- Email: [email protected]
HT003 Hot topics: Varia
Hot Topics
78
Tuesday, 7 June 2005, 15.30 17.00, Hall 03
HT002 Hot topics: Basal ganglia pharmacology Chair: Treoor Archer, GSteborg, Sweden
Co-Chair: Luigi Zecca, Segrate, Italy
•
Functional neuroanatomy
A. Di Rocco*
*New York, NY, USA
•
Basal ganglia neuropharmacology; insights gained from intraoperative microdialysis in Parkinson's disease patients
agonists were potent ligands at D3 receptors revealing respectively 100-, 18- and 56-fold lower affinity at D2 receptors, mimic!ring tile selective D3 receptor antagonist, $33084 (100-fold). Tile proportion of high affinity binding sites recognized by $32504, pramipexole and ropinirole in membranes derived from cells co-expressing D3 and D2 sites was higher fllan in an equivalent mixture of membranes from cells expressing D3 or D2 sites, consistent with tile promotion of heteroclimer formation by agonists. In contrast, the percentage of high and low affinity sites (biphasic isotherms) recognised by $33084 was identical. Fmlctional actions were determined by co-transfection of a chimeric adenylyl cyclase (AC)-V/VI insensitive to D3 receptors. Accordingly, D3 recepmr-transfected cells were irresponsive to agenists while, in D2 receptor-lransfected cells, all agonists suppressed forskolin-stimulated cAMP production with modest potencies. In contrast, in cells co-transfected with both D3 and D2 receptors, $32504, repinirele and pramipexole potently suppressed the activity of AC-V/¥I with EC50s 33-, 19- and ll-fold lower than those at D2 receptors, respectively, despite similar maximal effects. These data suggest that actions at D3/D2 heterodimers might be involved in the functional actions of antiparkinsonian agents.
1~ Stanzione*, E. Fedele, A. Stet~a~fi, S. Galati, O. Pepicelli, L. Brusa, M. Pierantozzi, A. Peppe, A. Pisani, E Mazzone
Wednesday, 8 June 2005, 15.30-17.00, Hall 02
*Roma, Italy Objective: Deep brain stimulation (DBS) of tile subthalarnic nucleus (STN) in Parldnson's disease (PD) patients, a clinically effective treatment in the advanced disease stage, augments STN-driven excitation of the internal globus pallidus (GPi). However, DBS-induced changes in tile other basal ganglia nuclei are largely unknown,. In the present study, biochemical effects of STN-DBS have been studied in two basal ganglia stations (putamen and GPi) in addition to a thalamic relay nucleus. Method: In eight advanced PD patients, mldergoing surgery after prolonged drug withdrawal, microdialysis samples were collected from GPi, putamen (PUT) and antero-ventral thalamus (VA) every 10 minutes, at a flow rate of 5 ~tL/min, before,
~ T h e
role of synaptic and extrasynaptic dopamine receptors in Parkinson's disease
A. Carlsson*
*Gdteborg, Sweden
•
Heterodimerization of dopamine D2tD3 receptors reveals an unexpected level of pharmacological diversity
R. Maggie*, M.J. Millan, G.U. Corsini
*Pisa, Italy Recombinant, human dopamine D3 and D2 receptors form functional heterodimers upon co-expreasion in COS-7 cells. Herein, as compared to their effects at D3 and D2 monomers, the actions of the anfiparldnsonian agents, $32504, ropinirole and pramipexole, were characterized at D3/D2 heterodimers. In binding assays with tile antagonist, [3H]nernonapride, all
HT003 Hot topics: Varia Chair: Albert Ludolph, Germany
Co-Chair: Fabrizio Stocchi, Roma, Italy
~ l s
atypical parkinsonism in the Caribbean caused by the consumption of annonacae?
