Monograph Series on Aging-related Diseases: XII. Parkinson's Disease-Recent Developments and New Directions

Natalie Kontakos and Julie Stokes

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects voluntary, co-ordinated movement. It is a disease of late middle age, usually affecting those over the age of 50. Although the discovery of PD is often attributed to James Parkinson and his 1817 monograph entitled The Shaking Palsy,¹ descriptions of parkinsonian syndromes date back to the ancient Ayurvedic literature of India, from 4500 to1000 BC.² The first breakthrough in PD research was in the 1960s, when the dopamine hypothesis and levodopa therapy were introduced.¹ There has since been much progress in disease definition and diagnosis, surveillance, knowledge of etiology and disease progression, and treatment. Although the cause of PD is not yet known and a cure has not been found, the past few years of research have lead to a greater understanding of the disease. As well as providing an overview of PD, this report focuses on the recent advances and the future directions of PD research.

Background and Natural History

PD is a chronic and progressive disorder of the central nervous system. It is the most common form of the parkinsonian syndromes, a group of motor system disorders that share the primary symptoms of tremor, rigidity and bradykinesia. Most studies indicate that there must be two of these three features for a diagnosis of parkinsonism.^3-5

Parkinsonian syndromes occur when the neurons that lie in the brain stem's substantia nigra ("black substance") are destroyed.⁴ The neurotransmitter dopamine is normally produced in the neurons of the substantia nigra. These neurons connect with other neurons in the corpus striatum, which in turn send messages to the motor-controlling areas of the cortex. Dopamine is depleted as the neurons of the substantia nigra diminish in number; therefore, the number of signals to the corpus striatum and from there to the cortex are decreased. The normal functioning of the motor system is thus disrupted (Figure 1).

FIGURE 1

Difference between a normal brain and a parkinsonian brain

Depletion of dopamine in the brain can come about in a number of ways. Parkinsonian syndromes may be induced by drugs, viral infections, hereditary diseases or metabolic causes. Parkinsonism and syndromes such as progressive supranuclear palsy and multiple system atrophy may present as relatively pure parkinsonism in the early stages of disease, with nonparkinsonian signs becoming more prominent with time. Other degenerative diseases of the central nervous system may either occur concurrently with PD or may exhibit some parkinsonian symptoms. Stroke, tumours, trauma and other nondegenerative conditions may influence the level of dopamine in the substantia nigra and/or corpus striatum and thus include parkinsonian features.

PD is different from most other parkinsonisms in that the cause of the destruction of the substantia nigra leading to dopamine reduction is not known.⁴ Many ideas, such as the "oxidative stress model",^6,7 have been brought forward to explain how PD begins, but none has been fully accepted.

The pathological classification of PD includes the degeneration of specific groups of nerve cells, including the substantia nigra.⁴ Poor circulation or arteriosclerosis cannot explain the location of the affected cells. PD can also be diagnosed after death on the basis of the Lewy body, a round inclusion found within degenerating neurons. Lewy bodies are highly characteristic of the disease.

Burden of Disease

Morbidity

According to a recent World Health Report, PD affects 3,765,000 individuals worldwide, and the condition is diagnosed in 305,000 people per year.⁸ In 1996, there were 2,635,000 people with PD who were chronically disabled and 58,000 deaths. Although PD affects individuals worldwide in all ethnic groups and from all socio-economic backgrounds, statistics reflecting the disease's morbidity and mortality vary widely from place to place. In fact, a recent review of the worldwide occurrence of PD⁹ revealed that there was a 13-fold difference between the highest (Uruguay) and the lowest (China) prevalence estimates in door-to-door studies, and a 3-fold difference between the highest (Iceland) and the lowest (Libya) locations in studies relying on data from sources such as hospitals, physicians and health insurance records. Incidence estimates exhibited a 10-fold difference between the highest (United States) and lowest (China) areas.

These ranges in prevalence and incidence may suggest environmental or genetic clues to the disease's etiology. They may also be due to other factors, such as differences in diagnostic procedures or population groups. Since this review standardized the rates for all studies to a single population, the variations cannot be attributed to populations of different age structures. Case ascertainment may be used to explain the difference in estimates between door-to-door studies and other studies that do not actively seek out individuals with PD.

The literature in the past has been quite consistent in reporting higher PD rates in primarily Caucasian populations as compared with Asian or black populations. More recent studies indicate that the variation in the prevalence of PD among different ethnic groups is not as large as it was once thought to be, but prevalence still varies from study to study.^10-17 A greater consistency in study methodologies probably explains this shift.

