimed to examine the risk of PD in an Australian population associated with environmental exposures using a structured questionnaire of known reliability. Method: A consecutive series of 198 clinic-based PD cases, and 191 population-based matched controls were recruited. Control participants were randomly selected from the Australian Commonwealth Electoral Roll and matched to cases on age, sex and current residential suburb. Extensive environmental exposure data were collected in face-to-face interviews. The first 35 cases and 42 controls participated in a test-retest repeatability study of tile exposure assessment questionnaire. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets. Results: The majority of exposures examined were reported with moderate to high repeatability (kappa >0.70 in most cases). Smelting was negatively associated with PD (OR 0.59, 95%CI: 0.36-0.95) with a doseresponse relationship evident (packyears OR 0.98, 95%CI: 0.97-0.99, p < 0.001). Ceffee-drin!dng (OR 0.51, 95%CI: 0.29 0.91) and tea-drin!dng (0.59, 95%CI: 0.31-1.10) were also associated with decreased risk of PD. Regular exposure to pesticides was associated with increased risk of PD (OR 2.25, 95%CI: 0.69-7.30), as was drinking bore/well water for more than 20 years (OR 2.33, 95% 0.60 9.020. Regular exposure to solvents (OR 0.95, 95%CI: 0.52-1.76) or metals (0.85, 95%CI: 0.45-1.62) were net associated with increased risk of PD. Conclusion: This study ceT~irrned tile well-established negative relationship with smoking, coffee, and tea drinking. The environmental exposures of pesticide use and well-water were associated with increased risk of PD as evidenced by the substantial point estimates. However, the imprecision of these estimates preclude any definitive conclusions based on this study alone.
~
A
n
unusual form of movement disorders resembling parkinsonism-plus syndrome caused by 'home-made' narcotic
I. Khatiashvili*, M. Janelidze, M. Megrelishvili, R. Shakarishvili
*TbiJisi, Georgian Objective: A wide range of toxins causing parkinsonism is distinguished. A new form of toxic encephatolepathy with predominant symptoms of
Guided Poster Tours parldnsoniarn was observed in tile last 10 15 years in tile post soviet countries. Method: We studied 20 patients (15 male, 5 female, age range 18 35 years) with a history of drug abuse who had used injections of certain 'home-made' narcotic made of pseudedeophedrine, precipitated by K1VinO4 . Results: The clinical presentations were highlighted with very typical symptematelogy. The core symptom was akinesia predominantly in legs resulted in great gait difficulties with start hesitation. In 15 cases gait was broad-based. All patients suffered from frequent retrepulsive falls caused by the insufficiency of reactive and rescue postural reflexes. Dysartria occurred in a form of faint and slurred speech combined with hypo!dnesia and pseudobulbar palsy. Peculiar forced smile appeared along with articulation giving inane and senseless expression to tile face. Prominent nenspecific hypotrophy in arm and leg muscles had six patients. Spreaded fibrillations owing to anterior horn lesion confirmed by electroneurornyographic examination took place in 2 cases. Large-fiber axonopathy was observed in other 4 cases. Mild autonomic disturbances occurred in 9 cases. In all the cases on MRI bilateral T1 hyperintensity of inner segrnents of globus pallidus and midbraln reflecting manganese deposition were found. Moderate cortical atrophy was also observed. Hyperintense T1 signals were also revealed in cerebellum in 12 cases and in the white matter of hemispheres in 6 cases. We observed 2 'pseudo familial' cases reflecting intetinvolvement of family members in drug abuse. The unusual form of movement disorders resembling parkinseniarn-plus syndrome caused by 'home-made' narcotic is progressive and poorly responding both to dophaminergic drugs and chelates as well.
