Understanding Parkinson Disease

PARKINSON DISEASE (PD) is second only to Alzheimer disease in frequency as a neurodegenerative disorder in the United States. At least a half a million Americans are affected, producing an annual societal cost of $20 billion.¹ Most cases of PD begin after age 50 years and there is an increasing age-related prevalence to at least age 80 years. Among individuals older than 70 years, 1.5% to 2.5% have PD.² With the increasing age of the population and growth of the number of elderly individuals, a substantial increase in PD can be anticipated. This changing demographic creates a scientific imperative to better understand the causes of PD and improve management of its symptoms.

In this issue of THE JOURNAL, Tanner and colleagues³ provide important new information regarding the origin of PD. In a compelling study of 193 twin pairs, the authors demonstrate that genetic factors do not play a major role in causing typical PD. Equally significant, they show that genetic factors are important when the disease begins before the age of 51 years. This study is a critical step in understanding PD; it suggests that research is best focused on environmental causes for typical PD while studying genetic factors that contribute to the occurrence of early-onset disease.

Several previous studies have failed to find an increase in the concordance among monozygotic twins suggesting the limited contribution of genetic factors to typical PD.^{4 - 6} However, these studies were relatively small compared with the one reported by Tanner et al.³ In some studies, identification of cases relied on chart review or databases and thus some cases concordant for mild PD could have been missed. The genetics of PD have continued to be controversial with some arguing for an as yet unidentified genetic factor.^{7 - 8} The study by Tanner et al³ with its large number of twins and advanced methods including examination of all twin pairs provides more conclusive evidence against a role for genetic factors in the typical form of the disease.

Since it was discovered that exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce a syndrome with features of classical PD, the concept that the disease might be a product of environmental toxins has gained momentum.^{9 - 12} Case-control studies have identified a number of candidate risk factors or exposures including pesticide use, living in a rural environment, consumption of well water, exposure to herbicides, and proximity of residence to industrial plants, printing plants, or quarries.^{13 - 17} The new data from Tanner and colleagues³ suggest that leads obtained from case-control studies and other types of population investigations are likely to hold the key to understanding the origin of PD. Chemical resemblances between MPTP and some herbicides and pesticides, the increased use of these agents in rural environments, and possible contamination of well water by these compounds are observations that may be linked, suggesting an MPTP-like environmental toxin that is more widely distributed or present in higher concentrations in rural than in urban environments.

Recent research has focused on genetic causes of PD. Linkage of the disorder to chromosome 4q21-q23 in a large Italian kindred¹⁸ was followed by demonstrating that the mutation at this location was in the α-synuclein gene. The identical mutation also was present in 3 Greek kindreds.¹⁹ While this mutation appears to be a rare cause of PD and has not been found in patients with typical late-onset disease, identification of this mutation and the anticipated definition of the molecular events leading from the mutation to cell death will provide substantial insight into the pathogenesis of the illness. Given the identity of the pathologic changes in hereditary and sporadic PD, it is likely that similar mechanisms are involved in both types of disease. In hereditary cases, the mutation may activate a lethal cascade of events, whereas in sporadic disease, environmental triggers may induce the deadly sequence. The α-synuclein mutation results in a substitution of alanine for threonine in the protein structure which in turn disrupts the α-helical secondary structure of the protein in favor of a β-pleated configuration.^{1 ,19} This change in structure renders the protein dysfunctional and leads to the cellular pathologic events. The distribution of synuclein in the brain is similar to the distribution of Lewy bodies found in PD and dementia with Lewy bodies. Further study of the role of the altered structure of synuclein and its role in premature cell mortality may suggest neuronal protective strategies useful for preventing the onset or slowing the progression of idiopathic as well as familial PD.

All families with PD in which the α-synuclein mutation has been identified have involved early-onset PD (ie, onset before age 50 years). As a general rule, these young-onset patients tend to have the earlier appearance of levodopa-related dyskinesias and motor fluctuations, more frequent dystonia as an early or presenting sign, and less evidence of cognitive impairment.^{20 - 21}

In addition to the central observations regarding the absence of a genetic factor in typical PD, several other clinically relevant findings emerge from the research by Tanner and colleagues.³ In this study, participants were examined regardless of whether they were thought to have parkinsonism. As a result, 18 new cases of PD were diagnosed among 193 twins. This suggests that nearly 10% of patients with PD are unrecognized by their physicians as having the disorder. Lack of identification of PD will become a more urgent problem as successful neuroprotective strategies are identified and the need for initiation of therapy as early as possible in the disease course will be warranted. Thirteen twins with an initial diagnosis of PD were eventually given some other diagnosis at consensus review. Thus, while in some cases PD is unrecognized, in others an alternative condition such as essential tremor leads to misdiagnosis of PD. Recognition and accuracy of diagnosis of PD are 2 important areas for future research.

There have been recent advances in the treatment of PD. Substantial evidence indicates that a basic mechanism in the illness is the formation of hydrogen peroxide, and oxygen-derived free radicals produce lipid peroxidation of cell membranes leading to cell death.²² Selegiline is a monoamine oxidase type A inhibitor that limits the formation of free radicals derived from oxidation of dopamine, and application of this agent in clinical trials suggests an effect on disease progression consistent with a neuroprotective action.^{23 - 25} While the effect of selegiline on the course of PD is controversial, this agent represents the first step toward development of more potent neuroprotective agents that are capable of prolonging cell life and function.

Pramipexole and ropinirole, new selective dopamine D₃ receptor agonists, extend the armamentarium of anti-PD agents beyond the existing mixed dopamine receptor agonists (bromocriptine and pergolide) and the dopamine precursor, levodopa.^{26 - 27} Increasing refinement in receptor manipulation strategies allows more effective symptom relief and individualization of PD therapy. However, these agents have little effect on the underlying disease process and do not modify the eventual emergence of disability. Pharmacotherapeutic strategies that promote cell survival and normalize cell function are critically needed.

Surgical therapies for PD also have made recent gains. Although the initial enthusiasm for transplantation of adrenal medullary tissue to the caudate nuclei has decreased,^{28 - 30} transplantation of human fetal dopamine cells continues to show promise but still is regarded as an experimental procedure.^{31 - 35} Stereotactic pallidotomy has become widely practiced and provides relief for patients with advanced PD, particularly those with motor fluctuations and dyskinesias.^{36 - 38} This procedure is particularly important because it benefits patients in later phases of the illness when medications have become less useful and medication adverse effects become more prominent.

Neuropsychiatric aspects of PD also are better understood and managed. Dementia, depression, hallucination, and psychosis associated with PD have been studied and new therapeutic strategies have emerged. Advances in medical and surgical therapies have provided substantial improvement in the quality of life of patients with PD. Nevertheless, these approaches are largely directed toward symptom management and eventually must give way to identification of environmental hazards that can be eliminated and raising the level of public health, or to chemopreventive strategies that can be administered to exposed, at-risk, or minimally symptomatic individuals. The therapeutic nihilism traditionally implied in the term "degenerative" is giving way to the dissection of the sequence of the molecular events that lead from the initial trigger to cellular extinction. The contribution by Tanner et al³ allows refocusing of the research on environmental triggers for typical PD and genetic influences in early-onset disease.