Statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one series to another. Nevertheless, the overlap of the two diseases may be more than fortuitous, as indicated earlier in this chapter. The majority of the demented Parkinson patients show some Alzheimer-type changes but there are some in whom few plaques or neurofibrillary changes can be found and instead display cortical neuronal loss accompanied by widespread distribution of Lewy bodies, marking the process as Lewy body dementia and not Parkinson disease.
Of interest had been the observation, both in humans and in monkeys, that a neurotoxin (known as MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]) produces irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra. The toxin, an analogue of meperidine, which was self-administered by addicts, binds with high affinity to monoamine oxidase, an extraneural enzyme that transforms MPTP to a toxic metabolite, pyridinium MPP (1-methyl-4-phenylpyridinium). The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The mechanism by which MPTP produces the clinical aspects of the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the influence of gamma-aminobutyric acid (GABA) of the subthalamic nucleus. The notion of some other environmental toxin as a cause of Parkinson disease has been stimulated by the MPTP findings (see Uhl et al; also the review by Snyder and D’Amato). For example, in some epidemiologic studies Parkinson disease is slightly more frequent in industrialized countries and in agrarian regions where organophosphates are commonly used, but its universal occurrence would argue against this hypothesis. Despite extensive study, no chemical toxin, heavy metal, or infection has been causally related to the disease. Some plausible theories hold that a toxin might be implicated only on a genetic background predisposing to the disease. The MPTP disease serves as a model for the neurophysiologic and neurochemical changes of Parkinson disease because of destruction of the substantia nigra, but in most other respects it does not reflect the naturally occurring disorder (including the absence of Lewy bodies).
Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent, however, epidemiologic studies suggest that a familial occurrence may be as high as 15 percent. A lack of concordance of Parkinson disease in twins was at first thought to negate the role of genetic factors but a study of dopamine metabolism using PET scanning showed that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction, whereas only a small portion of dizygotic twins showed these changes (Piccini et al). These data indicate a substantial role for inherited traits, even in cases of ostensibly sporadic Parkinson disease.
Mutations in at least 10 genes (the most important being SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and others) that have been related to typical or “classical” forms of Parkinson disease but only 5 percent of patients have monogenic forms of disease. Some of these and several others have been only tentatively identified or are risk factors rather than being obligate markers of disease. More importantly for the clinician, the majority of typical cases is tied to the combined effects of fairly common sequence variants, too numerous to list here. Several of these have stood out as being more common than others or offering biological insights into the nature of Parkinson disease (see the review by Lill and Klein for a more extensive listing and explanation of these genes).