Parkinson’s Disease (from hereon PD) is an extrapyramidal disorder characterized primarily by massive idiopathic degeneration of dopaminergic neurons in the substantia nigra, resulting in greatly decreased levels of dopamine in the striatum. The diagnosis, which is essentially a clinical judgment due to the lack, thus far of a simple diagnostic test, has historically been on the basis of the presence of at least two of the three main features of PD: bradykinesia (or akinesia or hypokinesia), rigidity, and resting tremor. In addition to these symptoms, most PD patients also show postural disturbances, impaired righting reflexes, and abnormal ocular movements. The extent of the disease and its symptoms can be quantified by one of a few similar scales, including the motor examination of the Unified Rating Scale for Parkinson’s Disease, in which each of 14 motor aspects are scored from 0 to 4 and the scores totaled. The items in this particular scale are as follows: 1) speech; 2) facial expression; 3) tremor at rest; 4) action or postural tremor of hands; 5) rigidity; 6) finger taps; 7) hand movements; 8) rapid alternating movements of hands; 9) foot agility; 10) arising from chair; 11) posture; 12) postural stability; 13) gait; and 14) body bradykinesia or hypokinesia. In addition to the typical idiopathic PD, PD-like symptoms may be seen in a variety of other disorders, such as striatonigral degeneration (which I will mention later), Parkinsonism-dementia complex on Guam, supranuclear palsy, and occasionally Alzheimer’s Disease.
The resting tremor usually seen in PD primarily affects the digits, hands and arms, head, and lips, and ceases during voluntary movement and sleep. This tremor characteristically has a high amplitude and a very stable frequency of 4-6 Hz. This is very different from normal physiological tremor, which has a low amplitude and a frequency of 8-12 Hz. A technique has been found that reveals a rhythmic 4-6 Hz tremor immediately following voluntary movements even in those PD patients that do not show clinically obvious resting tremor, indicating that even in PD patients without observable tremor, the abnormal mechanisms for generating the pathological 4-6 Hz tremor exist, but for some unknown reason do not normally come into play. Tremor analysis of this type may be of use in strengthening uncertain diagnoses of PD, or possibly in providing an early indication of the onset of the disease As to the cause of the tremor, it has generally been postulated to result from oscillatory activity of thalamocortical loops, independent of actual basal ganglia circuitry. Recent findings involving the subthalamic nucleus, however, suggest that the basal ganglia may actually participate directly in tremor production in PD.
The rigidity seen in PD is different than UMN lesion rigidity in that it is present to an equal extent in opposing muscle groups. When resting tremor is also present, the rigidity can be felt as resistance to passive muscle movement, which is overcome as a series of jerks, called cogwheel rigidity. When tremor is not observable the rigidity is referred to as plastic rigidity.
Bradykinesia or hypokinesia refers to the difficulty in initiating new movements. Once initiated, the movements are slow and deliberate, and movements such as swinging of the arms during walking are lost. The face is expressionless and is often described as mask-like. The voice is usually very soft, unmodulated, and sometimes slurred.
Abnormal ocular movements have generally not been utilized as diagnostic features of PD mainly because: 1) these movements are very difficult to identify without much time and equipment; and 2) data until fairly recently has been conflicting concerning the relationships of various aspects of ocular movements with PD. These conflicts have probably mainly been due to differences in drug treatment and severity of illness of subjects of experiments in the past, etc. Recent studies specifically designed to rule out these discrepancies have found that in general, PD patients have significantly altered saccade latency, amplitude and peak velocity, smooth pursuit peak velocity, optokinetic nystagmus maximal and mean velocities, and vestibulo-ocular reflex (VOR) suppression by vision or imagination. VOR gain, however, remains normal. Also, there was a direct relationship between the degree of alteration of ocular movements and the degree of disease. This was expected because ocular movements are an example of general motor function.
The normal substantia nigra is divided into two parts, the pars compacta and the pars reticulate. The pars compacta is rich in large pigmented cells that contain high concentrations of dopamine, and the nigrostriatal fibers leaving this region are the main efferents of the substantia nigra. Specifically, dopaminergic neurons in the lateral portion of the pars compacts project primarily to the putamen, while the caudate nucleus is supplied more by the medial portion. These dopaminergic nigrostriatal neurons fire constantly and spontaneously at a set rate, releasing a constant level of dopamine into the striatum. It has been shown recently that there are also striatonigral fibers, which are organized in a manner reciprocal to the nigrostriatal fibers except that the majority seem to project to non-dopaminergic neurons in the pars reticulate. Nevertheless, they are thought to exert some type of regulatory effect on the dopaminergic pars compacta neurons. These fibers are not really important in the disease process of PD.