•
Parkinson's disease among inuit in Greenland: Organochlorines as risk factors
O. Kelclkj~er*, L. Wermuth, P. Bjerregaard
*Sonderborg, Denmark Objective: AIM of the study: To investigate polychlorinated biphenyls (PCBs) and otganochlorinated pesticides (OCs) as possible risk factors for Par!dnson's disease (PD) in an arctic population which has never been done before. Introduction: The arctic area has for decades been contaminated by PCBs and OCs with accumulation in tile marine food as a result. The indigenous population (Inuit) with its high consumption of marine animals therefore bioaccumulates tile olganochlerines. Method: STUDY DESIGN: Case-control study of Inuit in Greeenland. METHODS: Plasma from 39 PD (25 males and 14 females)(mean age 68 yr) and 122 controls (57 males and 65 females)(mean age 61 yr) was analysed for 31 PCBs and OCs by dual-cohimn gas chromatography with dual electron-capture detection or gas chromatography with negative chemical ionisation mass spectrometry. Results: Plasma concentrations of PCBs and OCs were markedly increased in both PD and controls. The concentrations did not differ between tile PD-cases and tile controls except for DDE (a persistent metabelite of DDT). The mean DDE concentration was higher in the PD-cases (36.0 microg/l;range 0.3-273; s.d. 57.5) than in the controls (15.0 microg/l; range 0.8 43; s.d. 8.2). The difference was statisdcally significant for leg transformed DDE values after control for age and sex (p = 0.027). Conclusion: The prevalence of PD in Inuit is twice that found in the island of Als, Denmark. A few epidemiological studies indicate a possible connection between exposure to pesticides and PD. That exposure to organochlorines may be an important risk factor for PD among Inuit in Greenland maybe in genetic susceptible individuals requires more investigations.
•
179
Extrapyramidal symptoms in a group of Italian dental laboratory technicians
G. Meco*, G. Meco, E. Fabrizio, G. Di Brigida
*Rome, Italy Objective: The etiopathogenesis of sporadic parkinsonism is probably clue to an interaction between environmental and genetic factors. Many epidemiological studies and case-reports show an association between exposure to neurotoxins (solvents, pesticides, metals) and parkinsoniarn. A juvenile parkinsonism exposed to high level of neurotoxins represent an natural model to study tile role of environmental factors in tile onset of extrapyramidal symptoms. In the clinical practice the identification of patients with suspected toxic etiology is linked to collect an accurate occupational history. Method: The clinical history of juvenile parkinsonian patient (male, 50 years) with a slow progression and a persistent asymmetry symptomatology (mild bradykinesia and rigidity to right arm, UPDRS motor score of 12) after six years of duration disease induce an accurate evaluation of his occupational history. Results: The acute levedepa-test show an improvement o f 44%. The dosage of copraernia and ceruloplasmin are normal.. Tile cerebral magnetic resonance, motor evoked potentials, electromyography and electronenrography are normal. The patient not take antiparkinsonian drugs. This patient work as a dental laboratory technician in a public school and has been probably exposed to mercury sulphate for many years. We have visited fourteen men dental laboratory technicians among twenty-seven workers of this public school (age mean 48.8±5.9 yrs) and have identified six subjects wit a mild postural tremor, bradykinesia and rigidity. However, for each subject is not possible actually diagnose a parkinsonism. On the contrary tile high prevalence of parkinsonian signs in a small group of juvenile workers of same occupational environment is not frequent and should be evaluated carefully Conclusion: We believe that the evaluation of possible association between exposure to neurotoxins arnong dental laboratory technician and onset of extrapyramidal symptomatology should be considered in the clinical practice.
~
A
delayed-onset carbon disulfide (CS2) neurotoxicity mimicking cerebellar type of multiple system atrophy
D.-'K Kim*, J.-I. Seek, W.-Y. Lee, E.-J. Chung
*Seoul, Republic of Korea Objective: To report a case resembling cerebellar type of multiple system atrophy that developed several years after cessation of 17 year-history of carbon disulfide (CS2) exposure. Method: A 53-year-old man developed a slowly progressive cerebellar dysfunction and autonomic insufficiency about 3 years age. Extrapyramidal features were not prominent. He was exposed to CS2 in rayon viscose plant for 17 years and these manifestations were appeared 8 years after retirement from work. Careful history taking, laboratory evaluation and brain magnetic resonance imaging were performed to exclude other diseases. Results: His medical history about combined disease, alcohol intake, nutritional status, drugs and family history were not remarkable except occupational exposure to CS2. Laboratory evaluation including blood cell count, routine biochemical test, peripheral blood smear, thyroid function test with auteantibody and gone analysis for trinucleotide repeat revealed normal. Brain MRI showed no abnormality except diffuse atrophy of the cerebellum and brainstem. Conclusion: According to the absence of other causes of cerebellar atrophy except occupational exposure to CS2, we aasume that our case was due to delayed-onset carbon disulfide (CS2) neurotoxicity. The toxic effect of carbon disulfide may appear several years after cessation of exposure, when tile effect of toxic damage overcome tile brain functional reserve.
