Roger C. Duvoisin

Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: Implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity

The 1-methyl-4-phenyl-pyridinium ion (MPP+) is the four electron oxidation product of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP). MPP+ can be formed by the oxidation of MPTP by monoamine oxidase B to the intermediate dihydropyridinium species, MPDP+, which is spontaneously transformed to MPP+. In the present study, MPP+, like the mitochondrial toxin rotenone, inhibited pyruvate-malate respiration in isolated mitochondrial preparations. Moreover, the stereotaxic administration of both MPP+ and rotenone caused damage to the dopaminergic nigrostriatal pathway. These data clearly demonstrate that a mitochondrial toxin, administered stereotaxically, is extremely neurotoxic. The data lend support to the concept that MPTP-induced neurotoxicity may be due to the detrimental actions of enzymatically formed MPP+ on mitochondrial function.

A clinical genetic study of Parkinson's disease: Evidence for dominant transmission

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinsons disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD

A case‐control study of twin pairs discordant for Parkinson's disease A search for environmental risk factors

A previous study of twins with Parkinsons disease (PD) revealed low concordance, suggesting that genetic factors play a minor role in the etiology of PD. To identify possible environmental determinants of PD while maximally controlling for hereditary factors, 31 monozygotic twin pairs discordant for PD were interviewed by telephone. Information about possible risk factors was obtained from systematic and uniform interviews with cases and controls. The only statistically significant result was less cigarette smoking by PD patients (p < 0.05). Thirteen dizygotic discordant twin pairs were evaluated with the same techniques, but there were no statistically significant differences between affected and unaffected twins.

Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B

Two selective and potent inhibitors of monoamine oxidase (MAO) type B, namely AGN-1133 (N-methyl-N-propynyl-1-indanamine) and AGN-1135 (N-propynyl-1-indanamine), given to mice prior to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) protected against the neurotoxic effects of MPTP. For example, mice treated with these agents prior to MPTP, did not exhibit the decrement in the neostriatal content of dopamine and its metabolites normally seen after MPTP administration. These data lend further support to the concept that the oxidation of MPTP by MAO-B to its corresponding pyridinium analog, 1-methyl-4-phenyl-pyridinium (MPP+) is an important feature of the neurotoxic process.

Follow-up study of risk factors in progressive supranuclear palsy

The cause of progressive supranuclear palsy (PSP) is not known and has been little studied.The one previous controlled epidemiologic survey, performed at our center in 1986, found small-town experience and greater educational attainment as PSP risks, but, in retrospect, these results may have been produced by ascertainment bias. Since that time, several anecdotal reports have implicated heredity and various environmental exposures in the cause of some cases of PSP. To clarify the results of the previous study and to evaluate the more recently implicated candidate factors in a controlled fashion, we mailed a validated 69-item questionnaire to 91 personally examined patients with PSP and 104 unmatched controls with other neurologic conditions for which they had been referred to our tertiary neurologic center. We were able to match 75 subjects from each group by year of birth, sex, and race and subjected them to a separate matched-pair analysis. We allowed surrogates to supply any or all of the responses. Questions concerned hydrocarbon, pesticide, and herbicide exposure; urban/rural living; auto repair and other occupations; head trauma; educational attainment; maternal age; and family history of PSP, parkinsonism, dementia, and other neurologic conditions. A statistically significant finding was that patients with PSP were less likely to have completed at least 12 years of school (matched odds ratio = 0.35, 95% CI = 0.12-0.95, p = 0.022; unmatched odds ratio = 0.44, 95% CI = 0.21-0.89, p = 0.020). We hypothesize that this result may be a proxy for poor early-life nutrition or for occupational or residential exposure to an as-yet unsuspected toxin. Future studies should examine these potential risk factors in PSP. NEUROLOGY 1996;47: 148-154