In 1817, James Parkinson published his famous treatise: "An Essay on the Shaking Palsy," describing the symptoms which now collectively bear his name. Although many scientists before his time had described various aspects of motor dysfunction (ataxia, paralysis, tremor) Parkinson was the first to collect them into a common syndrome; one which he believed formed a distinctive condition. His sixty-six page essay contained five chapters describing symptoms, differential diagnoses, causality, possible treatments, and prospects for future study. What is most intriguing concerning Parkinson’s analysis (besides its consistent accuracy) is the fact that his clinical observations and inferences were made by watching the movements of six elderly males at a distance along the streets of London.
The symptoms seen in Parkinson’s Disease (PD) are of two distinct types: (1) a degeneration of normal actions and movements coupled with; (2) the appearance of abnormal-type behaviors. Positive symptoms are those behaviors not usually seen in normal people; since they occur often in patients with PD, they are thought to be mechanistically inhibited by normal physiological systems. However, when these systems degenerate or become damaged, they are released and abnormal behavior is the result. The main abnormalities seen in Parkinsonian patients are resting tremor, muscular rigidity, and anesthesia. Resting tremors occur while the patient is motionless; the symptoms disappear during activity or when the patient is asleep. They most often encompass alternating movements of the limbs, hands and head; for instance, one diagnostic tremor known as "pill-rolling," consists of repetitive rolling motions of the forefinger past the thumb. Other involuntary movements include postural changes which are made either as a response to inhibit tremor and muscle stiffness, or attempted unconsciously, without any apparent explanation (the latter is usually the case). These simple movements are referred to as akathesia and can occur during inactivity as well as with motion. Muscular rigidity, on the other hand, reveals an increase in tonicity of both flexors and extensors, especially in the distal limbs. Resistance to movement is seen to a point. However, if sufficient force is used, the muscles give and movement occurs briefly over a short distance. Rigidity is then re-initiated after the movement has stopped. This form of stepwise motions is referred to as cogwheel rigidity; its severity is variable depending on localization of the lesion, extent of neural damage, and progression of the disease over time. It is culminated by an increased slowness with difficulty beginning and continuing most every kind of movement.
Negative symptoms are not indicative of abnormal movements or actions. Rather, they are classified as revealing an absence or inability to perform certain behaviors. Such disorders fall into particular categories based on the type of movement in which the patient is deficient. There are three such categories: disorders of posture, locomotion, and speech. Disorders of posture are divided into deficits of equilibrium and fixation. Disorders of fixation center on the inability of a patient to begin or to maintain a part of his/her body in its normal position. Usually what is seen is a drooping of the head and arms, in addition, vertebral posture is not sustained which causes the patient to be propelled forward to a point of either moving or falling. Similarly, disorders of equilibrium are based on the inability of a patient to remain standing or sitting upright without additional support.
Disorders of locomotion focus on the decreased proprioceptive sensations of the patient—the inability to support the body, to maintain balance and to transfer weight smoothly from one leg to another during movement. A Parkinsonian individual typically walks with a broad based gait, taking short shuffling steps forward in an effort to maintain balance. Some patients may exhibit festinating movements which are seen to be initiated by a leaning forward, followed by an increased rate of stepping until the patient seems to be uncontrollably running.
Speech disturbances are also seen to be related to symptoms of rigidity; this actually causes an inability to produce vocal language. Akinesia is symptomatically revealed by an absence of movement, mainly seen in the face. Thus, patients can be seen to lack any facial expression: no eye blinking, twitches, and often a lack of speech. This can also be observed when the patients attempt to eat, since they have difficulties chewing and swallowing.