180
Guided Poster Tours
•
Neurodegeneration with brain iron accumulation: Clinical, radiographic and genetic heterogeneity and corresponding therapeutic options F. Clement*, D. Devon, C. Moreaux, P. Coubes, A. Destee, L. Defebvre *Lille, France
Objeetive: Nenrodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz syndrome, is a heterogeneous group of disorders. We compare tile clinical, radiographic and genetic features of two patients and discuss corresponding therapeutic approaches. Results: tn tile first case, progressively generalizing dystonic symptoms appeared during childhood. A mutation in the gene encoding pantothenate ldnase 2 (PANK2) was found. Brain MRI showed bilateral hypersignals within the globns pallidi on T2-weighted images. The patient was successfully treated by pallidal deep brain stimulation (DBS). In tile second case an adult onset with parkinsonism was observed, for which no PANK2 mutation was found. T2-weighted brain MR images revealed significant hyposignals (suggestive o f iron deposits) localised in tile cerebellar dentate nuclei and in the globi pallidi, the red nuclei and the snbstantia nigra. An anfipar!dnsonian treatment was initiated. Conclusion: The clinical, radiographic and genetic heterogeneity of NBIA has to be underlined.
•
Pestiviruses and the environmental etiology of Parkinson's disease J. Adams*, W.L. An, S. Yardiey, I. Mackenzie, S. Byrne, A.J. Stoessl *Vancouver, Canada Objective: The cause of Parkinson's disease (PD) remains unknown. Although a small proportion of patients have an inherited form, most are thought to have sporadic disease. Increased relative risk has been demonstrated for individuals exposed to rural living, farming and wellwater consumption. Furthermore, recent epidemiological evidence from our centre has raised tile possibility that PD may arise from transient exposure to some environmental factor, either a toxin or virus. Bovine viral diarrhea (BVD) virus, a pestivims, can result in neurological dysfunction, including tremor, in lambs (Border disease). BVD cytopathogenidty requires insertion of a ubiqnitin-like element, highly comparable to mammalian nbiquitin, in a non-structural coding region. Altered ubiquitin processing has been identified in at least 2 inherited forms of PD (PARK 2 and PARK 3), and altered protein handling has been implicated as a major factor in all forms of the disease. We sought to determine whether subjects with sporadic PD had been previously exposed to BVD. Method: Serum samples were obtained from 20 subjects with sporadic PD and 20 age-matched healthy controls and examined for antibodies to BVD using a viral neutralization assay. Subjects with age <50, unable to provide consent, or with atypical forms of par!dnsonism were excluded. In addition, polymerase chain reaction (PCR) for BVD virus was performed on post-mortem tissue samples (substantia nigra) from two sporadic Par!tinson's disease patients. All subjects gave written informed consent. The study was approved by the Clinical Research Ethics Board of the University of British Columbia. Results: Antibodies to BVD were not detected in subjects with PD or in controls. Similarly, BVD virus was not detected by PCR in snbstantia nigra. Conclusion: Previous exposure to bovine viral diarrhea virus is unlikely to be a significant factor in tile etiology of Parldnson's disease.