Recent incidence studies conducted in the United States and Europe all reveal PD incidence rates between 8 and 13 per 100,000.^15,18-20 All studies that included information specific for each sex reported higher incidence rates among males than females. The high male incidence rate in a study completed in Manhattan, United States,¹⁵ is largely attributed to the incidence rate among black males; in comparison to the rate among white males it was consistently higher in every age group, with a 4-fold difference in those over the age of 80. The duration of disease is probably shorter in black males, since the same study observed lower prevalence rates among black as compared with white males.

A Swedish study that used records from a health maintenance organization (HMO)²⁰ observed a higher crude incidence rate among whites than among blacks, Hispanics or Asians; Asians had the lowest rate. A cohort of male Hawaiian residents, of primarily Japanese or Okinawan ancestry,¹⁸ had an incidence rate in between that of the Manhattan study and the HMO study. The authors concluded that environmental factors were more important than genetic factors in this group of men, since Asian incidence rates reported previously were lower.

All studies showed incidence rates that increased linearly with age up until the age of 75. At this point, the incidence rate in most groups either plateaued or continued to increase linearly. The incidence rate in the Hawaiian cohort, however, decreased, and the rate among males in Manhattan increased even more steeply.

Morbidity in Canada

There are few data describing the prevalence and incidence of PD in Canada. Since most patients do not require hospital care on an in-patient basis, hospital separation rates underestimate the prevalence of PD. These rates are also problematic in that they are not based on the number of individuals but, rather, on the number of discharges. An individual can therefore be counted more than once. Despite the drawbacks, hospital separation rates can be useful in detecting general differences and trends. The overall hospital separation rate for PD (coded as paralysis agitans ICD-9 332.0) for the 1991-1995 period was 15.4 per 100,000 among men and 8.9 per 100,000 among women (Table 1). There was considerable variation from province to province, ranging from 8.0 per 100,000 in Newfoundland to 19.3 per 100,000 in Saskatchewan. This variation may be partly explained by different disease coding or hospital admission practices.

During 1991-1995, hospital separation rates increased with age and peaked among individuals aged 80-84. Males had higher hospitalization rates than females in every age category (Table 2), and the overall hospital separation rates were higher among males in every province.

Over time, standardized mortality rates have increased among both males and females. The increase among males from 1977-1981 to 1992-1996 was greater (93%) than the increase among females (79%). As with hospital separation rates, the increase in PD mortality is largely attributed to a greater increase of PD in older age groups than in younger age groups. The mortality rates in younger age groups, however, have not decreased to the extent that hospital separation rates have.

Risk Factors

Environmental Factors

The search for an environmental agent causing PD has been quite intensive. It heightened in the mid to late 1980s when MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a rare contaminant of heroin, was found to elicit clinical and pathological features virtually identical to those of PD.^32,33 It was thought that an environmental toxin with chemical and physical properties similar to MPTP could lead to PD. Although no such toxin has been found to be causally associated with PD, studies have offered substantial evidence to eliminate certain hypotheses and to explore other hypotheses further.

Rural living

Although studies in the past had pointed to an association between rural living and PD, the most recent studies are quite inconsistent in their results. Not only are the results inconsistent, but so are the periods of exposure under investigation.

Two studies found elevated and significant odds ratios (ORs) for rural living near the time of diagnosis,^34,35 whereas another study found PD mortality to be positively correlated with population density.³⁶ A Chinese study that found an OR of less than 1 for living in small cities did not specify the exposure period of interest.³⁷ One study from the US found an elevated and significant OR for a history of rural residence only for blacks and not for other ethnic groups.³⁸ The average population density of places of residence from birth to the time of diagnosis did not differ between cases and controls in one study,³⁹ and another showed no association between the place of residence for the first 15 years of life and the risk of PD.⁴⁰ Since PD is believed to have a long latent and asymptomatic period,⁴¹ the probable relevant exposure period would be earlier rather than later in life.

Because there are many specific exposures associated with rural areas, recent studies have attempted to measure these exposures in order to explain the association between PD and areas of low population density.

Three recent studies^36,42,43 have found an association between PD and agricultural work. One of them⁴³ looked solely at death certificates, and another³⁶ found a positive correlation between the number of PD deaths and farming density. In the third study,⁴² the OR for grain and crop farming was significant in univariate analysis but not in multivariate analysis. A German study reported an elevated and significant relative risk associated with mushroom harvesting during childhood and adolescence;⁴⁴ however, no association was found with previous farm activity or employment in agricultural work, living on a farm or having a farm near to the home, having contact with farm animals or involvement in slaughter. Other recent studies^34,38 have found no association between PD risk and farming.