A. Lannuzel*, G.U. HSglinger, E Champy, RE Michel, E. Hirsch, M. Ruberg
*Pointe-a-Pitre, Guadeloupe Background: An abnormally high frequency of an atypical, nonL-DOPA-responsive, akinetic-rigid syndrome sharing some similarities with PSP has been identified in the Caribbean island of Guadeloupe. It was associated in a case-control study with tile regular consumption of plants from the annonaceae family, especially Annona muricata (corossol, soursop) (Caparros-Lefebvre et al, Lancet 1999) suggesting a possible causal role for a toxin. Objective: Annonaceae contain two major groups of potential toxins: alkaloids and acetogenins. We wished: (1) to identify and quarnify tile most abundant of these compounds in the plant; (2) to characterize the mechanism underlying their toxicity. Design/Methods: We assessed the toxicity of the two alkaloids reticuline and coreximine and that of tile acetogenin amlonacin using a model system of mesencephalic dopaminergic (DA) neurons in culture. We also infused male Lewis rats i.v. for 28d with annonacin (3.8 or 7.6 m g ~ d ) to compare them to vehicule-infused rats. Results: Our initial work has shown that the alkaloids reficuline and coreximine were toxic for DA neurons in culture (Lannuzel et al., Mov disord 2002). However, the following studies were focused on annonacin for two reasons: (1) amlonacin was found to trigger neurodegenerative changes at much lower concentrations than the alkaloids; (2) annonacin is a known mitochondrial toxin, a property shared by other parldnsoniarninducing compomlds. We showed that annonacin operates indeed as a selective and powerful inhibitor of complex I of the mitochondrial respiratory chain (IC50 30riM) and that it !rills DA neurons by impairment of energy metabolism (Lannuzel et at., Nenroscience 2003). Annonacin was approximately 50-fold more potent than tile dassic complex I inhibitor MPP+ in inducing neuronal death. Infused intravenously for 28 days in rats annonacin induced a loss of nigral dopaminergic neurons and striatal dopaminergic fibers. However, the toxicity was not restricted to the nigrosttiatal system but was pronounced and widespread in other basal garlglia and bvainstem nuclei (Champy et al., J Neurochern 2004), consistent
Hot Tepics
79
with clinical picture of tile disease in patients, tn a recent quantitative study, we have shown that tile fruit of Annona muricata and teas prepared from its leaves, both o f which are commonly consumed in Guadeloupe, contain high levds of annonacin. Conclusions: These studies adds further support to the concept that alimentary consumption of Annonaceae may be contribute to the pathogenesis of tile atypical parldnsonian syndrome in Guadeloupe. Supported by: INSERM, Ministate de l'Ontre Mer (French West Indies Ministry), University Hospital of Pointe 5 Pitre, PSP Foundation, GISmaladies Rare.
-10Hz and ~30Hz peaks into separate components. Subjects with greater bradyldnesia had a tendency towards increased ~ 10Hz coupling and reduced ~30Hz coupling that was partially reversed with L-dopa. Conclusion: These results suggest that the two peaks typically found in tile EEG/EMG coherence spectrum represent two spatially overlapping, distinct processes that may be isolated with suitable signal-processing techniques. The lower ~10Hz peak may represent pathological oscillations within the basal ganglia which may be a contributing factor to bradykinesia in PD.
•
•
Genetic and DAT studies of familial Parkinson's disease in Taiwan C.-S. Lu*, Y.H. Chou-Wu, WS. Wu, R.S. Chen, ~H. Weng, T.C. Yen, H.C. Chang *Taoyuan, Taiwan
We here present the findings of genetic and dopamine transporter investigations on a series of 84 patients from 61 families with familial Par!dnson's disease in Taiwan of Chinese ethnic. The genetic analysis was by means of SSCR DHPLC, real-time PCR, and direct sequencing for tile 8 genes including o~-synuclein, parkin, UCHL1, D J-l, PINK1, and LRRK2, and CAG repeat number ofataxin 2 and ataxin 3. The dopamine transporter concentration was also measured by 99mTc-TRODAT-1 SPECT imaging for tile clinical and genetic correlations. The results showed 13 par!tin patients from 7 families (mean age at onset 27.4±10.5 years), 2 PINK1 sibs from 1 family (17.5±0.7 years), 1 LRRK2 patient from 1 family (47 years), 8 SCA2 patients from 5 families with parldnsonian phenotype (44.9±10.9 years), and 3 SCA3/Machado-Joseph disease patients from 1 family with parldnsonian phenotype (38.3 ±5.1 years). There were remaining 56 patients from 46 families without genetic mutation found. Compound heterozygous and heterozygous mutations rather than homozygous mutation were most frequent found in par!tin gene, which was also the most common genetic causes in early onset recessive familial Parldnson's disease. The DAT concentrations in the striatum analyzed by 99mTc-TRODAT SPECT were markedly decreased in those genetically caused parkinsonian patients. We concluded that genetic causes contributed to about 25% o f our familial Par!dnson's disease up to now. The parkin mutation was the most frequent genetic causes of early onset Parldnson's disease.
