The primary neurochemical lesion of PD results from the deficiency of striatal dopamine. There is a loss of nerve cells in the pigmented substantia nigra pars compacta, in the locus ceruleus in the midbrain, and in the globus pallidus and putamen. Other monoaminergic systems besides the dopaminergic system can be affected in PD. Histochemical studies confirm degeneration of both the noradrenergic locus ceruleus system and the serotonergic raphe nuclear groups. The cholinergic system is affected as well, most notably with the nucleus basalis of Meynert (Langston, 1992). It is estimated that the loss of 70% or greater of substantia nigra neurons and a loss of 80% or more of striatal dopamine are necessary to have the clinical symptoms of PD. This suggests a longer presymptomatic phase during which selective neuronal cell death progresses.

The cause of PD is unknown. The role of genetics in the disease has been debated for many years, and that controversy continues. Studies of monozygotic and dizygotic twins with an index case of PD have been variably interpreted and suggest that genetics may not bear a strong influence on the cause of PD (Ward et al, 1983).

Positron emission tomography (PET) studies have shown that asymptomatic twins of parkinsonian patients commonly have abnormalities of striatal dopamine uptake. If these findings are valid, a genetic predisposition for PD would be supported. Attempts to identify the gene or genes that may be involved in the development of PD are in progress. One large family with parkinsonism, the Contursi kindred, has been well studied for several years (Golbe et al, 1990). In 1996, researchers announced that the region of the chromosome responsible for the genetic transmission of parkinsonism in the Contursi family was found, probably with an autosomal dominant type of genetic inheritance. However, this chromosome area cannot be linked to all cases of familial PD (Polymeropoulos, 1996).

Recently, a team of researchers at Washington University School of Medicine in St. Louis has characterized a rare disease, aceruloplasminemia, that causes a rare form of Parkinsons. Aceruloplasminemia is caused by a mutation in the ceruloplasmin gene located in chromosome 3, which is involved in iron transport. Patients with this disease do not make ceruloplasmin, a protein that removes iron from the cells. Then the iron accumulates in cells in the brain’s basal ganglia region and causes neurological problems. These include the tremors and gait abnormalities associated with PD. This genetic form of PD was discovered during a study of a Japanese family with Parkinson’s symptoms and low levels of ceruloplasmin. This finding gives researchers important new information that could lead to innovation in the diagnosis and treatment of PD. (Harris et al, 1998)

There is also a mitochondrial genetic hypothesis that reported the activity of Complex I of mitochondria from both substantia nigra and platelets of patients with PD to be less than that of controls. This decrease is also noted in Huntington’s disease and Leber’s disease. Thus, while the fall in Complex I is not specific, it may still be a useful marker of idiopathic parkinsonism. The mitochondrial genetic hypothesis suggests that there could be a biochemical test to identify PD in an early stage. (Langston, 1992)

Many researchers have focused their interest on the possibility that PD may be caused, at least in part, to environmental factors. This fact was supported by the development of Parkinsonian symptoms in several young people after they used an illegal drug (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, abbreviated MPTP) related to the narcotic meperidine. A single dose of this compound can cause selective destruction of the nigrostriatal dopaminergic neurons. (Langston et al, 1983). It is thought that the sequence of events involves MPTP successive oxidation by monoamine oxidase B to the dihidropyridinium and pyridinium ion derivatives. The latter compound (1-methyl-4-phenylpyridium; MPP+) is actively and specifically accumulated in the dopaminergic terminals by the dopamine uptake system. It is also accumulated nonspecifically by mitochondria and acts as a reversible inhibitor of mitochondrial oxidative phosphorylation at the level of NADH dehydrogenase (complex I). It appears that the resultant loss of ATP-generating capacity, with consequent changes in the ability to maintain membrane potentials, calcium ion homeostasis, and consequent free radical generation, may be sufficient to cause neuronal degeneration (Taipton et al, 1993).

There is no investigation that supports a viral etiology for PD. After the pandemic of encephalitis lethargica (1919–1926), many cases of parkinsonism were observed but no definite causal relation was established to a specific virus. Transient parkinsonian features may occur during the acute or convalescent phases of a variety of viral encephalitides, including measles, Japanese B, and western equine. Rarely, parkinsonism may remain as a permanent sequela (Langston et al, 1992).

Unrecognized environmental toxins structurally similar to MPTP may play a role in the etiology of PD. The major culprits are suspected to be industrial chemicals, herbicides, and pesticides in well water. Exposure to manganese dust or carbon disulfide causes parkinsonian symptoms, and the diagnosis is suggested by an accurate occupational history. Parkinsonism sometimes occurs as a result of severe carbon monoxide poisoning.