Pesticide exposure

The similarity between the structures of the MPTP metabolite MPP+ and the herbicide paraquat encouraged the investigation of a possible relation between pesticide exposure and PD (Table 5).^{34,35,39,45-48} A study in Taiwan indicates that the OR for PD was 2.0 among those subjects who had used both paraquat and other herbicides/pesticides when compared with those exposed to pesticides and herbicides other than paraquat.⁴⁸ Recent studies have consistently shown an increased risk of PD with pesticide exposure, and in some this has achieved statistical significance.

Well water

Well water has also been implicated in PD. Of all the recent studies, only those conducted in Italy⁴⁹ and Spain⁵⁰ have found a positive association between drinking well water and the risk of PD. A study that examined the relation between PD mortality and the proportion of well water users in Michigan showed a negative correlation between the exposure and the disease,³⁶ and a Chinese study also reported a decreased risk of PD associated with drinking well water.³⁷ Four studies found no association,^38-40,48 and no contaminant thought to contribute to the cause of PD has been found in well water.

Metal exposure

Some metals, such as manganese and mercury, have been shown to induce parkinsonian signs and symptoms in individuals who were heavily and acutely exposed.⁵¹ Recent epidemiologic studies have looked at mainly occupational metal exposure as a risk factor for PD. No significant ORs were found in studies conducted in British Columbia⁴⁷ or Alberta.⁴⁵ A German study found only one significant OR for occupational exposure to lead.³⁹ This, however, was barely significant and only when compared with one of two control groups. Another OR that was just significant and involved only one control group was found for exposure to mercury through amalgam fillings. An ecological study reported that counties in Michigan with iron and copper industries had higher PD mortality rates.³⁶ In another study, elevated ORs for 20 years of occupational exposure to copper, manganese and various combinations of metals suggested that metal exposure may play a role in PD etiology.⁵² However, the finding that serum and urine levels of manganese, chromium and cobalt did not differ between PD patients and controls led the authors of another study to suggest that exposure to these metals is unrelated to PD.⁵³

Non-metallic toxins

The relation between PD and numerous other toxins has been investigated. Although one study⁵⁴ reported positive associations with plastic resins, epoxy resins, glues, paints and petroleum, it also found a multitude of other exposures not to be significant, leading to a problem with multiple comparisons. Higher mortality rates from PD were found in counties with paper and chemical industries.³⁶ Other studies have not found a relation with industrial toxins,³⁵ carbon monoxide,^39,45 cyanide,⁴⁵ exhaust fumes³⁹ or glues, paints and lacquers.³⁹ More PD patients than control patients have reported that they had wood panelling in their homes;⁵⁵ this may implicate wood preservatives in the etiology of PD.

Head injury

Head injury has been implicated in the etiology of PD, possibly through the microglial cells, which are involved in the inflammatory process.⁶ Two of four^35,39,45,56 recent studies found significant ORs with head trauma. The OR in one of these was barely significant and existed only in a comparison with one control group;³⁹  the other reported an OR that remained significant after multivariate analysis.⁴⁵ Studies examining head trauma may involve recall bias, and this issue should be addressed in future studies.

Smoking

Epidemiologic studies have consistently shown smoking to be protective for PD. The majority of recent studies seem to support this relation, as they have reported ORs of less than 1 (Table 6).^{34,39,40,45,56-59} In addition to this evidence, a prospective study involving the Honolulu Heart Study revealed a significant relative risk of 0.39.⁶⁰ Some experimental evidence supports the idea that nicotine may be protective for PD. One study showed that chronic nicotine intake in rats decelerated the age-associated decrease in dopamine receptors and in dopamine re-uptake.⁶¹

Other case-control studies, however, do not support the claim that smoking is protective for PD. Longitudinal Gompertzian analysis, which considers the three dimensions of genetics, environment and selective early mortality, demonstrates that a neuroprotective influence does not explain the negative association between PD and smoking.⁶² The negative association has been explained by the fact that smokers die sooner than non-smokers.

Tzourio et al.⁵⁸ found no overall protective effect of smoking in relation to PD but, when adjustments were made for age, tobacco was found to be protective in the younger age group while representing an increased risk in the older age group.

Although smoking has been found to be protective for PD, it is an important risk factor for many other major diseases, and the adverse effects of smoking far outweigh any possible benefits.