Cardiovascular aspects of Parkinson disease D.S. Goldstein* *Bethesda, MD, USA
This lecture is about abnormalities of brain regulation of the cardiovascular system in Parkinson disease (PD). Orthostatic hypotension (OH) in PD has been thought to be a side effect of treatment with levodopa; however, recent studies have shown that virtually all patients with PD+OH have abnormal blood pressure responses to tile Valsalva maneuver and markedly decreased baroreflex-cardiovagal gain, regardless of levodopa treatment. Such patients also have markedly decreased sympathetic noradrenergic innervation of the left ventricular myocardium, as indicated by sympathetic nenroimaging, in marked contrast with normal innervation in multiple system atrophy. Moreover, most patients with PD who do not have OH have diffuse or localized loss of cardiac sympathetic innervation. PD therefore appears to involve not only a central catecholarninergqc lesion, with loss of dopamine cells of the nigrostriatal system, but also a peripheral catecholaminergic lesion, with loss of post-ganglionic norepinephrine cells of the sympathetic nervous system, especially in the heart. Tile mechanism and clinical significance of cardioselective sympathetic denervation in PD remain unknown. Conclusions The findings indicate that LNG caused endothelium-independent relaxations o f isolated jugular veins by inhibition of protein ldnase C and activation of the cAMP effector pathway.
•
~ R o l e of cytokines in neuroinflammatory process in Parkinson's Disease T. Nagatsu*, M. Sawada, K. Imamura * Toyoake, Japan
Objective: To determine if novel methods establishing patterns in EEGEEG and EEG-EMG coupling can infer subcortical influences on the motor cortex, and the rdationship between these subcortical rhythms and bradyldnesia. Background: Previous work has suggested that bradyldnesia may be a result of inappropriate oscillatory drive to the muscles. Typically tile signal processing method of coherence is used to infer coupling between the EEG and EMG, which demonstrates 2 peaks: one, -10Hz, which is pathologically increased in PD, and a -30Hz peak which is decreased in PD, and influenced by pharmacological manipulation of GABAA receptors. Method: We employed a novel multi-periodic squeezing paradigm which incorporated both response selection and unpredictable timing. Three PD subjects (on and off L-dopa) and three normal subjects were recruited. Extent of bradyldnesia was inferred by reduced relative performance of the higher frequencies of the squeezing paradigm. We employed wavelet coherence, Independent Component Analysis (ICA) and Empirical Mode Decomposition (EMD) to determine EEG/EMG and EEG/EEG coupling. Results: The wavelet coherence method detected a significant solitary peak in EEG-EEG coherence at about -25 Hz over the primary motor cortex (M1). However, SMA-M1 resultedin a single peak at around 10Hz. The ICA/EMD approach looldng at EEG/EMG coupling also untangled tile
Objective: The objective of the study was to investigate whether the production of cytoldnes in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) is neuroprotective or neuretuxic. Method: Activation ofmicroglia and gene expression of cyto!dnes were examined in the substantia nigra (SN) and putamen of pos~nortem brains by immunohistochernistry and Western blots of major histocompatibility complex (MHC) class II, ICAM-1 (CD54), LFA-1 (CDlla), TNF-alpha, and IL-6. Results: The number of MHC class II-positive activated microglia, which were also ICAM-I(CD54)-, LFA-I(CD1 la)-, TNF-alpha-, and IL-6positive, increased in the putamen and SN during the progress of PD. At tile early stage activated micr@ia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. On the other hand, Sawada with co-workers found that micr@ia in a culture experiment converted from the protective to toxic subtypes upon expression of the HW-1 Nef protein. These results suggest that activated microglia may change in vivo from neuroprotective to neurotexic subtypes as degeneration of TH-positive dopaminergic neurons in tile SN progresses in PD. Conclusion: The cytokines produced from activated micr@ia in the SN and putamen may act initially in neuroprotection, but may later become neurotoxic during the progress of PD.