•
Reduced dopaminergic neurotransmission in immunodeficiency virus infection: Involvement of retroviruses in Parkinsonism M. Jenuwein*, C. Scheller, S. Pohli, R. Burger, T. Tatschner, P. Riederer, E. Koutsilieri *Illertissen, Germany Objective: Motor disorders are usually complications of HIV and especially Parldnsonian features are common in HIV-infected patients during the late state of the disease, showing also additional signs of HIV dementia as cognitive impairment and behavioural abnormalities. Although the pathogenesis of HIV dernentia is incompletely understood and certainly multifactorial, many of these symptoms may be attributed to abnormalities in the dopamine rich basal ganglia. Our primary focus of investigations was tile putamen, which is part of tile nigro-striatal dopamine system and the main involved system in Parkinson disease. Method: Changes in the dopaminergic system during early, asymptomatic infection and late stages of tile disease were investigated using simian immunodeficiency virus (SIV)-infected macaques. Animals were sacrificed 8 57 weeks following infection and their brains were analysed using HPLC and Western Blot. Results: We determined levels of dopamine, its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Moreover, we investigated changes in tile expression of cyclicAMP response element binding protein (CREB), which is involved in tile signaling pathway of dopamine. We found a significant reduction of dopamine levels in the putamen of SIV-infected macaques in comparison to arfinfected animals already during the asymptomatic stage of the infection. In animals that reached tile AIDS-stage of SIV-infection dopamine content was further decreased. The concentration of DOPAC was raised in SIV-infected monkeys, whereas HVA remained constant. Dopamine deficits were accompanied by a significantly reduced expression of the transcription factor CREB. Conclusion: These results support the hypothesis, that HIV dementia may be an additional cause of Par!dnsonism and parldnsonian syndromes can be regarded as manifestation of HIV-Dementia.
•
Influence of menses, pregnancies and estrogen use on Parkinson's disease in Chinese women
L. Chert*
*27anjin, China Objective: To investigate the association of Parkinson's disease (PD) with menses, pregnancies and estrogen use in Chinese women. Method: The study included 120 women with idiopathic PD and 120 normal control subjects. The two groups were matched by age. All subjects had a Mini-Mental State Exam score ~>27. Cumulative length of pregnandes, age of menarche, age and type of menopause, and estrogen use were investigated in PD and control groups. The data were analysed through conditional logistic regression. Results: The PD cases had experienced shorter fertile life than control subjects (OR 1.025; 95%CI: 0.964 to 1.089). Conclusion: The shorter fertile life increased risk of PD in Chinese women. Tile endogenous estrogens play a role in tile devdopment o f PD.
178
Results: Acute SIN-1 or MPP+ treatments caused dose-dependent protein nitration reaching a maximum of 8-fold by 10 mM SIN-1 or 2-fold by 10 ~tM MPP+. Chronic MPP+ or rotenone treatments caused maximum protein nitration by 1 pM (2-fold) or 50 nM (4-fold) respectivdy. Cotreatment with L-NAME (300 [xM) prevented protein nitration by acute MPP+. Conclusion: Protein nitration and dopamine depletion by MPP+ or rotenone treatments are closely related, but inhibition o f protein nitration did not prevent dopamine depletion in tile acute MPP+ model. Whether protein nitration plays a role in dopamine depletion and neuronal cell loss under chronic conditions remains to be investigated.
consistent autephagy is observed using lysesome markers and electronic microscopy. Conclusion: Similarly to tile results found in a neuroblastoma cell line, dopamine may trigger a death program when accumulated in the cellular cytosol. This could happen in duparninergic neurons when the equilibrium between vesicle storage, intramitochondrial metabolism and plasmatic dupamine re-uptake is disrupted and tile depamine concentration increases in the cell cytosol
Tuesday, 7 June 2005, 12.30 13.30, Hall 15.1 PT021
~ l n
quest for the molecular brain: New models of Parkinson's disease
R. Constantinescu*, B. Janetzky, H. Reichmann
*Dresden, Germar~y Objective: The project aims to set up two new cell culture models of Par!dnson's disease (PD) and employ them for investigating mitochondrial oxidative stress, apparently a major cause of idiopathic PD. Furthermore, the potency of coenzyme Q10 (a bieenergetic agent and antioxidant) for neureprotection will be assessed. Method: The human neuroblastema cell line SH-SY5Y (which possesses many of the qualities of human neurons) was differentiated into dopaminergic neurons using a long-term perfusion culture system, retinoic acid and mitotic inhibitors. Using these cells, we established two models: The pharmacological model of PD involves usage of rotenone as a potent neuretoxin that inhibits the Complex I of the mitochendrial respiratory chain. The RNAi model aims at disrupting the mitochondrial free radical scavenging system (by knocking down the nuclear-encoded, mitechondrial MnSOD gene). JC-1, a fluorescent mitochendrial membrane potential sensor, will give indications on the extent of mitochondrial depolarization. Results: The treatment with retenene increased, as expected, the oxidative stress in neurons, as measured using JC-1. The simultaneous treatment with retenene and ceenzyme Q10 produced a far smaller depolarization, leading to recovery ofintexicated neurons. Optimization of the RNAi model is underway and tile results are very promising. Conclusion: Our findings indicate that the pharmacological model gencrated PD-like molecular symptoms. The coenzyme Q10 exhibited a good rescuing efficiency in this model. Further experiments have to be performed to finalize the RNAi model and to test the coenzyme Q10 in this model.
