Parkinson syndrome (PS) is a common disorder in the North American population. The annual incidence rate is 20.5/100,000 population and the mean survival after onset is approximately 12.3 years. The estimated prevalence rate is about 300/100,000 population. The incidence and prevalence rates rise with advancing age. Both the widespread use of levodopa and the improved health care in general have increased the longevity in PS. The survival in PS from the time of the first clinic visit is still significantly shorter when compared with the regional age and sex matched population. The cause of IPD may be related to some environmental factor(s) – most likely a toxin. Genetic factors are not the cause but in some families, may predispose to IPD.

Levodopa is the most potent symptomatic treatment for Parkinson’s disease but adverse reactions are common and the initial response is not maintained. Further there is recent evidence that suggests that free radicals generated from the oxidative metabolism of dopamine may contribute to the pathogenesis of Parkinson’s disease. This raises the possibility that levodopa therapy by way of its conversion to dopamine may promote free radical formation and accelerate the rate of neuronal damage. Levodopa sparing strategies designed to minimize the cumulative levodopa dosage employed over the course of the disease seem a rational way to treat Parkinson patients in face of current information. Such a strategy would include the use of dopamine agonists as primary symptomatic therapy, the introduction of levodopa as an adjunct when dopamine agonists can no longer sufficiently provide satisfactory clinical control and the use of the lowest dose of levodopa that will provide satisfactory clinical control. In this way symptomatic control is not compromised on theoretical grounds, but the cumulative levodopa dose is minimized in an effort to reduce the likelihood of free radical formation with their potential adverse consequences on disease progression.

The major complications of therapy in PD are motor, autonomic and psychiatric. Motor complications may be associated with altered striatal bioavailability of levodopa, and may in part respond to changes in timing of drug administration, redistribution of dietary protein and the use of controlled-release preparations. Since long-term complications seem to be associated with higher cumulative doses of levodopa, the early use of adjunctive agents such as deprenyl and/or dopamine agonists is encouraged. Autonomic effects include impaired bladder and bowel function, impotence and postural hypotension. If conservative measures are ineffective, pharmacotherapy with domperidone, fludrocortisone, indomethacin or adrenergic agents may be required. Depression in PD is associated with decreased levels of noradrenaline and 5-HT and responds to tricyclic antidepressants. Drug-induced psychosis reflects stimulation of mesolimbic-cortical dopamine receptors. Alternatives include reduction of medication, the use of atypical neuroleptics (which may act at novel subtypes of the dopamine receptor) and electroconvulsive therapy.

Features common to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.

Abiotrophy is hypothesized to explain the onset and time course of deficits in Parkinson’s disease (PD) Abiotrophy includes: 1) exposure to agent(s) causing the death of dopaminergic nigrostriatal neurons (DNSns), 2) gradual death of DNSns with age, 3) summation of 1) and 2) until DNSn numbers fall below a threshold for detectable neurological deficits. Murine DNSn death following methyl-phenyl-tetrahydropyridine (MPTP) exposure occurs according to an exponential relationship while age-related death of DNSns occurs according to a second exponential relationship. Summing the two exponential losses overestimates experimental DNSn death showing a simple abiotrophic model is not sufficient. Aged murine DNSns greatly increase their dopamine synthesis and the density of their striatal axon terminals which may explain the above threshold. Murine DNSns die gradually after MPTP exposure and L-deprenyl treatment rescues MPTP-damaged DNSns by a previously undiscovered action, altering the abiotrophic interactions and possibly explaining the slowed progression of PD found with deprenyl treatment.

Levodopa-induced dyskinesia, one of the most frequent long-term side effects of antiparkinsonian therapy, is often attributed to denervation supersensitivity of dopamine receptors and perhaps more specifically the D-1 receptor. The available evidence based not only on clinico-pathological studies in patients but also on results of experiments performed on methyl-phenyl-tetrahydropyridine (MPTP)-treated monkeys suggests that the mechanisms may be more complex than heretofore believed. Thus it appears that no single receptor is the sole culprit, that some form of denervation supersensitivity is probably involved but not in the form of increased density of dopamine receptors. Moreover, other neurotransmitter systems must be considered such as GABA, excitatory aminoacids and peptides. The MPTP monkey model remains very useful for predicting the potential of new drugs for inducing dyskinesia. Such trials however must be performed in drug-naive animals.

Positron emission tomography (PET) allows the study of physiological and neurochemical processes which would otherwise be inaccessible, using radioactive labels on biological compounds to follow their fate in the body. By analysing changes of concentration with time we can measure blood flow, neuronal metabolism and receptor ligand interactions. In Parkinson’s disease (PD), PET has been used to examine the dopaminergic deficit and its relationship to motor performance. It has also been shown to detect asymptomatic dopaminergic lesions that have implications for the etiology of PD. In untreated PD there is increased density of D2 binding sites, while in chronically treated PD with motor fluctuations, D2 receptor density is reduced. [18F]-fluorodeoxyglucose studies of demented PD patients show a pattern of cortical metabolism similar to Alzheimer’s disease. Activation studies, which measure changes in blood flow during the performance of motor tasks, show reduced activation of medial frontal areas in PD.

