Vol 6 n° 3 - Parkinson's disease
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2 8 1 B a s i c   r e s e a r c h Copyright © 2004 LLS SAS.  All rights reserved www.dialogues-cns.org Postmortem studies in Parkinson’s disease Andreas Hartmann, MD No animal model to date perfectly replicates Parkinson’s disease (PD) etiopathogenesis, and the anatomical orga- nization of the nigrostriatal system differs considerably between species. Human postmortem material therefore remains   the   gold   standard   for   both   formulating hypotheses for subsequent testing in in vitro and in vivo PD models and verifying hypotheses derived from exper- imental PD models with regard to their validity in the human disease. This article focuses on recent and rele- vant fields in which human postmortem work has gen- erated significant impact in our understanding of PD. These fields include Lewy body formation, regional vul- nerability of dopaminergic neurons, oxidative/nitrative cellular stress, inflammation, apoptosis, infectious and environmental agents, and nondopaminergic lesions. © 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:281-293. Keywords: Parkinson’s disease; pathogenesis; etiology; postmortem study; Lewy body formation; dopaminergic neuron; cellular stress Author affiliations: Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, France Address  for  correspondence:  Andreas  Hartmann,  MD,  Centre d’Investigation Clinique, Hôpital de la Salpêtrière, 47, Boulevard de l’Hôpital, 75013 Paris, France (e-mail: hartmann@ccr.jussieu.fr) he  history  of  human  postmortem  studies  in Parkinson’s disease (PD) begins at the end of the 1950s with two seminal papers: Carlsson’s original suggestion that dopamine (DA) may be a transmitter in the central nervous system (CNS) and be involved in the control of motor function, and thus in the parkinsonian syndrome 1; and the article by Ehringer and Hornykiewicz, 2 which proved the significant reduction in DA concentration in the neostriatum of patients suffering from sporadic PD. In  1973,  these  initial  observations  were  followed  by demonstration of a correlation between DA cell loss in the substantia nigra pars compacta (SNpc,  Figure 1) and striatal DA concentrations in PD. 3 Interestingly, this study suggested that the classical parkinsonian symptom triad of PD appears when striatal DA concentrations are low- ered by approximately 80%; however, this decline corre- sponds to only 50% of SNpc DA neuron loss, suggesting that a subset of nigral DA neurons may be morphologi- cally intact, but functionally impaired.This concept is sup- ported by the finding that 15% of melanized neurons in the human SNpc no longer express tyrosine hydroxylase (TH;  the  rate-limiting  enzyme  in  DA  synthesis),  but remain morphologically intact. 4 This concept of the suf- fering, ie, metabolically compromised, neuron is impor- tant in pathophysiological and therapeutic terms, since it suggests that a subpopulation of nigral DA neurons are amenable to restorative therapies. After a general outline on the potential and limitations of human postmortem studies in PD, I will explore major questions regarding etiology, pathogenesis, and treatment of PD with reference to human postmortem studies. The role of human postmortem studies in PD research There has been considerable debate over the importance of human postmortem studies in PD research. This con- troversy is based on the many limitations of postmortem research. Human postmortem studies in PD suffer from T