•
Mechanisms of cell damage by dopamine in SH-SY5Y cells
X. Pol Gimenez*, C. G6mez, M. Barrachina, I. Ferrer, S. Ambrosio
*L'Hespitalet de LLobregat, Spa#~ Objective: Doparnine (DA) could play a central role in neuronal dopaminergic degeneration in Parkinson's disease and other neurodegenerative disorders. Tile rnechaniarns leading to neuronal damage and death are not yet fully understood Method: We have used human neuroblastoma SH-SY5Y cells, that are sensitive to dopamine, with the aim to deep in the molecular mechanisms through which dopamine may damage tile cell Results: DA enters the cell in a dose-dependent and saturating way. DA triggers a redox cycle that causes a slight increase in peroxidation (DCFH) and a decrease in the reductive power of the cell, that could be assessed by MTT, NADH concentration and GSH/GSSG relationship. Such an effect is reflected in: decrease of cell viability, decrease of oxygen consumption, increase in cytosolic calcium concentration. Calpain, p38 and JNK are transiently activated. The transcription factors C/EBPj3 and GADD153/CHOP increase their expression, o~-Synuclein, but not parkin or UCHL-1, increases also its expression, probably triggered by C/EBP[3. Parameters of endoplasmic reticulum stress (grp78) are activated and a
Etlopathogenesis
-
Environmental
toxins
Chair: Coral Gartner, Forest Lake, Brisbane, Australia Co-Chair: ©le Koldkjce~ Sonderborg, Denmark
~ R i s k of Parkinson's disease and environmental exposures C. Gartner*, D. Battistutta, M. Dunne, P. Silburn, G. Mellick
*Forest Lake, Brisbane, Australia Objective: Environmental exposures have been implicated in tile aetiology of Parkinson's Disease (PD), although findings have been inconsistent. Few report on the reliability of the exposure measurement methods employed, one potential source of inconsistency. This study aimed to examine the risk of PD in an Australian population associated with environmental exposures using a structured questionnaire of known reliability. Method: A consecutive series of 198 clinic-based PD cases, and 191 population-based matched controls were recruited. Control participants were randomly selected from the Australian Commonwealth Electoral Roll and matched to cases on age, sex and current residential suburb. Extensive environmental exposure data were collected in face-to-face interviews. The first 35 cases and 42 controls participated in a test-retest repeatability study of tile exposure assessment questionnaire. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets. Results: The majority of exposures examined were reported with moderate to high repeatability (kappa >0.70 in most cases). Smelting was negatively associated with PD (OR 0.59, 95%CI: 0.36-0.95) with a doseresponse relationship evident (packyears OR 0.98, 95%CI: 0.97-0.99, p < 0.001). Ceffee-drin!dng (OR 0.51, 95%CI: 0.29 0.91) and tea-drin!dng (0.59, 95%CI: 0.31-1.10) were also associated with decreased risk of PD. Regular exposure to pesticides was associated with increased risk of PD (OR 2.25, 95%CI: 0.69-7.30), as was drinking bore/well water for more than 20 years (OR 2.33, 95% 0.60 9.020. Regular exposure to solvents (OR 0.95, 95%CI: 0.52-1.76) or metals (0.85, 95%CI: 0.45-1.62) were net associated with increased risk of PD. Conclusion: This study ceT~irrned tile well-established negative relationship with smoking, coffee, and tea drinking. The environmental exposures of pesticide use and well-water were associated with increased risk of PD as evidenced by the substantial point estimates. However, the imprecision of these estimates preclude any definitive conclusions based on this study alone.