Endogenous toxins may also be responsible. In particular, the normal neurotransmitter dopamine readily oxidizes to produce free radicals that destroy the dopaminergic nerves. Although the precise role of dopamine itself remains unclear, the evidence relating PD to damage by free radicals remains compelling. This evidence includes increased iron levels, increased lipid peroxidation, decreased peroxidase and catalase levels, increased superoxide dismutase levels, and decreased glutathione levels.

Movement disorders result from disease of the basal ganglia. This consists of the caudate and the putamen (together called the striatum), the internal and external segments of the globus pallidus, the subthalamic nucleus, and the substantia nigra. Cortically initiated movements are facilitated and competing movements are inhibited through the influence of the basal ganglia.

The activity of the output structures of the basal ganglia (the internal segment of the globus pallidus and the pars reticulata of the substantia nigra) is controlled by two opposing striatal pathways, the so-called direct and indirect routes. The direct pathway consists of the striatal projections to the substantia nigra pars reticulata and the globus pallidus interna. This pathway is (gamma-aminobutyric acid) GABA-ergic and inhibitory, expressed mainly on the dopamine D₁ receptor. This direct route then functions to facilitate thalamocortical projections that reinforce cortically initiated movement. An alternative polysynaptic (indirect) pathway involves striatal GABA-ergic, inhibitory neurons that express the dopamine D₂ receptors and project to the globus pallidus externa, which has an inhibitory effect on the subthalamic nucleus (Hutchinson et al, 1997). This nucleus has excitatory glutamatergic feedback on the globus pallidus externa and excitatory glutamatergic input on the substantia nigra pars reticulata and the globus pallidus interna. The final effect of the indirect pathway is that striatal activity would lead to disinhibition of the subthalamic nucleus, which in turn, through its excitatory projections, leads to a higher activity of the neurons in the basal ganglia output nuclei and a stronger inhibition of their targets.

A balance between direct and indirect pathways is crucial to the normal functioning of the basal ganglia–thalamocortical circuits. It is also important to the balance among dopamine receptors in each pathway because, interestingly, dopamine has opposing effects on the two striatal output pathways—a stimulatory effect on the D₁ receptor-containing direct pathway and a suppressing effect on the D₂ receptor-containing indirect pathway) (Groenewegen, 1997).

In PD, loss of dopaminergic cells in the substantia nigra leads to striatal dopamine depletion. This depletion results in decreased activity of the direct pathway and increased activity of the indirect pathway. This results in reduced thalamic excitation of the motor cortex and loss of facilitation of cortically initiated movement. (The two striatal output pathways are out of balance and act in the same direction.) This may be explained, at least in part, the hypokinesia characteristic of PD. The resting tremor of PD is less readily explained by the model but may result from effects on cholinergic interneurons in the striatum (Olney & Aminoff, 1998).

PD usually commences in middle or late life and leads to progressive disability with time. One study reported that compared with nondemented elderly people in the same community, patients with PD have a two- to fivefold increased risk of death. The risk is strongly related to the presence of severe extrapyramidal symptoms, especially bradykinesia (Louis et al, 1997); the mean time of survival is 13 to 14 years after the onset of clinical signs (Eichhorn & Oertel, 1994).

There is some discrepancy in the ethnic and sex distribution of PD. Some authors consider that the disease occurs more commonly in men than women; others insist it has an equal sex distribution. Although the disease occurs in all ethnic groups, most reports show that PD is more common among whites than nonwhites (Lanska et al, 1997). The prevalence is 1 to 2 per 1000 for the general population and 1 per 100 among people older than 65 years. A recent study indicated that 15% of persons ages 65 to 74, and more than half of all persons over 85, have some extrapyramidal disorders (Aminoff, 1998). The disease occurs with less frequency among the young, although about 5% of PD patients develop the illness before the age of 40.

So gradual and insidious is the onset of PD that patients can rarely pinpoint the precise date it began. Initial manifestations are often noted by someone other than the patient. Usually it is someone close to the patient who notices some subtle changes, perhaps in posture or manner of walking or moving. Eventually the patient becomes aware that something is indeed wrong. There may be persistent tiredness, minor aches and pains, or a vague sense of malaise. Perhaps the patient feels a lack of energy or a sense of nervousness and irritability. Performance on the job may be declining for no apparent reason. The patient may notice that things that were formerly performed easily, without a thought, now require conscious effort.

Diagnostic mistakes may occur early in the course of the disease because there are almost as many initial symptoms as there are patients. The diagnosis can be made with certainty only when three characteristic signs are present: tremor, rigidity, and bradykinesia.