Cortical muscle coupling in Parkinson's disease bradykinesia M.J. McKeown*, S.J. Palmer, R. Sash, R.G. McCalg, R. Abu-Gharbieh * Vancouve~ BC, Canada
78
Tuesday, 7 June 2005, 15.30 17.00, Hall 03
HT002 Hot topics: Basal ganglia pharmacology Chair: Treoor Archer, GSteborg, Sweden
Co-Chair: Luigi Zecca, Segrate, Italy
•
Functional neuroanatomy
A. Di Rocco*
*New York, NY, USA
•
Basal ganglia neuropharmacology; insights gained from intraoperative microdialysis in Parkinson's disease patients
agonists were potent ligands at D3 receptors revealing respectively 100-, 18- and 56-fold lower affinity at D2 receptors, mimic!ring tile selective D3 receptor antagonist, $33084 (100-fold). Tile proportion of high affinity binding sites recognized by $32504, pramipexole and ropinirole in membranes derived from cells co-expressing D3 and D2 sites was higher fllan in an equivalent mixture of membranes from cells expressing D3 or D2 sites, consistent with tile promotion of heteroclimer formation by agonists. In contrast, the percentage of high and low affinity sites (biphasic isotherms) recognised by $33084 was identical. Fmlctional actions were determined by co-transfection of a chimeric adenylyl cyclase (AC)-V/VI insensitive to D3 receptors. Accordingly, D3 recepmr-transfected cells were irresponsive to agenists while, in D2 receptor-lransfected cells, all agonists suppressed forskolin-stimulated cAMP production with modest potencies. In contrast, in cells co-transfected with both D3 and D2 receptors, $32504, repinirele and pramipexole potently suppressed the activity of AC-V/¥I with EC50s 33-, 19- and ll-fold lower than those at D2 receptors, respectively, despite similar maximal effects. These data suggest that actions at D3/D2 heterodimers might be involved in the functional actions of antiparkinsonian agents.
1~ Stanzione*, E. Fedele, A. Stet~a~fi, S. Galati, O. Pepicelli, L. Brusa, M. Pierantozzi, A. Peppe, A. Pisani, E Mazzone
Wednesday, 8 June 2005, 15.30-17.00, Hall 02
*Roma, Italy Objective: Deep brain stimulation (DBS) of tile subthalarnic nucleus (STN) in Parldnson's disease (PD) patients, a clinically effective treatment in the advanced disease stage, augments STN-driven excitation of the internal globus pallidus (GPi). However, DBS-induced changes in tile other basal ganglia nuclei are largely unknown,. In the present study, biochemical effects of STN-DBS have been studied in two basal ganglia stations (putamen and GPi) in addition to a thalamic relay nucleus. Method: In eight advanced PD patients, mldergoing surgery after prolonged drug withdrawal, microdialysis samples were collected from GPi, putamen (PUT) and antero-ventral thalamus (VA) every 10 minutes, at a flow rate of 5 ~tL/min, before,
~ T h e
role of synaptic and extrasynaptic dopamine receptors in Parkinson's disease
A. Carlsson*
*Gdteborg, Sweden
•
Heterodimerization of dopamine D2tD3 receptors reveals an unexpected level of pharmacological diversity
R. Maggie*, M.J. Millan, G.U. Corsini
*Pisa, Italy Recombinant, human dopamine D3 and D2 receptors form functional heterodimers upon co-expreasion in COS-7 cells. Herein, as compared to their effects at D3 and D2 monomers, the actions of the anfiparldnsonian agents, $32504, ropinirole and pramipexole, were characterized at D3/D2 heterodimers. In binding assays with tile antagonist, [3H]nernonapride, all
HT003 Hot topics: Varia Chair: Albert Ludolph, Germany
Co-Chair: Fabrizio Stocchi, Roma, Italy
~ l s
atypical parkinsonism in the Caribbean caused by the consumption of annonacae?
