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This report provides the first detailed neuropathological study of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in humans. All 3 subjects self‐administered the drug under the impression it was “synthetic heroin” and subsequently developed severe and unremitting parkinsonism, which was L‐dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

This report provides the first detailed neuropathological study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was “synthetic heroin” and subsequently developed severe and unremitting parkinsonism, which was L-dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time-limited insult to the nigrostriatal system can set in motion a self-perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

In a previous study, we demonstrated that patients with MPTP-induced parkinsonism (MPTP-IP) had a pattern of cognitive change similar to that in nondemented patients with idiopathic Parkinson's disease (PD). The present study addressed cognitive change in MPTP-exposed but relatively asymptomatic (MPTP-AS) individuals. We examined them for general intellectual function, construction, language, memory, executive function, attention, and reaction time, and compared their performance with data obtained in the previous study from patients with MPTP-IP and drug addict controls. Each MPTP-AS individual had some subtle parkinsonian signs, but in no case would these be sufficient for a diagnosis of PD. PET studies showed that these individuals had significantly reduced uptake of labeled 6-fluorodopa into the striatum. MPTP-AS and MPTP-IP groups performed comparably and were significantly worse than controls on tests of construction and category naming. The MPTP-AS group performed at a level between the other 2 groups on a test of executive function. The 3 groups performed comparably on all other measures. The similarity of the pattern of intellectual change in MPTP-AS to that seen in MPTP-IP and idiopathic PD supports the idea that the dopamine system mediates a specific set of cognitive functions and suggests that cognitive change can occur in the presence of few or no motor signs of parkinsonism.

Ten patients with Parkinson's disease suffering severe motor fluctuations completed a double-blind, placebo-controlled, crossover trial of duodenal infusion of levodopa/carbidopa to determine if this technique improved the duration of functional time by reducing plasma levodopa level variability. With infusion, seven patients experienced increased functional “on” hours and decreased number of “off episodes; however, two patients were slightly worse and one patient experienced no benefit. All 10 patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements. Five patients continued to use infusion 12 to 20 months after completion of this study. Selected patients with Parkinson's disease who experience severe motor fluctuations may benefit from duodenal infusion with an improved and prolonged response to medication.

To determine the relative contribution of genetics and environment to essential tremor using a twin study method.