Occurrence of Parkinsonian symptoms is very slow and usually progressive. James Parkinson summarized his observations of the disease in his 1817 essay:
"So slight and nearly imperceptible are the inroads of this malady, and so extremely slow its progress...that the patient cannot recall the onset. The first symptoms perceived are, a slight sense of weakness with proneness to trembling...most commonly in one of the hands and arms." "... in less than twelve months or more, the morbid influence is felt in some other part." After a few more months the patient is found...less strict than usual in preserving an upright posture. "As the disease proceeds ... the hands fail to answer the dictates of the will. Walking becomes a task which cannot be performed without considerable attention...care is necessary to prevent frequent falls." "The disease proceeds, difficulties increase: writing can now be hardly...accomplished; and reading, from the tremulous motion, is accomplished with some difficulty." Later "the propensity to lean forward becomes invincible, and the patient is forced to step on the toes and fore part of the feet...irresistibly impelled to take much quicker and shorter steps, and thereby to adopt willingly a running pace."... The bowels which had all along been turbid, the expulsion of the faeces requiring mechanical aid." Finally "his words are now scarcely intelligible...no longer able to feed himself...saliva is continually draining from the mouth, mixed with particles of food he is no longer able to clear from the inside of his mouth." Lastly "sleepy exhaustion" with "incontinence and a loss of articula-tion.(1)
Due to the limited access to his patients, Parkinson did not refer to the intellect being hindered by the disease; nor did he explain the rigidity of axillary structures and extremities. These were recognized later by Trousseau and Charcot in the mid-to-late 1800’s who noted that: "their intellect ... gets weakened at last; the patient loses his memory, and his friends notice soon that his mind is not as clear; precocious caudacity sets in." And in reference to the rigidity: "...peculiar attitude of the body and its members, a fixed look, and immobile features." (1)
There are a number of different inducer’s of Parkinsonian-like symptoms. An example of known pathogenic PD is the post-encephalitic kind, which arose after the winter appearance of viral sleeping sickness (encephalitis lethargica) in 1916-17; moreover, several industrial toxic substances are known to cause PD (manganese, carbon monoxide, carbon disulfite, etc.). Parkinson’s can also result from arteriosclerotic brain disease, syphilis, and brain tumors. All of the above known causes however, are secondary to idiopathic Parkinson’s Disease, to which the underlying cause is not yet known. Nevertheless, extensive research has constructed a plausible set of criteria which in effect has defined the pathological onset. PD can be characterized by two distinguishing features: morphologically, by the appearance of intraneural cytoplasmic inclusions (Lewy bodies) with a specific pattern of neuronal cell loss in the pars compacts of the substantia nigra; and histochemically, with a severe topographically-specific loss of dopamine (DA) in the substantia nigra and the striatal nuclei (2). Various studies have indicated neuropathological changes occurring in areas other than the nigrostriatal pathway. Catecholamine cell groups of brain stem nuclei, noradrenergic areas of the locus coeruleus, substance P-containing neurons in the pedunculopontine tegmental nucleus, and serotonin-synthesizing neurons of the median raphe, have all been observed to experience degeneration typical of Parkinsonian histopathology (3). Although these changes have been observed in various patients with PD, the criteria used for the DAergic nigrostriatal pathway seems to be that which is clinically used when defining Parkinsonian pathogenicity.
Parkinson’s Disease has been the focus of much research since it was first diagnosed. Current hypothesized models on the causality of PD are those which support the diagnostic pathological hallmarks of the disease; therefore the proposed models must be in agreement with the typical pattern seen with idiopathic symptoms. In discussing the causes of PD, one immediately questions what effects age has in inducing Parkinsonian-type symptoms. PD is
primarily seen in individuals over forty years old. Moreover, a substantial correlation between loss of striatal dopamine (DA) concentrations and aging has been statistically verified in various labs: there appear to be a gradual loss of dopamine at a rate of approximately 5 to 8% per decade (4). Furthermore, research has shown that by the time an individual reaches the age of sixty, there is usually a 40-50% reduction in striatal DA. These concentrations are not seen to cause any Parkinsonian symptoms, however, since the remaining DAergic neurons seem to compensate for the deficiency. In fact, it has been noted that approximately 80% or more of the nigrostriatal DA needs to be lost before symptoms begin to appear (4). The question that needs to be asked is whether or not cell loss occurring as a result of old age is similar to the damage seen in idiopathic PD. Observations of patients with idiopathic Parkinsonism have shown that striatal DA loss is not diffusely spread over the entire system. Rather, a specific interregional pattern of damage is seen: the putamen is regularly the more affected of the two striatal nuclei, losing more than 95% of its dopamine compared with approximately 80% loss in the caudate nucleus (2). Age-related striatal dopamine loss does not mimic the interregional caudate-putamen pattern of idiopathic PD; in fact the conditions are opposite each other (2). In regard to the inter-regional pattern of cell damage, this uneven loss of striatal DA between caudate and putamen poses a question with regards to functionality. Research findings have suggested a possible sep-aration in the functional roles of the putamen and the caudate. According to recent evidence, the putamen seems to be a part of a cortical-subcortical neuronal loop with predominantly motor relationships; while the caudate nucleus is related to the psychomotor function and motivation, indicative of connections with frontal association cortex (5). Whereas the link between motor dysfunction and DA deficiency in the striatum has been defined, the distinct roles of each striatal nuclei have not. This research suggests the putamen as having a greater role in motor control while the caudate nucleus has more involvement with the cognitive alterations seen in PD.
