Parkinson’s disease: A syndrome not a disease
ABSTRACT: Current thinking concerning the etiology of Parkinson’s disease recognizes two broad groups: genetic and environmental, which are not mutually exclusive. The occurrence of disease may depend on the "dose" of genetic predisposition combined with the "dose" of environmental exposure. What seems certain is that Parkinson’s disease is not really one disease, but is rather a syndrome for which there are many distinct etiologies. We are beginning to identify some of the genes responsible, and new ideas are emerging concerning environmental risk factors. In particular, the traditional and conventional notion of a long pathological process deriving from protracted environmental exposure has been questioned, and a new model is available for testing, one that involves a transient environmental event killing some nigral dopaminergic cells, and damaging others so that their life expectation is reduced.
Accumulating evidence indicates that what we call Parkinson’s disease is not a disease for which we can expect to find a specific cause.
As we learn more about Parkinson’s disease and the other two common neurodegenerative disorders, Alzheimer’s disease and amyotrophic lateral sclerosis, the same pattern of information emerges. It seems that these are not three distinct diseases, but rather they are three syndromes. By syndrome we may infer a collection of symptoms and signs that "run together," for which there may be many different causes. Thus the entities Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis are comparable to such terms as meningitis, stroke, and peripheral neuropathy.
As we uncover specific etiologies, we begin to catch a glimpse of variation in the clinical picture that tends to be associated with a particular etiology, and also a particular pathology. For example, patients with a family history of Parkinson’s disease tend to develop symptoms at a younger age than those who do not have a family history. The many discoveries generated through the techniques of molecular biology have identified several genes that can lead to Parkinson’s disease, so, in a sense, we already know that there are multiple etiologies.
Thirty years ago, medical students were taught that the Lewy body was the pathological hallmark of Parkinson’s disease. Now we know that Lewy bodies are quite nonspecific findings. They also occur in such disorders as Hallervorden-Spatz disease, dementia with Lewy bodies, and subacute sclerosing panencephalitis. We also know that some patients who fulfill all the diagnostic criteria for "clinically definite idiopathic parkinsonism" have loss of dopaminergic nigrostriatal neurons without any Lewy bodies. Thus we can no longer expect that postmortem examination will confirm or refute the diagnosis of Parkinson’s disease.
Indeed, we are being forced to conclude that the concept of Parkinson’s disease is as misleading as the concepts of meningitis, stroke, and peripheral neuropathy. Even the most modern methods of characterizing patients with Parkinson’s disease fail to discriminate, for example, between those with sporadic idiopathic parkinsonism and genetic idiopathic parkinsonism.
Another illustration of the problem of definition comes from consideration of the natural history. The progression of idiopathic parkinsonism tends to be slow in younger patients, and it also tends to be slower in patients who present with a clinical picture dominated by tremor. The differences are sufficiently striking for observers to have coined the terms benign Parkinson’s disease and malignant Parkinson’s disease to describe the two ends of the spectrum of slowly versus rapidly progressive parkinsonism.
With this background, it is perhaps better to employ the term idiopathic parkinsonism rather than Parkinson’s disease, since present evidence points so firmly to the existence of multiple etiologies for what we have, in the past, implied to be the single entity Parkinson’s disease.
Familial idiopathic parkinsonism
For many years it has been recognized that there exists a group of patients with idiopathic parkinsonism who have a family history of the disorder. Of course, the mere presence of a family history does not prove a genetic etiology. For example, for many years tuberculosis was thought to be genetic because it tended to cluster within families. Because families share the same environment, there is an increased likelihood for an environmental risk factor to strike more than one family member.
However, modern genetic studies have shown, beyond doubt, that there is a group of some 15% to 20% of parkinsonian patients in whom genetic factors contribute an important etiological role. In one autosomal dominant form of idiopathic parkinsonism, the α-synuclein gene has been identified on chromosome 4q. The gene product, α-synuclein, is concentrated in Lewy bodies, but it also appears in other structures. An autosomal recessive form of parkinsonism, often presenting at a young age, has been shown to be caused by the parkin gene, on chromosome 6q.
Parkin is a protein that seems to have enzymic properties, and it seems to be concerned with the ubiquitination of proteins within nerve cells (ubiquitin is a protein that plays a role in targeting other proteins for breakdown). The locus for another gene has been identified on chromosome 2p. While the expansion of our knowledge of genetic parkinsonism is impressive, there are many more genes to find, for if we take the α-synuclein gene, the parkin gene, and the locus on chromosome 2p, these collectively occur in only a minority of those patients who have family histories that suggest genetic etiologies. In all probability, we will know of many more genes and many more gene products associated with idiopathic parkinsonism by the end of the next decade.