Diet

Diet has only recently been implicated in the etiology of PD. According to the oxidative stress model, an increase in antioxidants would prevent damage and death to dopaminergic cells by scavenging more free radicals. Therefore, antioxidants present in foods and available in supplements would be protective for PD. Epidemiologic studies that have examined the association between antioxidants and PD have been inconsistent (Table 7);^63-68 no study replicated any finding of a negative or positive association. The two prospective studies^63,65 used dietary history information collected before PD was diagnosed; in one,⁶³ the period from dietary to disease assessment was only a few years.⁶³ Since the disease process is thought to start many years before the individual is symptomatic, the dietary information obtained in the latter study may be irrelevant in terms of PD etiology. The other three studies^64,66,67 did not fare any better, in that they were case-control studies whose data focused on the individual's dietary pattern over the previous year.

Three other case-control studies^34,44,68 examined the relation between PD and foods rich in vitamin E. Although there was no difference in intake of foods rich in vitamin E in two of the studies,^44,68 the third reported an elevated and significant OR for nuts and seeds, which are rich in vitamin E.³⁴ One of these studies⁶⁸ found a higher intake of vitamin C in PD patients.

Studies relating antioxidant serum levels with PD status have also been performed. Three studies^69-71 found no difference in vitamin E serum levels between PD patients and healthy controls. One of these studies⁷⁰ also found no difference in vitamin A levels but did find higher vitamin C levels in PD patients; the vitamin C levels in controls, however, were low compared with established data in young healthy individuals. It is important to note that these studies included levels measured after the time of diagnosis and may not reflect levels before disease onset.

The relation between other dietary variables and PD etiology has also been recently examined. An ecological study reported significant and positive correlations between age-adjusted mortality rates in 17 different countries and the per capita consumption of total dietary protein and meat.⁷² In addition to the limitations inherent in ecologic studies, the study not only used mortality rates, which in comparison to other statistics do not accurately indicate the prevalence of PD, but also used figures from 1952 to 1958, which do not reflect the present rates. Two case-control studies^64,66 found an elevated and significant OR with fat intake. One of these⁶⁶ also reported elevated and significant ORs for cholesterol, iron and lutein. Since lipids are one of the major sources of free radicals, the increase in fat and cholesterol intake is consistent with the oxidative stress model. The positive association with lutein may be a result of PD, as many patients increase their consumption of lutein to manage the disease's symptoms.

A German study reported that PD may be related to a variety of foods.⁷³ PD patients consumed more chocolate, desserts, organ and raw meats, and less beer and coffee. The relation between the disease and these food items might be related to the effects of biogenic amines (chocolate), insulin levels (foods rich in refined carbohydrates), infectious agents (organ and raw meats), ethanol (beer) and caffeine (coffee) on the dopaminergic system. Another study has also found a negative association between alcohol consumption and PD.⁷⁴

Infections

The idea that PD may be infectious in origin is largely due to the onset of parkinsonian symptoms in individuals infected with the virus associated with lethargic encephalitis in the 1920s.⁷⁵ Numerous studies have failed to find an association between PD and a variety of common viruses and bacteria. Chicken pox, measles, rubella, mumps, the Spanish flu⁴⁵ and the Nocardia species⁷⁶ were all found to be unrelated to PD in recent studies. A study conducted in the United Kingdom reported that PD patients were more likely to recall suffering from croup or diphtheria in childhood.⁵⁶ It is important to note however, that these results are not based on antibody serum levels and that the neurotoxin produced by the organism of diphtheria cannot cross the bloodSbrain barrier.

An etiologic hypothesis involving whooping cough was brought forward when a positive relation between PD and whooping cough outbreaks in one-year birth cohorts was found in Iceland.⁷⁷ PD patients also had higher antibody responses to coronaviruses than did healthy controls, suggesting an association between these RNA-containing viruses and PD.⁷⁸ The observation that there is a higher prevalence of gastrointestinal ulcers in PD patients has led to the hypothesis that Helicobacter pylori, the Gram-negative bacterium responsible for the majority of cases of ulcers, may have a role in PD etiology.⁷⁹

Genetics and Inherited Factors

For many years, epidemiologists focused most of their attention on environmental risk factors. Hereditary influences seemed less likely because twin studies in the past had shown similar concordance rates among monozygotic and dizygotic twins.^55,80,81 More recently, however, there has been a growing interest in genetic factors, largely due to the realization that family history is an important risk factor in the etiology of PD.

