The literature is reviewed on the afferents and efferents of the caudate/putamen, globus pallidus and substantia nigra, and on the neurotransmitters occurring in the various tracts. Emphasis is placed upon the diverse roles played by GABA and glutamate as transmitters in motor pathways and upon the probability that the substantia nigra pars reticulata plays a pivotal role in the output of the basal ganglia. Excessive stimulation of the projection from the pedunculopontine tegmental area to the substantia nigra is shown to cause destruction of dopaminergic neurons in the latter nucleus, suggesting another possible mechanism for cell death in Parkinson’s disease.

Most disorders of motor activity including disturbances of muscle tone and of locomotor activity observed in patients with neurological disorders have been reproduced experimentally in animals. Most motor disorders of the extrapyramidal type including those associated with Parkinson’s disease and choreiform and athetoid involuntary movements, have been reproduced exclusively in primates. This is most likely related to the highly complex organization of the extrapyramidal and related nervous mechanisms subserving the corresponding peculiar type of motor control in the primate brain. Other types of motor disturbances including cervical and trunkal dystonias, ataxia, hypotonicity, spasticity and intention tremor, however, have been successfully induced in various mammalian species. The latter types of motor disorders are related to disturbances of central nervous mechanisms which show similar patterns in the brains of different animal species. Histopathological and neurochemical changes associated with extrapyramidal disorders have been discovered and more precisely determined as a consequence of the development of new technical approaches. Therefore numerous morphological, physiological and neurochemical data concerning the extrapyramidal system are now available but a better knowledge of their precise and subtle interrelationship is greatly needed in order to develop more efficient therapeutic procedures.

Evidence from a variety of sources indicates that the mesolimbic-mesocortical dopamine projections may play an important role in some types of reward or reinforcement processes in animals. There is circumstantial evidence that this is also true in humans. Since a reduced ability to experience pleasure or reward (i.e. anhedonia) is a cardinal feature of clinical depression, and since the mesolimbic and mesocortical dopamine projections have been shown to degenerate in Parkinson’s disease, it is suggested that damage to these reward-related systems may contribute directly to the high incidence of depression that has been reported in this disease.

The neuroleptic/dopamine receptor, with its picomolar affinity for potent neuroleptics, is the functional dopamine receptor of the brain. This receptor has been termed the D2 dopamine receptor, and it inhibits or interferes with dopamine-stimulated adenylate cyclase. This D2 receptor has two states, each having different affinity for dopamine. The high-affinity state, termed D2high, has a 10 nM affinity for dopamine and is the functional correlate for dopamine autoreceptors and for the dopamine receptor in the pituitary gland. The low-affinity state, termed D2low, has a 2000 nM affinity for dopamine, and may possibly represent the desensitized state of the dopamine receptor or the functional post-synaptic receptor.

Evidence supporting the validity of the ‘two dopamine receptor’ hypothesis is presented. The availability of the ‘first generation’ of selective agonists and antagonists of the D-1 and the D-2 dopamine receptors provides pharmacological support for the hypothesis. The demonstration that stimulation of the D-2 receptor either inhibits or has no effect upon adenylate cyclase activity while stimulation of the D-1 receptor enhances cAMP formation provides biochemical support for the hypothesis. Finally, binding assays demonstrating two affinity states for the D-1 and the D-2 receptors are briefly discussed.

The recognition of the dopaminergic properties of some ergot derivatives has initiated new therapeutical approaches in endocrinology as well as in neurology. The pharmacological characterization of the different ergot derivatives during the last decade has largely improved our understanding of central dopaminergic systems. Their development has yielded valuable information on the pharmacology of dopamine receptors involved in the regulatory mechanisms of prolactin secretion and in striatal functions.

The clinical application of such new neurobiological concepts has underlined the therapeutical interest of such compounds either in the control of prolactin-dependent endocrine disorders or in the treatment of parkinsonism. Owing to their pharmacological profiles, dopaminergic agonists represent a valuable clinical option especially in the management of Parkinson’s disease in view of the problems arising from chronic L-Dopa treatment.

The major anatomical connections of the basal ganglia are reviewed, emphasizing the inputs to the striatum and efferent projections from the major output nuclei, the internal segment of globus pallidus and the pars reticulata of substantia nigra. The results from lesioning experiments, electrical stimulation, and chronic recording of single neuron activity have provided a wealth of data concerning the physiology of the basal ganglia. Although the deficits resulting from disease of the basal ganglia are well recognized, the specific role which these structures play in the control of normal movements remains speculative.