An alternative hypothesis linked to the age-related theory is the one suggesting previous and early damage to the substantia nigra resulting in partial damage to DAergic neurons. This would provide an explanation for the patient remaining asymptomatic until the 80% threshold of damage is reached. Moreover, an elaboration of the hypothesis suggests that after such a damaging insult to the nigrostriatal system, compensatory mechanisms might increase DA turnover in the remaining nigral neurons. This could cause an increased oxidative stress on the neurons, as the enzyme monoamine oxidase (MAO) degrades the DA generating hydrogen peroxide in the process. Increased free radicals could overload the effects of detoxifying enzymes in the striatum; thus a cycle of additional neuronal damage could set in, and the 80% threshold could be reached quicker than normally (4).
A different theory focuses on the sequence of events which leads to PD, coupled with a proposed mechanism of action by which cell damage occurs. With the discovery of a selective nigral toxin, found to induce persistent Parkinsonism in both humans and other primate species, scientists began to study the process by which nigral cell death might occur. This substance, known as 1-methyl--4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes selective destruction of DA containing cells within the substantia nigra. Since it does not encompass any of the secondary structures outside of the nigrostriatal pathway, MPTP destruction does not provide an exact replica of the pathology seen in idiopathic PD (6). However, it does give an impetus for further study into the processes by which PD occurs, as well as providing an excellent animal model.
Mechanism of Action of MPTP in Nigrostriatal Cell Death
The various pathways in the MPTP mechanism were first elucidated from primate studies. The first observation was that a substance other than MPTP was found in abundance over a significant period of time in the brain. This chemical was identified as 1--methyl-4-phenyl-pyridinium (MPP+), and was found to be a by-product of MPTP degradation by MAO-B. With this discovery, it was proposed that MPP+ was the toxigenic factor and not MPTP. The actual mechanism was proposed by Nicklas et. al. who discovered that MPP+ produces oxidative stress by inhibiting the oxidation of mitochondrial NAD-linked substrates (7). What was found was that MPP+ inhibits mitochondrial energy metabolism along the NADH--ubiquinone reductase complex (complex I) of the mitochondrial membrane; this would mainly produce increasingly lower levels of ATP as the oxidative phosphorylation pathway could not be completed (6). Cell death due primarily to insufficient energy production would be the inevitable result.
To further try to explain the toxicity of MPP+, it was suggested that another mechanism of cell destruction involved the generation of free radicals. However, when MPP+ was found to be quite stable not producing toxic hydroxides and superoxides, an alternative explanation was posed. Recent evidence suggested that MPDP+ -- an intermediate in the degradation of MPTP—might be involved in redox reactions with MPP+ to produce toxic oxygen radicals, thus implicating the destructiveness of MPTP to DAergic nigral cells (6). In summary, the question does not revolve around the presence of MPTP actually existing in Parkinsonian patients. Rather, the mechanism itself poses a possible revelation by which nigral cells are particularly vulnerable. Could certain physio-logical processes be occurring which would be similar to the cellular destruction seen in MPTP cytotoxicity? Research suggests a correlation.
Studies of Parkinson’s patients, assessing lipid metabolism and subsequent free radical generation, discovered a selective reduction in nigral polyunsaturated fatty acids (PUFA) -- the substrate for lipid peroxidation. This was also confirmed by finding similar increases in another peroxidation intermediate, malondialdehyde, again specifically for the substantia nigra. These data suggest the presence of some ongoing toxic process found even at the end stages of PD as might occur via free radical attack (6).
Further research indicate a possible activator of these free radicals to be an increase in endogenous iron within the substantia nigra, coupled with generalized decreases in ferritin throughout the Parkinson brain. Since ferritin—a substance used to detoxify potentially high levels of iron—was found at correspondingly lower levels, it was proposed that this alteration in iron handling could contribute to the pathological changes associated with PD within the nigral system (6).
Moreover, in an attempt to find similarities with the MPTP model, Schapira et. al. performed additional studies on Parkinson patients, analyzing the function of nigral mitochondria in idio-pathic PD. Their results suggested a decreased function of enzyme activity in the complex I system, as compared with other proteins in the respiratory-chain (8). These data prove to be similar to results testing the MPTP mechanism of action, and provide support for the means by which MPTP selectively damages nigral cells in the human brain.
Thus, besides providing an efficient animal model, studies with MPTP toxicity suggest a possible means by which some of the Parkinson symptomology might be occurring. Regardless of its link to PD causality, what it has done, is give a pathological mechanism on a physiological and biochemical level; something which appears to be consistent with the neurohistological deficits already seen.
VARIOUS TYPES OF TREATMENT FOR PD
Since there is no known cure for PD, treatment is based on relieving symptoms and maximizing patient comfort. Various kinds of therapy—such as clinical counseling (concerning expected symptomology, nature of the disease, its effects, etc.) and physical therapy to cope with the muscular dysfunction are complimentary to exogenous drug treatments.
