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Cannes, 1997 The articles cited and reviewed below were presented at a 1997 symposium in Cannes, France, and subsequently printed as a supplement to the September 1998 issue of Annals Of Neurology. The format here is like that of the Current Science Reviews but posted separately, due to the number of items: Cell Death and Neuroprotection in Parkinson's Disease P. 1 of 3 (Supplement 1, Vol 44, Ann Neur 1998; C. Olanow. ed) INTRODUCTION Poewe W, Wenning G; Ann Neur 1998;44S1:1-9: Despite many large studies, the rate of symptomatic progression and the neuroprotection by selegiline are uncertain. However, recent follow-up of the DATATOP cohort showed normal life span. Brooks D; Ann Neur 1998;44S1:10-18: Any biological marker for preclinical diagnosis remains elusive, but PET and SPECT scanning are effective diagnostic tools. Perl D et al; Ann Neur 1998;44S1:19-31: Numerous overlapping features of PD and AD suggest that they may be points in a continuous spectrum of neurodegenerative disease. Morrison B et al; Ann Neur 1998;44S1:32-44: Different groups of cells are selectively vulnerable in various neurodegenerative diseases, suggesting that they are related. ETIOLOGY Langston J; Ann Neur 1998;44S1:45-52: The long debate over epidemiology versus genetics in PD remains unresolved, but the future lies ahead. Gasser T; Ann Neur 1998;44S1:53-57: Status and progress in mapping possible genes for PD. Alpha- synuclein gene mutation remains a prime suspect. Wood N; Ann Neur 1998;44S1:58-62: Evidence of genetic factors in PD is overwhelming, but positive identification of any one in particular is still elusive. Polymeropoulos M; Ann Neur 1998;44S1:63-64: Reviews his discovery of the autosomal-dominant alpha-synuclein mutation, and suggests further that it may contain a clue to the pathology of PD. Borden K; Ann Neur 1998;44S1:65-71: Speculates about the function of normal alpha-synuclein and the role of its mutants in causing PD. PATHOGENESIS Jenner P et al; Ann Neur 1998;44S1:72-84: Failure to process structurally modified proteins such as alpha-synuclein in regions of the brain having oxidative stress may be a cause of both familial and sporadic PD. Cell Death and Neuroprotection in Parkinson's Disease P. 2 of 3 Munch G et al; Ann Neur 1998;44S1:85-88: They believe oxidative stress is decisive in PD. Certain chemical end products of neurodegeneration are increased during oxidative stress, and themselves influence glial cells to produce more oxidants such as superoxide and nitric oxide, in a vicious cycle. Schapira A et al; Ann Neur 1998;44S1:89-98: Mitochondria, little bodies that perform vital functions within cells, maintain their own independent DNA. Authors speculate that a defect in mitochondrial DNA, rather than the primary DNA of the cell nucleus, may be a contributing cause of PD. Mizuno Y et al; Ann Neur 1998;44S1:99-109: Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to the death of substantia nigral neurons in PD. Deficiency of mitochondrial Complex I appears to be an effect, rather than a cause, of neural death. Beal M; Ann Neur 1998:44S1:110-114: The defect of mitochondrial Complex I in PD may render neurons of the substantia nigra more vulnerable to toxic stimulation by neurotransmitters such as the glutamate NMDA. Antagonists to those substances have shown some neuroprotection in primates. Hirsch E et al; Ann Neur 1998;44S1:115-120: They suspect that a subpopulation of glial cells surrounding dopaminergic neurons [of the substantia nigra] may account for their highly selective vulnerability. Gash D et al; Ann Neur 1998;44S1:121-125: They review favorable and encouraging results from glial cell line-derived neurotrophic factor (GDNF) in rodent and monkey models of PD. GDNF has both protective and restorative effect. APOPTOSIS (Programmed Cell Death) Burke R, Kholodilov N; Ann Neur 1998;44S1:126-133: While apoptosis may be a normal occurrence, it also may be a feature of neurodegenerative disease, e.g., induced by MPTP in animal models of PD. More study of human postmortem tissue is needed to understand the molecular basis of apoptosis. Tatton W et al; Ann Neur 1998;44S1:134-141: Certain mitochondrial defects are known to cause apoptosis in a variety of non-neural cells, and several measures which counter those defects might be useful against neurodegenerative apoptosis. Tatton N et al; Ann Neur 1998;44S1:142-148: Preliminary indications are that apoptosis plays a role in PD, and more study hopefully will lead to better understanding. Authors describe their fluorescent double-labeling method for positively identifying neurons that have died via apoptosis. Cell Death and Neuroprotection in Parkinson's Disease P. 3 of 3 NEUROPROTECTION Melamed E et al; Ann Neur 1998;44S1:149-154: Levodopa definitely causes death by apoptosis of cultured neurons in vitro, but there is no evidence for that in living subjects, either animal models of PD or human patients. Effects of long-term exposure to levodopa urgently need more study. Koller W; Ann Neur 1998;44S1:155-159: Complications of long-term levodopa PD therapy such as motor fluctuations, dyskinesias, and mental status changes present a major challenge to the clinician. Shoulson I et al; Ann Neur 1998;44S1:160-166: The 8.2-year DATATOP trial which began in 1987 showed that selegiline (Deprenyl) delayed the need for starting levodopa, but it didn't postpone levodopa-related adverse effects after that. The mortality rate of the DATATOP cohort was 2.1% per year, nearly the same as an age-matched non-PD population. Olanow C et al; Ann Neur 1998;44S1:167-174: Reviews various possible ways that dopamine agonists might provide neuroprotection in PD: levodopa-sparing, receptor stimulation, direct anti-oxidant effects, restoration of dopaminergic tone to reduce excitotoxicity. Rodriguez M et al; Ann Neur 1998;44S1:175-188: Dopamine loss in PD disinhibits the subthalamic nucleus, which in turn overstimulates neurons of the substantia nigra and may thereby induce excitotoxic damage. Hence the hypothesis that treatment to reduce STN activity or to block glutamate receptors in the SN might be neuroprotective and slow the progress of PD. Marsden C et al; Ann Neur 1998;44S1:189-196: The causes of PD are being unraveled, rational neuroprotective therapy is near reality. Using fewer subjects for initial trials might permit testing more possible agents sooner, and thereby accelerate the search for a potent neuroprotective therapy. -- J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks, CA 91403-5013