Early Parkinson’s disease is taken to be the best human model of disordered basal ganglia function. An experimental study in Parkinsonians with swings in motor response to drug treatment suggests that general cognition is not controlled by dopamine mediated striatal activity. The variety of motor disorders in Parkinson’s disease cannot be explained by simple concepts. Although Parkinsonians cannot execute fast ballistic movements, an experimental study shows that they can adopt a predictive motor control strategy. It is argued that simple motor programs are not grossly disturbed in Parkinson’s disease. It is concluded that Parkinsonians cannot automatically execute learned motor plans.

From a review of the anatomical relationships and single unit activity in the components of the basal ganglia related to limb movement, it is concluded that the major outflow from basal ganglia circuits is via the motor cortex (area 4). Recent results of recording from area 4 neurons revealed that they preferentially “encode” the higher derivatives of movement, i.e. acceleration and jerk. In the parkinsonian (PK) patient and in the monkeys treated with l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), EMG responses to imposed loads show a markedly increased gain of the “M2” component which depends upon the integrity of area 4 and which correlates with the severity of PK rigidity.

The above observations are considered, along with those of others (demonstrating prolonged movement times, a decreased “repertoire” of voluntary movements fractionation of voluntary movements’, inability in tracking movements without visual input, and failure to improve performance in PK’s) in relation to a model of the interactions between sensory input and motor programs. Using this model, it is hypothesized that the above PK movement deficits, as well as rigidity, can be accounted for by abnormal processing of the mechanoreceptor sensory input utilized in the generation and execution of movements. The MPTP treated monkey is suggested as a model in which to directly test the hypothesis.

In the present paper we explore in some detail the hypothesis that the presence of familial aggregations in 10–15% of Parkinson’s disease cases is due in great part to the existence of well-defined familial subsets, rather than to chance occurrences. We describe the clinical and genetic characteristics of the two main subsets: “Essential tremor-related Parkinsonism” and the “Familial akineto-rigid Syndrome” previously identified.

The former type of Parkinsonism is associated at random, but with increased frequency, to an autosomal dominant disorder, usually essential tremor but occasionally OPCA. Two possible susceptibility factors were uncovered in this entity: an increased incidence of familial hyperthyroidism (augmentor factor) and a decreased incidence of the generally frequent HLA Haplotypes A1B8 or A2B5 (Protective factors).

The other presentation, the “familial akineto-rigid syndrome”, appears to be a definite disease entity with an autosomal recessive mode of inheritance (normal parents, increased incidence of identical parkinsonism in sibs, increased consanguinity rate in parents). This newly defined disorder deserves much further genetic and biochemical analysis.

A considerable proportion of patients with Parkinson’s disease report having affected relatives. However, anamnestic data obtained from probands on the occurrence of secondary cases among their relatives are of limited value. In considering the possible role of heredity in Parkinson’s disease it is necessary to carefully distinguish between the disease and other disorders such as essential tremor and olivopontocerebellar atrophy which may manifest parkinsonian features. Controlled family studies have shown only a very slight excess of secondary cases among index siblings as compared to spouse siblings. The concordance rate for Parkinson’s disease among identical twins is extraordinarily low and does not significantly exceed that among fraternal twins or that expected from the prevalence rate among siblings found in the controlled family studies. The available evidence indicates that heredity plays no significant role in the etiology of Parkinson’s disease. Consequently the disease must be considered to be acquired.

Epidemiology of parkinsonism for 13 years (1967 to 1979) in Rochester, Minnesota is evaluated. For each patient, two age- and sex-matched controls with comparable medical follow-up (mean 40 years before diagnosis) were selected from the same community. Smoking habits, dementia, acute and chronic illnesses and mortality patterns in the two groups are compared. The annual incidence rate was 20.5/100,000, which is virtually unchanged from previous reports on Rochester population. Cigarette smoking habits of cases and the controls before the index date were not significantly different. Prior to diagnosis of Parkinson’s disease, dementia was diagnosed significantly more frequently among the patients than the controls (P = 0.048). After diagnosis of parkinsonism dementia emerged nearly three times more frequently in patients than among the controls. Mortality rate in the entire parkinsonian population was similar to that reported from the same community between 1935 and 1966. Only 50% of the patients were treated with levodopa. Among those treated with levodopa the mortality rate was comparable to their controls. Because there were no definite criteria for administering levodopa therapy, higher frequency of dementia and prolonged survival in those treated with this drug could be attributed to the bias of case selection for treatment.