Drug therapy for PD is based on compensating for the loss of endogenous DA in the basal ganglia of affected patients. Pharmacological treatment has two main objectives: first, to increase the activity of remaining DA neurons (those which have, as yet, escaped damage); and second, to suppress activity in structures showing heightened activity due to an absence of adequate DA functioning. Drugs such as levodopa and monoamine oxidase inhibitors act to provide the cells with an increased access to DA; on the other hand, drugs like atropine act to decrease cholinergic activity which is de-inhibited by the lower DA levels.
In order to completely understand the actions and effectiveness of these drugs, it is important to know the molecular mechanisms of DA and its receptor system. At this point, there is experimental evidence indicating the existence of three different receptors for DA in the brain. They are functionally defined by the modes to which they are coupled to adenylate cyclase (AC) (9). In the AC effector system, the postsynaptic neuron is triggered by pre-synaptically released DA; intraneural transduction occurs by binding of DA to one of the three receptors. This leads to a corresponding change in AC activity which, in turn acts to induce activity of the second messenger, cAMP. D1 receptors have a stimulatory coupling effect on AC and induce an increase in cAMP; D2 receptors are coupled in an inhibitory manner and either decrease or have no effect on cAMP levels in the cell; finally, D3 receptors (which have homology with the D2) have no association with the AC protein (9).
As stated previously, Parkinsonian symptomology is not seen unless greater than 80% of the DA is depleted. The symptoms can manifest themselves either one or two ways. First, the remaining DA fibers can become overactive and; secondly, a general increase of supersensitive D2 receptors can occur at the neuronal terminals. This allows the undamaged DAergic neurons to have a greater effect due to their increased receptiveness and functional output. Other mechanisms occur to counterbalance the diminished DA activity such as: decreased serotonin and GABA effects (thought to inhibit DA function), decreased production of inhibitory D1 receptors, and increase in facilitatory norepinephrine. Symptoms become apparent when these compensatory mechanisms are insufficient in counteracting decreased DA function. Levodopa (L-dopa) is a drug which is able to cross the blood-brain barrier, unlike free DA. It is transformed to DA by the enzyme dopa-decarboxylase; the DA is then transported to the striatum via residual DAergic terminals (mainly from substantia nigra) where it is recognized by the DA receptors. Evidence suggests that the striatal activation of D2 receptors participates greater than the D1 receptors in reversing Parkinsonian manifestations (l0). As the disease progresses, L-dopa becomes less effective as well as being more difficult to admin-ister without causing side effects.
Frequently observed decline of therapeutic efficacy of L--dopa is presumably based on progressive degeneration of further nigral neurons, which represent the morphological substrate for DA biosynthesis from the physiological precursor of L-dopa, and for synaptic release from the striatal terminals (9).
Drug therapy must be continually corrected and re-evaluated, as the side effects from L-dopa treatments (rapid respiration, recurring tics, palilalia) might become as detrimental as the disease.
Alternating therapies either complement levodopa treatments or are still in the experimental stages. Dopamine agonists have been used in conjunction with L-dopa treatments and have been clinically shown to have superior long term results—if administered early on--than the respective monotherapy (9). Moreover, experiments with monoamine oxidase (MAO) inhibitors (which act to inhibit the degradation of DA from the brain) have suggested a means by which MAO might take part in the generation as well as the pharmaco--therapy of PD. MAO produces hydrogen peroxide during its degradation of biogenic amines, and the H2O2 formed is a precursor for cytotoxic radicals. Moreover, the presence of H202 enhances MAO-B activity which leads to increased degradation of DA and a positive feedback mechanism suggestive of DAergic cell death (11). Thus, the action of MAO inhibitors (i.e. L-prenyl) could possibly prevent this radical formation from cycling out of control and producing an overabundance of oxidative stress on the affected cells.
Because of its linkage with damage in and around the substantia nigra, PD suggests a relation between brain stem activity and motor coordination. Moreover, PD shows extensive variability in the severity and type of symptoms observed. This reveals the complexity of the interconnecting circuits responsible for creating organized, fluid movements. It also indicates an intrinsic difficulty in treatment, as individual therapies must be continually be maintained and evaluated in response to the progressive symptoms of the disease. Finally, because of the resemblance between many symptoms involving PD with the natural process of aging, an indirect model has been suggested to describe some of the neural degenerating mechanisms which occur as one advances in years. Despite increasingly promising research, PD remains for the most part idiopathic; furthermore, because the cause is not known, the treatments are not optimally successful. One can only wait for future experimental findings and hope that the discovery of a cure is not an impossible task.
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