A. Lannuzel*, G.U. HSglinger, E Champy, RE Michel, E. Hirsch, M. Ruberg
*Pointe-a-Pitre, Guadeloupe Background: An abnormally high frequency of an atypical, nonL-DOPA-responsive, akinetic-rigid syndrome sharing some similarities with PSP has been identified in the Caribbean island of Guadeloupe. It was associated in a case-control study with tile regular consumption of plants from the annonaceae family, especially Annona muricata (corossol, soursop) (Caparros-Lefebvre et al, Lancet 1999) suggesting a possible causal role for a toxin. Objective: Annonaceae contain two major groups of potential toxins: alkaloids and acetogenins. We wished: (1) to identify and quarnify tile most abundant of these compounds in the plant; (2) to characterize the mechanism underlying their toxicity. Design/Methods: We assessed the toxicity of the two alkaloids reticuline and coreximine and that of tile acetogenin amlonacin using a model system of mesencephalic dopaminergic (DA) neurons in culture. We also infused male Lewis rats i.v. for 28d with annonacin (3.8 or 7.6 m g ~ d ) to compare them to vehicule-infused rats. Results: Our initial work has shown that the alkaloids reficuline and coreximine were toxic for DA neurons in culture (Lannuzel et al., Mov disord 2002). However, the following studies were focused on annonacin for two reasons: (1) amlonacin was found to trigger neurodegenerative changes at much lower concentrations than the alkaloids; (2) annonacin is a known mitochondrial toxin, a property shared by other parldnsoniarninducing compomlds. We showed that annonacin operates indeed as a selective and powerful inhibitor of complex I of the mitochondrial respiratory chain (IC50 30riM) and that it !rills DA neurons by impairment of energy metabolism (Lannuzel et at., Nenroscience 2003). Annonacin was approximately 50-fold more potent than tile dassic complex I inhibitor MPP+ in inducing neuronal death. Infused intravenously for 28 days in rats annonacin induced a loss of nigral dopaminergic neurons and striatal dopaminergic fibers. However, the toxicity was not restricted to the nigrosttiatal system but was pronounced and widespread in other basal garlglia and bvainstem nuclei (Champy et al., J Neurochern 2004), consistent
Hot Tepics
79
with clinical picture of tile disease in patients, tn a recent quantitative study, we have shown that tile fruit of Annona muricata and teas prepared from its leaves, both o f which are commonly consumed in Guadeloupe, contain high levds of annonacin. Conclusions: These studies adds further support to the concept that alimentary consumption of Annonaceae may be contribute to the pathogenesis of tile atypical parldnsonian syndrome in Guadeloupe. Supported by: INSERM, Ministate de l'Ontre Mer (French West Indies Ministry), University Hospital of Pointe 5 Pitre, PSP Foundation, GISmaladies Rare.
-10Hz and ~30Hz peaks into separate components. Subjects with greater bradyldnesia had a tendency towards increased ~ 10Hz coupling and reduced ~30Hz coupling that was partially reversed with L-dopa. Conclusion: These results suggest that the two peaks typically found in tile EEG/EMG coherence spectrum represent two spatially overlapping, distinct processes that may be isolated with suitable signal-processing techniques. The lower ~10Hz peak may represent pathological oscillations within the basal ganglia which may be a contributing factor to bradykinesia in PD.
•
•
Genetic and DAT studies of familial Parkinson's disease in Taiwan C.-S. Lu*, Y.H. Chou-Wu, WS. Wu, R.S. Chen, ~H. Weng, T.C. Yen, H.C. Chang *Taoyuan, Taiwan
We here present the findings of genetic and dopamine transporter investigations on a series of 84 patients from 61 families with familial Par!dnson's disease in Taiwan of Chinese ethnic. The genetic analysis was by means of SSCR DHPLC, real-time PCR, and direct sequencing for tile 8 genes including o~-synuclein, parkin, UCHL1, D J-l, PINK1, and LRRK2, and CAG repeat number ofataxin 2 and ataxin 3. The dopamine transporter concentration was also measured by 99mTc-TRODAT-1 SPECT imaging for tile clinical and genetic correlations. The results showed 13 par!tin patients from 7 families (mean age at onset 27.4±10.5 years), 2 PINK1 sibs from 1 family (17.5±0.7 years), 1 LRRK2 patient from 1 family (47 years), 8 SCA2 patients from 5 families with parldnsonian phenotype (44.9±10.9 years), and 3 SCA3/Machado-Joseph disease patients from 1 family with parldnsonian phenotype (38.3 ±5.1 years). There were remaining 56 patients from 46 families without genetic mutation found. Compound heterozygous and heterozygous mutations rather than homozygous mutation were most frequent found in par!tin gene, which was also the most common genetic causes in early onset recessive familial Parldnson's disease. The DAT concentrations in the striatum analyzed by 99mTc-TRODAT SPECT were markedly decreased in those genetically caused parkinsonian patients. We concluded that genetic causes contributed to about 25% o f our familial Par!dnson's disease up to now. The parkin mutation was the most frequent genetic causes of early onset Parldnson's disease.