The postsynaptic action of dopamine has never been fully understood, for it seems to have both inhibitory and excitatory effects depending on the tissue it is innervating. In the putamen there are apparently two sub-populations of output neurons; one group projecting to the external globus pallidus (GPe), which then sends fibers to the internal globus pallidus (GPi) via the subthalamic nucleus (STN), and one group projecting directly to the GPi. Both of these striatopallidal connections are inhibitory. However, the dopamine from the substantia nigra seems to have opposite effects on the two sub-populations in the putamen. It seems to inhibit the inhibitory neurons projecting to the GPe, but to excite the inhibitory fibers projecting to the GPi. As if this isn’t confusing enough already, the fibers from the GPe to the STN are also inhibitory, but those from the STN to the GPi are excitatory. Therefore, there is duel innervation to the GPi, both inhibitory directly from the putamen and excitatory from the STN. These tend to balance each other out normally, resulting in a fairly steady-state output (which is inhibitory) to the thalamus (primarily the VL), which then sends excitatory fibers to the motor cortex. In summary, dopamine from the substantia nigra helps to maintain a steady-state low level of inhibitory activity of the GPi on the VL thalamus, which even though it is partly inhibited, still sends a low level of excitatory activity to the motor cortex. The following diagram will help to clarify this information:
As I mentioned before, the main pathological finding in PD that seems to result in the characteristic symptoms is a marked depletion of dopaminergic neurons that send their fibers from the substantia nigra to the striatum (nigrostriatal fibers). The lateral portion is almost always more severely affected, which supports the idea that the motor deficits in PD are due primarily to loss of dopamine in the putamen rather than the caudate nucleus. Because these cells are large and distinctly pigmented, their absence is easily identified in postmortem PD brains. As was previously stated, striatonigral fibers aren’t important in PD, and it follows that these fibers remain well preserved in the brains of PD patients. On the other hand, there is a rarer disease that in many ways mimics PD symptomology-wise. It is called striatonigral degeneration (SND) and results from degeneration of neurons in the putamen. Striatonigral fibers are thus destroyed, and since these fibers in some way help to regulate nigrostriatal fiber activity, some nigrostriatal fiber degeneration is also seen (though not to as great an extent as PD), resulting in some PD-like symptoms. However, the distinction is that in PD the degeneration begins in the substantia nigra and never involves striatonigral fibers, while in SND the disease begins in the putamen, and the substantia nigra is involved only indirectly.
Although the neuronal changes which take place in PD have been well studied, the mechanisms by which the alterations in the basal ganglia cause the motor abnormalities has been poorly characterized. One recent hypothesis implicates increased activity of the subthalamic nucleus (STN) in the motor deficits. This hypothesis has been tested in monkeys rendered Parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). -MPTP was found in the late 1970’s to be selectively toxic to nigral dopamine-containing cells and has been used extensively to produce PD in monkeys and other lab animals so that various aspects of the disease can be studied. The wealth of new information on the disease is largely due to this drug. Specifically, MPTP is converted to an active neurotoxin, 1-methyl-4-phenylpyridinium (MPP+ ) by monoamine oxidase B. most likely in glia. MPP+ then enters the dopaminergic cells of the nigrostriatal system via the dopamine reuptake system and is then concentrated within mitochondria by active transport. MPP+ is a specific inhibitor of NADH-ubiquinone reductase (mitochondrial Complex 1), which is the first enzyme-protein complex of the mitochondrial respiratory chain. By inhibiting this complex, MPP+ probably induces nigrostriatal cell death by depleting cellular ATP levels. In monkeys treated with MPTP, the characteristic PD symptoms of akinesia, muscular rigidity with cog-wheeling, an intermittent 5 Hz tremor, and postural instability are all observed beginning about 5-6 days after the first injection.