Tremor is usually the first to appear, is relatively slow (4 to 6 Hz), is present when the limb is supported or suspended (arm resting in lap or hanging by the side), and is abolished by complete relaxation (such as during sleep), or by voluntary
movement of the limb (Nutt, 1997). The tremor generally begins in one hand, to-and-fro flexion movement of the wrist, hand, thumb, and fingers that is most apparent when patient sits comfortably. The cupped hand’s appearance of shaking pills gave rise to the name “pill-rolling” tremor (Friedman, 1994). Then from one hand, the tremor spreads to the ipsilateral foot, subsequently to the contralateral limbs, and perhaps to the tongue and jaw. In addition to the resting tremor, many patients have a faster 6 to 9 Hz postural tremor (Nutt, 1997). It is important to distinguish the Parkinson’s resting tremor, which is frequently asymmetrical, from the essential tremor, which is symmetrical, and commonly affects upper extremities, head and voice, but only rarely the legs. The handwriting is large and irregular (tremorous), rather than small (micrographia) as in parkinsonism.

Rigidity, defined as an increase in resistance to passive movement, is a common clinical feature that accounts for the flexed posture of many patients. The most disabling feature is bradykinesia, a slowness of voluntary movement associated with a reduction in coordinated automatic movements, such as the swinging of both arms when walking. Other findings can include a masklike facies with widened palpebral fissures and infrequent blinking. There may be blepharoclonus (fluttering of the closed eyelids), blepharospasm (involuntary closure of the eyelids), and drooling of saliva from the mouth. Patients have difficulty rising from bed or an easy chair and tend to assume a flexed posture when erect.

Many patients with PD have difficulty turning over in bed. This difficulty in turning when lying flat is the result of inability to execute the sequence of axial movements required to achieve the task. This disability becomes more prominent with longer disease duration (Steiger et al, 1996). Walking is often difficult to initiate, and patients may have to lean forward increasingly until they can advance. The tension reflexes are unaltered, and the plantar responses are flexor. Repetitive tapping over the glabella produces a sustained blink response (Myerson’s sign), in contrast to the response of normal subjects. Other findings include psychomotor retardation, fatigue, sleep disorder, and unilateral findings. This presentation may lead to the misdiagnosis of depression or stroke.

Fifty percent of tremor patients do not have PD, and a broader differential diagnosis needs to be considered. The history should focus on the development of neurologic symptoms, depression, other concurrent medical illnesses (eg, hypothyroidism), medications, injuries (eg, falls), and occupational hazards. Drug-induced disease should be ruled out by the elimination of offending drugs such as neuroleptics, antiemetics (eg, metoclopramide), and antihypertensives (eg, reserpine, methyldopa). The physical exam should include a thorough mental status and neurologic exam. Typical physical signs: the tremor usually at rest, accompanied by “pill rolling” movement of the thumb and finger. Passive movement of the wrist or elbow may reveal cogwheel rigidity.

The gait features marche a petit pas (characterized by short steps with a tendency to accelerate), shuffling, lack of arm swing, and the turning of the body en bloc. Speech is often soft and monotonal, and it may be inaudible. Autonomic insufficiency may result in constipation, impotence, and orthostatic hypotension.

Mental changes such as dementia occur in about 15% to 20% of people with PD, and in 40% of patients older than 70 years (Kaufman, 1995; Aarsland et al, 1996). The so-called subcortical dementia of PD is distinguished from the cortical dementia of Alzheimer’s disease. In cortical dementias, cognitive deficits are characterized by impairments in language and memory, agnosia and apraxia. In subcortical dementias, cognitive deficits are characterized by a general slowness of the thought process and impaired manipulation of acquired knowledge (deficits in abstracting abilities, retrieval, and neurospatial functions) (Starkstein et al, 1996; Kuzis et al, 1997).

Depression affects almost 50% of PD patients, and psychosis is present in at least 10%. Visual hallucinations, delusions, and chronic confusion are the most common psychotic features. This psychosis is most often attributable to a combination of dementia, antiparkinsonian medications, and the toxic–metabolic encephalopathy from other illnesses (eg, pneumonia).

Early detection of PD is useful from the viewpoint of addressing patients about their future. The recent claims that a medication (deprenyl) may slow the progression of the underlying pathology provides a new justification for attempting to make a diagnosis as soon as possible, perhaps even while the patient is still clinically normal. The majority of the tests and possible early markers for idiopathic PD are still under research. The clinical diagnosis rests on the history and physical exam, finding the cardinal features of tremor at rest, postural and balance dysfunction, akinesia, bradykinesia, rigidity, and gait abnormalities.