Cardiovascular aspects of Parkinson disease D.S. Goldstein* *Bethesda, MD, USA
This lecture is about abnormalities of brain regulation of the cardiovascular system in Parkinson disease (PD). Orthostatic hypotension (OH) in PD has been thought to be a side effect of treatment with levodopa; however, recent studies have shown that virtually all patients with PD+OH have abnormal blood pressure responses to tile Valsalva maneuver and markedly decreased baroreflex-cardiovagal gain, regardless of levodopa treatment. Such patients also have markedly decreased sympathetic noradrenergic innervation of the left ventricular myocardium, as indicated by sympathetic nenroimaging, in marked contrast with normal innervation in multiple system atrophy. Moreover, most patients with PD who do not have OH have diffuse or localized loss of cardiac sympathetic innervation. PD therefore appears to involve not only a central catecholarninergqc lesion, with loss of dopamine cells of the nigrostriatal system, but also a peripheral catecholaminergic lesion, with loss of post-ganglionic norepinephrine cells of the sympathetic nervous system, especially in the heart. Tile mechanism and clinical significance of cardioselective sympathetic denervation in PD remain unknown. Conclusions The findings indicate that LNG caused endothelium-independent relaxations o f isolated jugular veins by inhibition of protein ldnase C and activation of the cAMP effector pathway.
•
~ R o l e of cytokines in neuroinflammatory process in Parkinson's Disease T. Nagatsu*, M. Sawada, K. Imamura * Toyoake, Japan
Objective: To determine if novel methods establishing patterns in EEGEEG and EEG-EMG coupling can infer subcortical influences on the motor cortex, and the rdationship between these subcortical rhythms and bradyldnesia. Background: Previous work has suggested that bradyldnesia may be a result of inappropriate oscillatory drive to the muscles. Typically tile signal processing method of coherence is used to infer coupling between the EEG and EMG, which demonstrates 2 peaks: one, -10Hz, which is pathologically increased in PD, and a -30Hz peak which is decreased in PD, and influenced by pharmacological manipulation of GABAA receptors. Method: We employed a novel multi-periodic squeezing paradigm which incorporated both response selection and unpredictable timing. Three PD subjects (on and off L-dopa) and three normal subjects were recruited. Extent of bradyldnesia was inferred by reduced relative performance of the higher frequencies of the squeezing paradigm. We employed wavelet coherence, Independent Component Analysis (ICA) and Empirical Mode Decomposition (EMD) to determine EEG/EMG and EEG/EEG coupling. Results: The wavelet coherence method detected a significant solitary peak in EEG-EEG coherence at about -25 Hz over the primary motor cortex (M1). However, SMA-M1 resultedin a single peak at around 10Hz. The ICA/EMD approach looldng at EEG/EMG coupling also untangled tile
Objective: The objective of the study was to investigate whether the production of cytoldnes in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) is neuroprotective or neuretuxic. Method: Activation ofmicroglia and gene expression of cyto!dnes were examined in the substantia nigra (SN) and putamen of pos~nortem brains by immunohistochernistry and Western blots of major histocompatibility complex (MHC) class II, ICAM-1 (CD54), LFA-1 (CDlla), TNF-alpha, and IL-6. Results: The number of MHC class II-positive activated microglia, which were also ICAM-I(CD54)-, LFA-I(CD1 la)-, TNF-alpha-, and IL-6positive, increased in the putamen and SN during the progress of PD. At tile early stage activated micr@ia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. On the other hand, Sawada with co-workers found that micr@ia in a culture experiment converted from the protective to toxic subtypes upon expression of the HW-1 Nef protein. These results suggest that activated microglia may change in vivo from neuroprotective to neurotexic subtypes as degeneration of TH-positive dopaminergic neurons in tile SN progresses in PD. Conclusion: The cytokines produced from activated micr@ia in the SN and putamen may act initially in neuroprotection, but may later become neurotoxic during the progress of PD.
Cortical muscle coupling in Parkinson's disease bradykinesia M.J. McKeown*, S.J. Palmer, R. Sash, R.G. McCalg, R. Abu-Gharbieh * Vancouve~ BC, Canada