To examine the involvement of the STN in PD motor deficits, researchers have injected ibotenic acid (IBO) into the STN of monkeys already rendered Parkinsonian by MPTP. The IBO quickly destroys much of the STN. within minutes, the monkeys begin to move their contralateral extremities, showing abatement of the akinesia. Purposeful movements are markedly increased and the monkeys are again able to feed and groom themselves. Tremor is almost completely abolished contralaterally. Muscle tone is reduced in the contralateral limbs as compared to the ipsilateral limbs. Some residual akinesia and clumsiness still remains, but in general most of the PD symptoms are reversed. This result, along with the finding that in Parkinsonian monkeys the activity of the STN was increased over normal monkeys, supports the hypothesis that excessive STN activity plays a strong role in the pathophysiology of motor abnormalities in PD. This excessive activity would be expected with decreased dopamine in the putamen due to degeneration of the substantia nigra, according to the model above (fig. 1) because there would be less inhibition of fibers from the putamen to the GPe, and since these fibers themselves are inhibitory, there would be greater inhibition on the GPe and thus less inhibition on the STN. Then, because the STN is excitatory to the GPi, the GPi would be more excited than normal. At the same time, decreased dopamine in the putamen would directly decrease inhibition on the GPi. Consequently, the activity of inhibitory fibers from the GPi to the VL thalamus would be greatly enhanced, producing the motor deficits of PD. Refer to fig. 2 below for a summary of this confusing system. Lesioning the STN, therefore, would decrease its excitatory activity on the GPi, thus decreasing its inhibitory influence on the VL. This scenario is summarized in fig. 3 below. Although it is not known to what extent the STN is involved in PD motor deficits and what other mechanisms may be involved, the STN does seem to contribute significantly. The results of these studies suggest a possible potential clinical application for surgical or pharmacological inactivation of the STN as a treatment for PD.
The cause of the specific cellular degeneration seen in PD is unknown. A putative environmental toxin has been postulated, but it is difficult if not impossible at this point to identify a particular agent or class of agents as the cause because it is likely that PD may be multi-factorial in origin and may also be partially dependent on factors such as age and genetics of the subject as well as time, dose, and duration of exposure to the agent or agents. Support for the idea that an environmental toxin may be partially responsible for PD comes from the finding that in postmortem PD brains, the mitochondrial Complex 1 activity in the substantia nigra was significantly reduced, which is what occurs in animals made Parkinsonian by MPTP. Theoretically, some toxin could be taken up into nigral mitochondria in much the same way as MPP+ and induce Complex 1 deficiency. Further support comes from a study done in China, in which it was found that occupational or residential exposure to industrial chemicals, printing plants, or quarries was associated with an increased risk of developing PD. In contrast, living in villages and exposure to the common things in village life, wheat growing and pig raising, were associated with a decreased risk for PD.
Dopaminergic nigrostriatal degeneration is the main pathological disorder in PD, but other neuropathological changes may also occur. How these changes affect the patients is still pretty much unknown, but some of them may be related to cognitive changes in PD (which I will discuss later). Degeneration and occasionally Levy bodies (which are large, dense, round bodies frequently seen in degenerating substantia nigra cells in PD and which are considered to be a "hallmark" of PD in the same way that neurofibrillary tangles are to Alzheimer’s Disease) frequently occur in the noradrenergic locus coeruleus, in the mainly cholinergic substantia innominata (nucleus basalis of Meynert), in substance P-containing neurons in the pedunculopontine tegmental nucleus, lateral reticular formation, and dorsal motor vagal nucleus, and in serotonin -synthesizing neurons in the median raphe. Obviously, dopamine is not the only neurotransmitter involved in PD. While it is probably mainly responsible for the major characteristic motor deficits of PD, these other neurotransmitter changes account for the wide diversity of motor, cognitive, and autonomic changes in different PD patients. This is where a great bulk of today’s research in PD is being done
Global dementia is often seen in PD patients, although researchers seem to be hesitant to give a percentage of the number of PD patients experiencing dementia. This dementia, rather than being a "symptom" (so to speak) of the PD, is instead almost always due to some other co-existing disease process, such as Alzheimer’s Disease. Even in the few cases where another disease is not found, patients with dementia- shown postmortem to have diffuse Levy bodies spread beyond the substantia nigra and basal ganglia, which is not typical of PD. Apart from global dementia, however, various isolated cognitive deficits have been found to occur in nearly every Parkinsonian patient. These deficits generally do not interfere with social or occupational functioning, but can be detected in neuropsychological testing. Because the problems are not usually seen with everyday functioning they have not been included in the list of general PD symptoms and only recently are beginning to be recognized as a typical Parkinsonian finding. The cognitive deficits are selective and are mainly problems involving the visuospatial subsystem of working memory, including verbal memory. Overall verbal ability, however, is retained. This compromised visuospatial function is independent of any dementia and is also independent of depression, which is a common finding in PD, affecting 30-50% of patients. The exact cause of these isolated cognitive deficits is unknown, but several researchers have suggested that a cholinergic deficiency may be at fault. Such a deficiency could result from degeneration of ascending cholinergic systems to the cortex (primarily frontal) and of ACh-producing neurons in centers such as the nucleus basalis of Meynert (substantia innominata), and these areas are often shown to be affected in PD patients postmortem. It is interesting and rather ironic that anticholinergic drugs were occasionally used in the past to reduce Parkinsonian rigidity, for if a cholinergic deficiency is partly responsible for cognitive deficits, anticholinergic therapy would surely increase these deficits.