~
A
n
unusual form of movement disorders resembling parkinsonism-plus syndrome caused by 'home-made' narcotic
I. Khatiashvili*, M. Janelidze, M. Megrelishvili, R. Shakarishvili
*TbiJisi, Georgian Objective: A wide range of toxins causing parkinsonism is distinguished. A new form of toxic encephatolepathy with predominant symptoms of
Guided Poster Tours parldnsoniarn was observed in tile last 10 15 years in tile post soviet countries. Method: We studied 20 patients (15 male, 5 female, age range 18 35 years) with a history of drug abuse who had used injections of certain 'home-made' narcotic made of pseudedeophedrine, precipitated by K1VinO4 . Results: The clinical presentations were highlighted with very typical symptematelogy. The core symptom was akinesia predominantly in legs resulted in great gait difficulties with start hesitation. In 15 cases gait was broad-based. All patients suffered from frequent retrepulsive falls caused by the insufficiency of reactive and rescue postural reflexes. Dysartria occurred in a form of faint and slurred speech combined with hypo!dnesia and pseudobulbar palsy. Peculiar forced smile appeared along with articulation giving inane and senseless expression to tile face. Prominent nenspecific hypotrophy in arm and leg muscles had six patients. Spreaded fibrillations owing to anterior horn lesion confirmed by electroneurornyographic examination took place in 2 cases. Large-fiber axonopathy was observed in other 4 cases. Mild autonomic disturbances occurred in 9 cases. In all the cases on MRI bilateral T1 hyperintensity of inner segrnents of globus pallidus and midbraln reflecting manganese deposition were found. Moderate cortical atrophy was also observed. Hyperintense T1 signals were also revealed in cerebellum in 12 cases and in the white matter of hemispheres in 6 cases. We observed 2 'pseudo familial' cases reflecting intetinvolvement of family members in drug abuse. The unusual form of movement disorders resembling parkinseniarn-plus syndrome caused by 'home-made' narcotic is progressive and poorly responding both to dophaminergic drugs and chelates as well.
•
Parkinson's disease among inuit in Greenland: Organochlorines as risk factors
O. Kelclkj~er*, L. Wermuth, P. Bjerregaard
*Sonderborg, Denmark Objective: AIM of the study: To investigate polychlorinated biphenyls (PCBs) and otganochlorinated pesticides (OCs) as possible risk factors for Par!dnson's disease (PD) in an arctic population which has never been done before. Introduction: The arctic area has for decades been contaminated by PCBs and OCs with accumulation in tile marine food as a result. The indigenous population (Inuit) with its high consumption of marine animals therefore bioaccumulates tile olganochlerines. Method: STUDY DESIGN: Case-control study of Inuit in Greeenland. METHODS: Plasma from 39 PD (25 males and 14 females)(mean age 68 yr) and 122 controls (57 males and 65 females)(mean age 61 yr) was analysed for 31 PCBs and OCs by dual-cohimn gas chromatography with dual electron-capture detection or gas chromatography with negative chemical ionisation mass spectrometry. Results: Plasma concentrations of PCBs and OCs were markedly increased in both PD and controls. The concentrations did not differ between tile PD-cases and tile controls except for DDE (a persistent metabelite of DDT). The mean DDE concentration was higher in the PD-cases (36.0 microg/l;range 0.3-273; s.d. 57.5) than in the controls (15.0 microg/l; range 0.8 43; s.d. 8.2). The difference was statisdcally significant for leg transformed DDE values after control for age and sex (p = 0.027). Conclusion: The prevalence of PD in Inuit is twice that found in the island of Als, Denmark. A few epidemiological studies indicate a possible connection between exposure to pesticides and PD. That exposure to organochlorines may be an important risk factor for PD among Inuit in Greenland maybe in genetic susceptible individuals requires more investigations.