Family history

Many epidemiologic studies have investigated the association between the risk of PD and a family history of the disease (Table 8).^{34,35,37,39,45,49,82-85} Most, if not all, studies have consistently reported a significantly elevated OR for a family history. Although it is possible that recall and selection biases may explain some of the observed association, the consistency, strength and universality of the results support a role for early life environmental exposures or some underlying genetic predisposition to the disease. Furthermore, a study by Uitti et al.⁸⁶ identified previously undiagnosed cases of PD among families who had reported no family history of the disease, suggesting that patients' reports of the absence of familial parkinsonism may be inaccurate. The results of this study also indicate that the weighted prevalence rate of familial parkinsonism is more than five times greater than the reported prevalence rates of PD in the general population.

A number of families with multiple cases of PD have been reported in the literature. Some of the most impressive kindreds include a family with 18 affected individuals within six generations.⁸⁷ Not only did autopsy findings include features consistent with PD, but clinical symptoms such as age of onset and responsiveness to levodopa were also in agreement with typical cases. Other families include the Contursi kindred with 60 affected individuals in five generations.⁸⁸ A Greek-American kindred whose 16 affected members in three generations showed asymmetric rigidity, resting tremor, bradykinesia and postural instability were also responsive to levodopa.⁸⁹ The data from all of these families are consistent with an autosomal dominant mode of inheritance with reduced penetrance. In addition, a comparison between familial and sporadic cases of PD revealed that the clinical parameters and the course of disease were similar.⁹⁰

Genetic markers

Many researchers are attributing gene identification in one family as the biggest breakthrough in PD research since the observations of dopamine deficiency⁹¹ and subsequent successful symptom control with levodopa.⁹² An article first reported that genetic markers on chromosome 4q21-q23 were found to be linked to individuals with PD in a large Italian kindred.⁹³ Then, less than one year later, a second article described the exact gene and mutation thought to be responsible for PD in this family and other, Greek families.⁹⁴ A base pair substitution in the a-synuclein gene was found in affected members in these families but not in unaffected individuals or patients with sporadic PD. The function of the protein encoded by this gene is unknown; however, it is hypothesized that its mutated version clumps together in nerve terminals causing cell death. Although this mutation is thought to explain only a small fraction of familial PD cases, it is hoped that the discovery can provide clues in the other cases of PD.

Numerous other genes have been the subject of studies attempting to link inherited factors with PD. The cytochrome P450 family of enzymes is responsible for detoxifying many drugs and environmental agents.⁹⁵ Debrisoquine hydroxylase (CYP 2D6) is polymorphic in nature and results in different levels of metabolism from person to person. It is hypothesized that if exposures to environmental agents play a role in PD, abnormalities in detoxifying these agents may increase the risk of disease. This abnormality would increase the amount of toxin available to act on various points in the oxidative stress model.

Earlier studies assessed subjects' phenotypes by orally administering debrisoquine and measuring the amount of metabolite in urine. Subjects were labelled as extensive metabolizers or poor metabolizers, depending upon the percentage recovery of debrisoquine. Since no studies of white subjects revealed a significant OR^96-102 among poor metabolizers, studies focusing on individuals' genotype were conducted. These latter studies involved direct analysis of the CYP 2D6 gene and the determination of the specific variant associated with the poor metabolizer phenotype. The studies were very inconsistent in both their results and in the number of variants included in the genetic analysis. Although the results concerning the relation between PD risk and the most common variant, CYP 2D6B,^103-112 did not offer any conclusive evidence as to whether the CYP 2D6 gene is associated with PD, it may still play a role in a subset of individuals. Other members of the cytochrome P450 family, such as CYP 1A2 and CYP 3A4, may also be important in PD susceptibility.^113,114

An association has been identified between the slow acetylator genotype for N-acetyltransferase 2 and familial PD.¹¹⁵ This might increase the patient's susceptibility to environmental toxins; however, further study is required.

Mitochondrial gene defects

The activity of complex I, a group of proteins involved in aerobic respiration, has been observed to be deficient not only in the brain tissue of PD patients^116-118 but also in hybrid cells,¹¹⁹ skeletal muscle,^120,121 fibroblasts¹²² and, in some studies, platelets.^123,124 Complex I has also been found to be inhibited by the active metabolite of MPTP.¹²⁵ Since seven of approximately 40 subunits of complex I are encoded by mitochondrial DNA¹²⁶ and since this DNA is more easily damaged than nuclear DNA,¹²⁷ alterations in the mitochondrial genome, whether inherited or acquired through toxic agents, may be central to neurodegeneration in PD.