Deprenyl is a synthetic, selective inhibitor of the monoamine oxidase-B enzyme system. The mechanism of its beneficial effect in early and advanced Parkinson’s disease is not settled. Increased striatal dopamine accumulation, sensitization of surviving dopamine neurons with increased dopamine production and reduced nigro-striatal toxicity may all contribute. The standard daily dose of deprenyl is 10 mg. Selectivity may be lost at higher doses. Deprenyl is especially indicated in untreated patients, improving up to 50 percent of patients with mild motor fluctuations. Major symptomatic benefit also occurs in occasional levodopa treated patients. Adverse effects are common, however. Increase dyskinesias, confusion and hallucinations, nausea and postural hypotension may necessitate drug withdrawal or the use of low dose regimens. Caution should be exercised with older patients, those with ulcer disease, which may be worsened by deprenyl, and individuals with active ischemic heart disease where the safety of this drug is not yet clear.

The addition of a D2 agonist such as bromocriptine to L-Dopa therapy can often improve the response of patients with Parkinson’s disease dramatically. Simultaneous activation of D1 and D2 dopamine receptors can produce a synergistic effect on locomotion in rats and primates. However, despite the importance of this addition of a D2 agonist to the D1/D2 agonist L-Dopa, little is known of the sites of action of these agents. Recent work suggests that, in addition to D1 and D2 dopamine receptor sites in the striatum (caudate-putamen), L-Dopa and D1 agonists have important effects at D1 dopamine receptors in the substantia nigra. Animal experiments suggest that D1 and D2 dopamine receptor agonists probably also affect different outflow pathways from the striatum. An understanding of these pathways and how dopamine agonists affect them gives insight into some of the clinical problems experienced in treating Parkinson’s disease (the “on-off phenomenon, for example). D1/D2 dopamine receptors also differentially affect gene expression and regulation in the striatum. An understanding of the anatomical and biochemical location of the actions of dopamine receptor agonists will be important in maximizing the beneficial effects and minimizing the side-effects of both presently-used drugs and new treatments.

The rationale for sustained release oral levodopa preparations is to deliver levodopa in the areas of maximal intestinal absorption in a slow and predictable way, leading to stable plasma levodopa levels and brain dopamine levels, therefore resulting in a lengthened duration of action. Sinemet CR is the prototype of such preparations, with demonstrated efficacy in decreasing periods of akinesia in parkinsonian patients with mild to moderate motor fluctuations. Total doses of levodopa are raised 10 to 30% because of the lowered bioavailability; diphasic dyskinesias may increase at the end of the day. Tolerance is good in de novo patients and studies are in progress to establish if early treatment with Sinemet CR delays the onset or attenuates the severity of motor fluctuations as compared to standard Sinemet.

The use of the dopamine receptor agonists in Parkinson’s disease has a compelling logic. These agents are supposed to act independently of the dying cells of the substantia nigra directly on the cells of the striatum. Early clinical trials in advanced disease were only mildly impressive. Later they were found to be beneficial in early disease but their effectiveness waned. Their ultimate failure may reflect the fact that the majority of current agents do not stimulate D1 and D2 receptors in a physiologic ratio. The drugs may act presynaptically and with the eventual loss of the anatomic relationships between nigra and striatum the drugs fail. There is, however, a rationale to their current use. When used along with L-Dopa in early disease the development of late-stage fluctuations are reduced with the same anti-parkinsonian benefits. Merging this concept with the demonstrated effect of selegiline in slowing the course of the disease, the current practice of triple therapy with selegiline, L-Dopa and a dopamine receptor agonist emerges.

New methods of drug delivery and slowing down the progression of Parkinson’s disease (PD) are the major goals of research. More steady drug levels in the blood are possible by means of controlled-release preparations of levodopa and long-acting dopamine agonists, as well as transcutaneous duodenal tubes and pumps for controlled subcutaneous infusion. Patches containing dopamine agonists absorbed through the skin may be developed. The role of D1 agonists as compared with D2 agonists remains to be elucidated. Agonists on autoreceptors of dopaminergic neurons may potentially reduce excessive stimulation of the intact neurons and this may slow down the rate of neuronal death in PD. Monoamine oxidase-B inhibitors may have a potentially protective action on neurons. Investigations are being carried out to evaluate this claim. Catechol-o-methyl-transferase inhibitors may be helpful in theory. There is also recent interest in inhibitors of excitatory amino acids, which may contribute to neuronal loss in PD.