Levodopa, by itself or combined with carbidopa (Sinemet), continues to be the drug of choice for reducing PD symptoms, although it fails to stop the progression of the disease. Levodopa is a monoamine similar to dopamine except that it can cross the blood-brain barrier. Once in the brain it is converted to dopamine by the enzyme dopa--decarboxylase (appropriately named, for the enzyme simply removes a carboxyl group from the primary carbon of levodopa), and the dopamine is subsequently released in the striatum by residual dopaminergic terminals. Specific receptors in the striatum then bind the dopamine and reduce the symptoms of the disease. There are two types of postsynaptic dopamine receptors. The D1 type stimulates adenylate cyclase, producing more cyclic AMP, whereas the D2 type inhibits adenylate cyclase, lowering the cAMP level. Levodopa seems to reverse Parkinsonian manifestations by activating the D2 receptors more than the D1 receptors. In fact, studies have shown that PD patients treated with levodopa within two years from the onset of the disease survive (from treatment initiation) longer that patients treated with longer delay. Age and disease severity at the time of levodopa initiation are strong prognostic predictors for survival.
Levodopa is not without its problems, however. Within 4 to 5 years the majority of levodopa-treated patients begin to experience dyskinesia’s, many times choreiform in nature, as well as fluctuations in their motor response to the drug. Two types of motor fluctuations are recognized. Wearing-off responses may or may not occur, depending on the severity of the disease in a patient, the dosage of levodopa given, and the time given. When the drug wears off, it seems to do so rather suddenly, and sudden freezing spells as well as a return of Parkinsonian symptoms occur. Later, more complex on-off variations gradually begin to occur, resulting in sudden, unpredictable shifts from the under-treated to the over-treated state. In addition, dyskinesia’s usually begin to occur with increasing severity in patients with severe PD. These dyskinesia’s usually occur mainly at peak dosage of levodopa. All of these motor fluctuations seem to be a consequence of both natural disease progression and levodopa toxicity, and have been especially severe due to the fact that traditional levodopa therapy has taken the form of intermittent ingestion of the drug. Such periodic stimulation of the postsynaptic dopamine receptors is non-physiological, since the system normally operates under tonic stimulation by nigrostriatal fibers. Some researchers have suggested that this intermittent stimulation receptors may change the functioning of the dopamine receptors. For instance, in postmortem brains of PD patients who had been treated with levodopa therapy for a number of years, there is a relative increase in D1 receptor binding sites compared with those untreated. Since at the beginning of treatment, the D2 receptors seem to be the ones involved with alleviating PD symptoms, perhaps over several years there is a gradual buildup of D1 receptors for some reason, which may then be reflected as motor fluctuations. Whatever the exact mechanism, continuous replacement of dopamine instead of periodic replacement has proven to greatly ameliorate the disabling effects of such fluctuations and dyskinesia’s, and may even help to prevent their initial presentation.
A great deal of work has been done in the past several years to attempt to find a treatment better than drug therapy. It has been shown that transplantation of various kinds of catacholamine-producing tissues into the striatum of PD patients can be very beneficial as a treatment. The most favorable results have been obtained with the transplantation of fetal mesencephalic (nigral) tissue into the caudate nuclei of monkeys rendered Parkinsonian with MPTP, in which significant motor behavioral improvement after surgery was observed. The improvement seems to be due in part to dopamine derived from the fetal dopaminergic graft, but also to the apparent "sprouting" of remaining host dopaminergic neurons. It has been shown that MPTP selectively destroys the dopaminergic cells in the substantia nigra but spares the mesolimbic system originating from the ventral segmental area, and since the effects of MPTP so closely mimic true idiopathic PD, it is reasonably safe to assume that the same occurs in PD brains. The implantation of the tissue apparently stimulates these nearby remaining dopaminergic neurons to sprout new dopaminergic fibers into the caudate, and a pathway is thus established to carry host dopamine into the striatum. At this point it is unclear which source contributes more dopamine. The transplantation of human fetal nigral tissue into the striatum of PD patients has been attempted a few times and has been relatively successful in combination with immunosuppressive therapy; however, widespread clinical application of human fetal tissue implantation obviously presents serious immunological and ethical problems. To get around this barrier, other tissues have been investigated as possible transplantation choices.