Studies involving mitochondrial DNA mutation analysis first reported a large deletion of genetic material in PD patients.¹²⁸ Later studies, however, downplayed these results and suggested that this deletion was an age-related observation, independent of PD.^129-131 Although other mitochondrial gene defects have been found in the brains of PD patients,^132-135 many of these study designs have failed to control for age. Since mitochondrial DNA is exclusively maternally derived, maternal inheritance of PD would be expected if mitochondrial DNA were associated with the disease.

Two studies^136,137 that have specifically investigated maternal inheritance are divided as to whether their evidence supports the hypothesis that inheritance of an abnormal gene is responsible for familial PD. The study that did not support the hypothesis¹³⁶ simply compared the number of fathers and mothers of PD patients who also had the disease, whereas the study that supported the hypothesis¹³⁷ included only those families in which both a parent and multiple siblings had PD. The authors of the latter study argue that simple pedigree analysis may not be sensitive enough to detect a preponderance of maternal inheritance.

Genetic anticipation, a phenomenon in which the severity of disease increases in subsequent generations, has been reported for a number of families with a history of PD spanning multiple generations.^89,138,139 This observation is thought to be related to the expansion of trinucleotide repeats, as is the case in diseases such as Huntington's disease and myotonic dystrophy.¹⁴⁰ However, no difference in trinucleotide repeat expansion was detected in PD patients and controls^140,141 or between generations in PD families that displayed anticipation in age at onset.¹⁴⁰ The pedigree analysis of one large kindred suggested that the observation of anticipation may be associated with an age-related ascertainment bias.⁸⁸

Since PD is thought by some researchers to be similar to Alzheimer's disease (AD),^142,143 the apolipoprotein E (ApoE) gene, which is linked to AD susceptibility,^144-147 has been the focus of other genetic epidemiologic studies. With the exception of one study that reported a higher frequency of ApoE (epsilon)4 in PD patients with dementia than in those without dementia,¹⁴⁸ the (epsilon)4 allele has been found to be unrelated to PD.^149-156

Numerous other genetic and molecular endpoints have been recently examined. Negative results have been reported from studies involving superoxide dismutase,¹⁵⁷ dopamine receptors¹⁵⁸ and tyrosine hydroxylase,¹⁵⁹ whereas there have been positive results for lactoferrin receptors,¹⁶⁰ L-cysteine,^161,162 catalase activity,¹⁶³ nitric oxide^163,164 and catechol-O-methyltransferase.¹⁶⁵ One study examined linkage for numerous genes simultaneously in three families with autosomal dominant inherited parkinsonism.¹⁶⁶ Although in one family there were slightly positive results for CYP 2D6, there was evidence against linkage genes for glutathione peroxidase, tyrosine hydroxylase, brain-derived neurotrophic factor, catalase, amyloid precursor factor and copper zinc superoxide dismutase. As with environmental factors, there may be many genes that play a role in PD pathogenesis. Genetic susceptibility may limit the patient's ability to detoxify otherwise innocuous environmental factors and thereby lead to the degradation of dopamine-containing neurons in the nigrostriatal system.¹⁶⁷

Monoamine oxidases

Monoamine oxidases (MAOs) are degradative enzymes involved in the metabolism of toxins (A and B types)^32,168-170 and in the production of free radicals and hydrogen peroxide through the breakdown of dopamine (B type).^171-173 As with the genotypic CYP 2D6 studies, studies focusing on MAOs are very inconsistent. Although some show a relation between PD and a polymorphism of the gene encoding MAO type A and not B, and others show a relation between the disease and an MAO type B and not A polymorphism (Table 9),^174-179 the evidence seems to suggest that MAO enzyme variability may influence PD pathogenesis and progression.

One of the first gene-environment interaction studies in PD research involved an MAO-B polymorphism and smoking.¹⁸⁰ The study found an overall protective effect for smoking in PD similar to the results discussed previously. However, it further discovered that the inverse association was only present in individuals with a certain MAO-B variant. This breakthrough not only adds a genetic hypothesis to the list of ideas as to how and why smoking is protective, but it also emphasizes the importance of both genetic and environmental factors in PD etiology.