•
179
Extrapyramidal symptoms in a group of Italian dental laboratory technicians
G. Meco*, G. Meco, E. Fabrizio, G. Di Brigida
*Rome, Italy Objective: The etiopathogenesis of sporadic parkinsonism is probably clue to an interaction between environmental and genetic factors. Many epidemiological studies and case-reports show an association between exposure to neurotoxins (solvents, pesticides, metals) and parkinsoniarn. A juvenile parkinsonism exposed to high level of neurotoxins represent an natural model to study tile role of environmental factors in tile onset of extrapyramidal symptoms. In the clinical practice the identification of patients with suspected toxic etiology is linked to collect an accurate occupational history. Method: The clinical history of juvenile parkinsonian patient (male, 50 years) with a slow progression and a persistent asymmetry symptomatology (mild bradykinesia and rigidity to right arm, UPDRS motor score of 12) after six years of duration disease induce an accurate evaluation of his occupational history. Results: The acute levedepa-test show an improvement o f 44%. The dosage of copraernia and ceruloplasmin are normal.. Tile cerebral magnetic resonance, motor evoked potentials, electromyography and electronenrography are normal. The patient not take antiparkinsonian drugs. This patient work as a dental laboratory technician in a public school and has been probably exposed to mercury sulphate for many years. We have visited fourteen men dental laboratory technicians among twenty-seven workers of this public school (age mean 48.8±5.9 yrs) and have identified six subjects wit a mild postural tremor, bradykinesia and rigidity. However, for each subject is not possible actually diagnose a parkinsonism. On the contrary tile high prevalence of parkinsonian signs in a small group of juvenile workers of same occupational environment is not frequent and should be evaluated carefully Conclusion: We believe that the evaluation of possible association between exposure to neurotoxins arnong dental laboratory technician and onset of extrapyramidal symptomatology should be considered in the clinical practice.
~
A
delayed-onset carbon disulfide (CS2) neurotoxicity mimicking cerebellar type of multiple system atrophy
D.-'K Kim*, J.-I. Seek, W.-Y. Lee, E.-J. Chung
*Seoul, Republic of Korea Objective: To report a case resembling cerebellar type of multiple system atrophy that developed several years after cessation of 17 year-history of carbon disulfide (CS2) exposure. Method: A 53-year-old man developed a slowly progressive cerebellar dysfunction and autonomic insufficiency about 3 years age. Extrapyramidal features were not prominent. He was exposed to CS2 in rayon viscose plant for 17 years and these manifestations were appeared 8 years after retirement from work. Careful history taking, laboratory evaluation and brain magnetic resonance imaging were performed to exclude other diseases. Results: His medical history about combined disease, alcohol intake, nutritional status, drugs and family history were not remarkable except occupational exposure to CS2. Laboratory evaluation including blood cell count, routine biochemical test, peripheral blood smear, thyroid function test with auteantibody and gone analysis for trinucleotide repeat revealed normal. Brain MRI showed no abnormality except diffuse atrophy of the cerebellum and brainstem. Conclusion: According to the absence of other causes of cerebellar atrophy except occupational exposure to CS2, we aasume that our case was due to delayed-onset carbon disulfide (CS2) neurotoxicity. The toxic effect of carbon disulfide may appear several years after cessation of exposure, when tile effect of toxic damage overcome tile brain functional reserve.
180
Guided Poster Tours
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Neurodegeneration with brain iron accumulation: Clinical, radiographic and genetic heterogeneity and corresponding therapeutic options F. Clement*, D. Devon, C. Moreaux, P. Coubes, A. Destee, L. Defebvre *Lille, France
Objeetive: Nenrodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz syndrome, is a heterogeneous group of disorders. We compare tile clinical, radiographic and genetic features of two patients and discuss corresponding therapeutic approaches. Results: tn tile first case, progressively generalizing dystonic symptoms appeared during childhood. A mutation in the gene encoding pantothenate ldnase 2 (PANK2) was found. Brain MRI showed bilateral hypersignals within the globns pallidi on T2-weighted images. The patient was successfully treated by pallidal deep brain stimulation (DBS). In tile second case an adult onset with parkinsonism was observed, for which no PANK2 mutation was found. T2-weighted brain MR images revealed significant hyposignals (suggestive o f iron deposits) localised in tile cerebellar dentate nuclei and in the globi pallidi, the red nuclei and the snbstantia nigra. An anfipar!dnsonian treatment was initiated. Conclusion: The clinical, radiographic and genetic heterogeneity of NBIA has to be underlined.
