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Pattern of dopaminergic loss in the striatum of humans with parkinsonism induced by MPTP
  1. G V SAWLE
  1. Department of Neurology, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK
  1. guy.sawle{at}nottingham.ac.uk

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The small group of drug addicts in the United States who unwittingly injected a bad batch of synthetic narcotic around 1982 had no idea that some of their number would develop a Parkinson's disease-like illness within weeks.1 It transpired that the chemist who had made the offending drug had unwittingly synthesised 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which proved to be a potent and specific nigral toxin. A postmortem examination of one such affected patient showed prominent cell loss in the substantia nigra with a single eosinophilic inclusion similar to a Lewy body.

Not surprisingly, this discovery gave an enormous boost to the environmental theories of Parkinson's disease aetiology. But still, years later, we are no closer to identifying a unifying environmental toxin, and advances in our understanding of the genetics of familial parkinsonism have clearly demonstrated that environmental factors alone cannot be the answer. Nevertheless, observations of the manner in which MPTP is toxic has been a stimulus to research into mitochondrial function in Parkinson's disease and the MPTP model (using rodent or primate species) has become a standard and powerful tool in the laboratory investigation of parkinsonism. But what of the few patients affected by MPTP who were in the neurological headlines all those years ago? The answer is that they have been diligently followed up, both clinically and using functional imaging. This has not always been easy, due to the lifestyle chosen by some of the subjects.

The report by Calne et al of low18F-fluorodopa uptake in subjects who had been exposed to MPTP but were clinically well, demonstrated the potential of18Ffluorodopa positron emission tomography (PET) scanning as a marker of subclinical dopaminergic cell loss.2 Some others who escaped parkinsonism in the aftermath of their exposure have gone on to develop clinical parkinsonism years later.3 A few incapacitated patients underwent fetal cell implantation and their outcome data have been published.4

In this issue, pp313–316, Snow et al 5 report 18F-fluorodopa PET data from nine subjects who were exposed to MPTP about 10 years earlier, eight of whom developed mild parkinsonism. Idiopathic Parkinson's disease affects the ventrolateral tier of nigral neurons first, and this leads in turn to focal loss of the posterior putamen18F-fluorodopa signal, followed by involvement of the anterior putamen and caudate as the disease progresses to involve other nigral areas. In the patients with MPTP exposure, however, Snowet al reported a decrement of tracer uptake throughout the caudate and putamen. They also found less asymmetry of uptake than in patients with idiopathic Parkinson's disease. This difference in striatal 18F-fluorodopa uptake between patients with MPTP parkinsonism and idiopathic Parkinson's disease is a further indicator that these two conditions are not quite the same and the authors conclude that idiopathic Parkinson's disease is not caused by transient exposure to MPTP. A complicating factor which Snowet al consider in their manuscript is the known variability in the pattern of striatal involvement in MPTP animal models according to the dosing schedule used. Two of the subjects of Snow et al reported exposure to MPTP over 3 to 4 months, whereas others had shorter exposure.

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