Diagnosis

A PD diagnosis is not necessarily clear cut, since there is no single diagnostic test.^3,181 In order for the condition to be diagnosed, physical examination should reveal two of either tremor, rigidity or bradykinesia. All other causes and types of parkinsonism must be excluded. The criteria for a diagnosis of PD also include a positive response to dopaminergic drugs such as levodopa. PD may also be described in terms of its severity. Hoehn and Yahr stages express the extent of an individual's disability on an arbitrary scale with five levels. Stage I consists of unilateral involvement only, usually with minimal or no functional impairment; Stage V consists of confinement to bed or wheelchair unless aided.¹⁸²

As well, it has been reported that more than one quarter of PD patients exhibit dementia and that some patients with AD show signs of parkinsonism.¹⁸³ According to the Merck Manual of Geriatrics, a "clinical diagnosis is usually based on whether the motor signs were present before or after the cognitive decline".¹⁸³

PD can only be diagnosed in an individual once symptoms have developed; approximately 70% of neurons in the substantia nigra have been lost when symptoms first occur.⁶ This suggests an asymptomatic period in which the disease is progressing but the individual does not show any clinical signs. It would be advantageous, therefore, to develop a method of screening that would identify individuals at the earliest stage of neurodegeneration. Intervention would then focus on arresting the disease process rather than the current situation of primarily treating the symptoms. Although it is not known whether PD can be detected before symptoms are present, numerous strategies have been proposed.¹⁸⁴ Studies involving positron emission tomography (PET), movement time and the electrophysiological characteristics of tremor show that these methods may be useful in measuring preclinical dysfunction.

Treatment

Although there is no cure for PD, both pharmacological and surgical treatments are available.

The main treatment for PD is pharmacological and includes different drugs designed to either increase the amount of dopamine in the brain or suppress the overactive cholinergic system (anticholinergics).^185-188 As dopamine cannot cross the bloodSbrain barrier, an alternative to administering this neurotransmitter was first introduced in the 1960s with levodopa.

Levodopa, a precursor to dopamine, has long been the standard treatment of PD; however, it causes adverse effects such as nausea, vomiting and orthostatic hypotension. Although there seems to be wide agreement that levodopa increases survival rates, there is some debate as to when this therapy should be started.¹⁸⁹ Levodopa therapy initially works well, but after several years the majority of patients have either developed response fluctuations (wearing off and on-off phenomena) or dyskinesias (abnormal involuntary movements).¹⁸⁹ Those who assert that levodopa therapy should be started during the early course of the disease maintain that these motor complications reflect the progression of the disease, whereas those who argue in favour of delaying the drug believe that levodopa may cause toxic effects.

Other drugs, such as dopamine agonists, anticholinergic agents and amantadine, have been introduced as adjuncts to levodopa, their main function being to minimize its adverse side effects. Other negative effects, however, have emerged. For at least the past decade, selegiline, a selective inhibitor of MAO-B, has been the subject of controversy in PD treatment.^190-192 There is the question as to whether this drug has a neuroprotective effect on PD or simply a symptomatic effect.

An extensive review of pharmacological treatment approaches is beyond the scope of this Monograph Series; thus, the reader is referred to existing in-depth reviews.^193,194

In addition to drug therapy, there are three surgical procedures used for the treatment of PD.^195,196 These are ablative surgery, deep brain stimulation and fetal tissue transplantation.

Ablative surgical procedures involve placing a lesion in a circuit of either the globus pallidus (pallidotomy) or the thalamus (thalamotomy). Since dopamine normally modulates an inhibitory influence of the basal ganglia to the thalamus, a dopamine deficiency would result in less inhibition. A lesion would correct this situation in that it would mimic dopamine in terminating nerve signals from the globus pallidus to the thalamus. Thalamotomies have been found to be successful for individuals with severe tremor. Although pallidotomy is effective in relieving bradykinesia and severe "off" motor disability, further study is required to assess the adverse effects of the surgery.¹⁹⁷

Deep brain stimulation (DBS) is similar to ablative surgery but, rather than a lesion being created, a stimulating electrode is placed in the target. A recent study indicates that DBS and thalamotomy are equally successful in relieving tremor but suggests that DBS is preferable because of the ability to alleviate side effects and control tremor recurrence without further surgery.¹⁹⁸

Fetal tissue transplantation has also been performed in some PD patients. This procedure involves implanting fetal dopamine-producing tissue into the basal ganglia in the hope that this tissue will develop and continually produce dopamine in the patient. Despite progress, these procedures are still very experimental and have only been performed in a limited number of individuals with a small amount of time devoted to follow-up.

Research, development and trials for more effective drugs with fewer side effects are ongoing. Parkinsonian symptoms can also be managed to a limited extent through dietary modification¹⁹⁹ and specific exercises.²⁰⁰ Since PD patients vary with respect to their symptoms and disease severity, individuals will respond differently to the same treatment. Health care professionals must thus work alongside their patients to devise the best possible care.