Our experience in treating 7 patients with moderate to severe parkinsonism induced by l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is reviewed. Virtually all of the problems typically encountered with dopamine precursor and agonist therapy in treating Parkinson’s disease have been observed during a one and one half year follow-up period, including “end-of-dose” deterioration (or “wearing off’), “peak-dose” dyskinesias, “on-off” phenomena, and psychiatric complications. These have occurred much earlier than is typically seen when treating the idiopathic disease. This rapid evolution of therapeutic side-effects favors the view that at least some of the complications of dopamine precursor therapy may be related to severity of disease rather than the length of levodopa therapy. Finally, we suggest that the occurrence of this full array of therapeutic complications in patients with MPTP-induced parkinsonism furthers the analogy between this syndrome and Parkinson’s disease.

l-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in the pars compacta of the substantia nigra (A8 and A9 cells). MPTP or its metabolite enters nerve cells at the level of their terminals in the caudate nucleus and putamen leading to a disturbance in axoplasmic flow and retrograde degeneration. The species-dependent neurotoxicity of MPTP (primate vs. rodent) suggests that a biochemical property of the cell related to neuromelanin may be important in the mechanism of cell injury.

Local cerebral glucose utilization was measured in patients with predominantly unilateral Parkinson’s disease using 18F-2-fluoro-deoxyglucose and positron emission tomography. Preliminary results indicate the presence of asymmetric metabolic rates in the inferior basal ganglia. The structure comprising the largest portion of basal ganglia at this level is globus pallidus. These findings are consistent with metabolic studies on animals with unilateral nigrostriatal lesions in which pallidal hypermetabolism on the lesioned side has been demonstrated. Increased pallidal activity is likely secondary to a loss of inhibitory dopaminergic input to the striatum from substantia nigra.

[18F] 6-fluoro-L-dopa and positron emission tomography has been used to study intracerebral dopamine distribution in five control subjects and six patients with hemiparkinsonism. In the control subjects striatal, frontal and cingulate accumulations were clearly seen. In addition 18F concentrated in the region of the insula and the parietal lobe.

In the patients striatal accumulation 18F was reduced in the contralateral striatum, especially in the putamen. The uniformity of distribution of 18F in the striatum on the side of the parkinsonian signs was also irregular. This finding is consonant with the suggestion that intracerebral compensatory mechanisms prevent the manifestation of intracerebral dopamine deficiency from becoming obvious until a late stage of the disease.

The literature pertinent to the pathological anatomy subserving dementia in Parkinsonian patients is reviewed. Mechanisms discussed include cerebral cortical atrophy; hydrocephalus; Lewy body inclusions; neocortical lesions of the Alzheimer type; depletion of cholinergic, dopaminergic or noradrenergic transmitter systems; ‘subcortical’ dementia; and neuronal depopulation of the basal forebrain.

New autopsy data are presented to confirm that, contrary to published reports, most patients with parkinsonism who exhibit dementia do not have concomitant Alzheimer’s disease, and that some different pathogenetic mechanism must be sought to account for this increasingly common cause of cognitive decline in the sufferers of Parkinson’s disease.

According to their mental status, patients with Parkinson’s disease can be subdivided into three groups: (1) mentally normal patients; (2) patients with severe cognitive impairment and Alzheimer-type brain pathology (neuritic plaques, neurofibrillary tangles, granulovacuolar changes); and (3) demented patients without any evidence of Alzheimer changes. Neurochemically, irrespective of the presence or absence of Alzheimer-type brain pathology, demented Parkinson patients seem to have the same disturbance of cortical cholinergic neuron function as patients with Alzheimer-type dementia (Alzheimer’s disease), namely, reduced levels of cortical acetylcholine esterase and choline acetyltransferase activity. At present, the question whether the “cortical cholinergic deficiency” is the only (or sufficient) neurochemical basis for the cognitive impairment in Parkinson patients with dementia cannot be answered with certainty; the additional role of other neurotransmitter changes known to occur in the Parkinson brain, especially loss of cortical, hippocampal and subcortical noradrenaline and/or dopamine cannot be ruled out.

Effective control of parkinsonian symptoms can be achieved in a substantial number of patients by the judicious use of dopaminergic agents. To a considerable extent these drugs produce optimal therapeutic effects during the first 3–5 years of their use. Subsequently, efficacy diminishes with reemergence of parkinsonian symptoms as well as a number of untoward responses. The nature, frequency and mechanisms underlying the limitations of long term use of presently available anti-parkinson agents are discussed in this presentation.

Clinical and experimental evidence suggests that, in Parkinson’s disease, the late-occurring fluctuations in response to levodopa therapy are due to progression of the disease rather than to the therapy. Therefore, treatment with carbidopa/levodopa should be started early, because postponement does not provide patients with added benefits but deprives them of the most satisfying period of the therapeutic response.