Sporadic idiopathic parkinsonism
Important studies by Lee and colleagues and Schulzer and colleagues have shown that in sporadic idiopathic parkinsonism, the rate of loss of nigral dopaminergic cells is more rapid in the early stages of the illness and then tends to approach the normal age-related rate of loss. A mathematical analysis of the curve describing the rate of death of nerve cells can be interpreted, most simply, in terms of a transient event causing the illness.
The formulation of an event hypothesis contrasts with the traditional and conventional model of etiopathogenesis, which envisioned a continual process engaging all susceptible cells of the substantial nigra. The event hypothesis can be likened to a battlefield in which over a brief period of time some soldiers are killed outright, and others are wounded in such a way that their life expectancy is reduced. This concept has recently been reaffirmed.[16,17]
The sublethal damage would lead to the premature death of nigral dopaminergic cells at variable periods of time after the event has occurred. The notion of a latent period between the etiological event and the death of a cell is not unique in medicine. There are many examples of carcinogenesis that exemplify a latent period between an environmental risk factor and cell death. In sporadic idiopathic parkinsonism, progression of the illness would derive from the death of nerve cells after a variable latency and also from the normal age-related linear decline of aging nigral dopaminergic neurons.
We have several models that illustrate how a transient environmental factor can lead to progressive parkinsonism:
• Von Economo’s encephalitis often led to the appearance of parkinsonism several years after the infection, and in late life this condition progressed long after all evidence of active infection in the brain was over.
• Selective nigral damage from the toxin MPTP has also been shown to lead to the immediate death of nigral dopaminergic neurons and then, many years later, progression of active cell destruction.[19,20] MPTP is an organic molecule that could not be stored in the body, so here again we have a transient environmental factor leading to progressive illness.
• There are several case reports of head trauma leading to parkinsonism, and this condition, sometimes termed pugilists’ encephalopathy, or the punch drunk syndrome, has been shown to progress after cessation of traumatic events.[21,22]
How might an event damage nerve cells so that their life expectation is reduced? It is quite possible that some transient damage could leave a nerve cell alive, with increased vulnerability to some potentially noxious element in the neuron’s environment, such as excessive excitation or a concentration of free radicals that could normally be detoxified, posing a more serious challenge to the impaired defences of a "sick" nerve cell. Another model is suggested by the work of McGeer and colleagues.
Here, one can envision damage to a nerve cell leading to an atypical inflammatory reaction that culminates in the cell’s death. Finally, we must acknowledge that the mechanism underlying the progressiveness of nigral dopaminergic neurons in idiopathic parkinsonism may be something as yet unsuspected. It is intriguing to note that the gene products that play a role in progressive genetic parkinsonism (so far discovered) are both concerned with protein aggregation in the nerve cell. It could well be that the pathogenesis of idiopathic parkinsonism, genetic and sporadic, may involve a disruption in the biology of protein metabolism in nigral neurons. This is one of the most exciting areas of current exploration.
Finally, the event hypothesis has implications for epidemiological studies. If the etiology of sporadic idiopathic parkinsonism is transient, there is little wonder that epidemiologists have had so much difficulty in trying to find an environmental exposure that might have an etiological contribution. In this context, it is of considerable interest that a recent study has led to an intriguing clustering of occupations with an increased or a decreased risk of sporadic idiopathic parkinsonism.
At increased risk were loggers, miners, oil rig workers, teachers, and medical workers. In contrast, there was a decreased risk among individuals who spend most of their time at home. One possible interpretation of these findings is that the high risk group carries a greater risk of respiratory infections such as influenza.
This is self-evident for teachers and medical workers; the loggers, miners, and oil rig workers are at risk because they sleep in cramped quarters, similar to those of a military barracks—an environment well known to predispose to infective illness. In contrast, individuals at home are obviously exposed to fewer infective agents.
This new information allows the resurrection of the old hypothesis that sporadic idiopathic parkinsonism may, at least in some cases, be caused by viral infection. In keeping with this, recent Japanese studies on rodents have shown that a virulent form of influenza A is selectively trophic to the substantia nigra.
The term idiopathic parkinsonism is more appropriate, for Parkinson’s disease is really a syndrome that can result from several causes. Environmental factors are likely a major part in causation, and it may prove that these factors are one or more brief events rather than a long-term process.
Donald B. Calne, OC, DM. Parkinson’s disease: A syndrome not a disease. BCMJ, Vol. 43, No. 3, April, 2001, Page(s) 129-132 - Clinical Articles.
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