Prognosis and Co-morbidity

The introduction of levodopa has increased survival rates in PD patients. A recent study²⁰¹ showed that survival was markedly improved with its use. The benefits were only seen, however, if levodopa therapy was initiated in the earlier stages of disease. Although survival rates have increased with levodopa and other therapies, PD patients are still at increased risk of dying as compared with individuals of similar age. A cohort study of parkinsonian patients in England and Wales revealed that these patients had more than a twofold risk of dying compared with general population controls after 20 years of follow-up,²⁰² with very little difference between males and females. A similar study conducted in Scotland found a similar relative risk of 2.5, but this was only for 3.5 years of follow-up.²⁰³ Two US studies calculated relative risks of 2.7 over a mean follow-up of 2.5 years²⁰⁴ and 2.0 over a mean follow-up of 9.2 years.²⁰⁵ A higher mortality rate was recorded for institutionalized individuals with PD than for those without it in one study,²⁰⁶ but not in another one.²⁶

In one of the studies mentioned, the risk of death increased with increasing number of parkinsonian signs present.²⁰⁵ The presence of gait disturbance specifically was found to be associated with increased mortality risk. These observations must be interpreted with caution, since some of the studies included subjects with all forms of parkinsonism. In a study involving only subjects with PD, the duration from disease onset to Hoehn and Yahr stages I, II, III, IV and V were 4.0, 6.5, 7.9, 9.8 and 11.8 years, respectively.²⁰⁷ Patients who noticed unilateral symptoms initially had a better prognosis than those who first noticed bilateral symptoms. Seventy percent of all patients noticed unilateral symptoms initially, of which 91% spread to the other side. Louis et al. found that the severity of extrapyramidal signs was the single most important indicator of increased mortality in PD patients.²⁰⁴

PD patients also differ from the general population in terms of their specific cause of death. Some studies have found that individuals with PD are more likely to die of ischemic heart disease,^202,207 cerebrovascular disease,^202,204,208 pneumonia^204,208,209 and other respiratory diseases.²⁰² The reasons for these differences are not known but may involve competing causes of death, a secondary effect of treatment or common etiology.²⁰² Cancer mortality has been found by some to be significantly lower in PD patients than in an age- and sex-matched population.^204,208 However, this is only true for cancers that are thought to be related to smoking and is explained by the fact that PD patients are less likely to smoke.²¹⁰

Depression

Depression has been found to be more prevalent in individuals suffering from physical illnesses such as stroke, cancer and endocrine and metabolic disorders.²¹¹ The few recent studies that have examined the relation between depression and PD have been very inconsistent. This variability is largely due to the different criteria used to measure depression. Recent studies, however, have agreed that depression is more common in PD patients with dementia than patients without dementia.^212-215 Depression in PD patients was also found to be related to thought disorders²¹⁵ and autonomic failure.²¹⁶ Inconsistencies have  been noted for the relation between depression and age, disease course and impairment in the activities of daily living.^{214,215,217,218}

Conclusions

Implications for an Aging Population

Since the proportion of both Canada's and the world's population that is over 65 years of age will increase dramatically over the next three decades, the number of individuals with PD is expected to increase correspondingly. In fact, the percentage of Canada's population over the age of 65 is expected to increase from 11.6% in 1991 to 23.6% by the year 2016.²¹⁹ This translates into an 87% increase in the number of individuals requiring medical care on an in-patient basis and a 92% increase in the number of individuals dying from PD. The change will be greatest in the oldest age groups, in which the number of individuals affected with PD is expected to more than double.

Future Research

Although the past few years of PD research have been very productive, many questions remain.²²⁰ The identification of biological markers for PD will play an integral part in future research. This will enable researchers and physicians to diagnose the disease more accurately, develop treatments that slow or arrest disease progression once it has started and initiate steps towards preventing the disease. It would also allow individuals known to be at higher risk to be monitored before symptoms appear. Genetic research may lead to the identification of other genes that predispose individuals to PD, and further investigation of the role of environmental risk factors could supply important information for the development of prevention strategies. An understanding of the interplay between environmental and genetic factors could provide the key to future advances in PD research.

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Natalie Kontakos and Julie Stokes, Aging-related Diseases Division, Bureau of Cardio-Respiratory Diseases and Diabetes, Laboratory Centre for Disease Control, Health Protection Branch, Health Canada (funding provided by Division of Aging and Seniors, Population Health Directorate, Health Promotion and Programs Branch, Health Canada)

Correspondence: Julie Stokes, LCDC Building, Health Canada, Tunney's Pasture, Address Locator: 0602E2, Ottawa, Ontario  K1A 0L2

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