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Pestiviruses and the environmental etiology of Parkinson's disease J. Adams*, W.L. An, S. Yardiey, I. Mackenzie, S. Byrne, A.J. Stoessl *Vancouver, Canada Objective: The cause of Parkinson's disease (PD) remains unknown. Although a small proportion of patients have an inherited form, most are thought to have sporadic disease. Increased relative risk has been demonstrated for individuals exposed to rural living, farming and wellwater consumption. Furthermore, recent epidemiological evidence from our centre has raised tile possibility that PD may arise from transient exposure to some environmental factor, either a toxin or virus. Bovine viral diarrhea (BVD) virus, a pestivims, can result in neurological dysfunction, including tremor, in lambs (Border disease). BVD cytopathogenidty requires insertion of a ubiqnitin-like element, highly comparable to mammalian nbiquitin, in a non-structural coding region. Altered ubiquitin processing has been identified in at least 2 inherited forms of PD (PARK 2 and PARK 3), and altered protein handling has been implicated as a major factor in all forms of the disease. We sought to determine whether subjects with sporadic PD had been previously exposed to BVD. Method: Serum samples were obtained from 20 subjects with sporadic PD and 20 age-matched healthy controls and examined for antibodies to BVD using a viral neutralization assay. Subjects with age <50, unable to provide consent, or with atypical forms of par!dnsonism were excluded. In addition, polymerase chain reaction (PCR) for BVD virus was performed on post-mortem tissue samples (substantia nigra) from two sporadic Par!tinson's disease patients. All subjects gave written informed consent. The study was approved by the Clinical Research Ethics Board of the University of British Columbia. Results: Antibodies to BVD were not detected in subjects with PD or in controls. Similarly, BVD virus was not detected by PCR in snbstantia nigra. Conclusion: Previous exposure to bovine viral diarrhea virus is unlikely to be a significant factor in tile etiology of Parldnson's disease.
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Reduced dopaminergic neurotransmission in immunodeficiency virus infection: Involvement of retroviruses in Parkinsonism M. Jenuwein*, C. Scheller, S. Pohli, R. Burger, T. Tatschner, P. Riederer, E. Koutsilieri *Illertissen, Germany Objective: Motor disorders are usually complications of HIV and especially Parldnsonian features are common in HIV-infected patients during the late state of the disease, showing also additional signs of HIV dementia as cognitive impairment and behavioural abnormalities. Although the pathogenesis of HIV dernentia is incompletely understood and certainly multifactorial, many of these symptoms may be attributed to abnormalities in the dopamine rich basal ganglia. Our primary focus of investigations was tile putamen, which is part of tile nigro-striatal dopamine system and the main involved system in Parkinson disease. Method: Changes in the dopaminergic system during early, asymptomatic infection and late stages of tile disease were investigated using simian immunodeficiency virus (SIV)-infected macaques. Animals were sacrificed 8 57 weeks following infection and their brains were analysed using HPLC and Western Blot. Results: We determined levels of dopamine, its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Moreover, we investigated changes in tile expression of cyclicAMP response element binding protein (CREB), which is involved in tile signaling pathway of dopamine. We found a significant reduction of dopamine levels in the putamen of SIV-infected macaques in comparison to arfinfected animals already during the asymptomatic stage of the infection. In animals that reached tile AIDS-stage of SIV-infection dopamine content was further decreased. The concentration of DOPAC was raised in SIV-infected monkeys, whereas HVA remained constant. Dopamine deficits were accompanied by a significantly reduced expression of the transcription factor CREB. Conclusion: These results support the hypothesis, that HIV dementia may be an additional cause of Par!dnsonism and parldnsonian syndromes can be regarded as manifestation of HIV-Dementia.
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Influence of menses, pregnancies and estrogen use on Parkinson's disease in Chinese women
L. Chert*
*27anjin, China Objective: To investigate the association of Parkinson's disease (PD) with menses, pregnancies and estrogen use in Chinese women. Method: The study included 120 women with idiopathic PD and 120 normal control subjects. The two groups were matched by age. All subjects had a Mini-Mental State Exam score ~>27. Cumulative length of pregnandes, age of menarche, age and type of menopause, and estrogen use were investigated in PD and control groups. The data were analysed through conditional logistic regression. Results: The PD cases had experienced shorter fertile life than control subjects (OR 1.025; 95%CI: 0.964 to 1.089). Conclusion: The shorter fertile life increased risk of PD in Chinese women. Tile endogenous estrogens play a role in tile devdopment o f PD.