Much work has been done with the autologous transplantation of adrenal medullary tissue into the caudate. With lab animals this procedure has generally produced reasonably good results, but with humans the results have been extremely inconsistent. A few patients have reported some improvement in symptoms, but just as many have reported no change, and a few have even reported increased severity of symptoms. Because the gains have not exceeded the risks with this procedure, it will most likely not become standard procedure for some time, if at all.
As an alternative to adrenal medullary transplants one Group of researchers has reported autologous transplantation of the superior cervical ganglion (SCG) into the caudate of Parkinsonian monkeys. Favorable results were obtained with the procedure, so this may have future benefit to humans.
Concurrent with the recent explosion of gene therapy as a treatment for various diseases, several researchers have followed these lines by attempting gene therapy for PD on rats. Rat fibroblasts have been infected with a retroviral vector containing the cDNA for rat tyrosine hydroxylase (the enzyme ultimately responsible for the production of dopamine) and then grafted onto the caudate. Behavioral abnormalities were reported to be reduced in these rats. At this point, this procedure has not been attempted on monkeys, so it will likely be quite a while before it is considered for humans.
Tissue transplantation promises to be of great value in the future as a treatment for Parkinson’s Disease. However, it is evident that much needs to be learned about the effects of transplanting tissue into the brain. The mechanisms involved in the survival and function of the transplanted tissue and the responses of the host to the transplant, its secretions, and the trauma of its insertion are still poorly understood.
BIBLIOGRAPHY:
1. Lakie, M. and W. J. Mutch (1989). Finger Tremor in Parkinson’s Disease. J. Neurology, Neurosurgery, and Psychiatry; 52: 392-394.
2. Rascol, O. et. al. (1989). Abnormal Ocular Movements in Parkinson’s Disease. Brain; 112: 1193-1214.
3. Rajput, A. H. et. al. (1989). Parkinsonism and Neurofibrillary Tangle Pathology in Pigmented Nuclei. Annals of Neurology; 25: 602-6.
4. Bergman, H., Wichmann, T., DeLong, M. R. (1990). Reversal of Experimental Parkinsonism by Lesions of the Subthalamic Nucleus. Neuroscience; 249: 1436-1438.
5. Dubois, B. et. al. (1990). Cholinergic Deficiency and Frontal Dysfunction in Parkinson’s Disease. Annals of Neurology; 28: 117-121.
6. Goto, S. et. al. (1989). Subdivisional Involvement of Nigrostriatal Loop in Idiopathic Parkinson’s Disease and Striatonigral Degeneration. Annals of Neurology; 26: 766-770.
7. Mercuri, N. B. et. al. (1989). Physiology and Pharmacology of Dopamine D2-Receptors. Neurology; 39: 1106-1108.
8. Halliday, G. M. et. al. (1990). Neuropathology of Immunohistochemically Identified Brainstem Neurons in Parkinson’s Disease. Annals of Neurology; 27: 373-385.
9. Tanner, C. M. et. al. (1989). Environmental Factors and Parkinson’s Disease. Neurology; 39:660-664.
10. Schapira, A. H. V. et. al. (1990). Mitochondrial Complex 1 Deficiency in Parkinson’s Disease. J Neurochemistry; 54: 823-827.
11. Fischer, P. et. al. (1990). Memory Deficits in Advanced Parkinson’s Disease. J. Neural. Transm.; 2: 59-70.
12. Bradley, V. A., Welch, J. L., Dick, D. J. (1989). Visuospatial Working Memory in Parkinson’s Disease. J. Neurology, Neurosurgery, and Psychiatry, 52: 1128-1135.
13. Mohr, E. et. al. (1990) Selective Deficits in Cognition and Memory in High-Functioning Parkinsonian Patients. J. Neurology, Neurosurgery, and Psychiatry; 53: 603-613.
14. Mohr, E. et. al. (1989). Dopamine and Memory Function in Parkinson’s Disease. Movement Disorders; 4: 113-120.
15. Mouradian, M. M. et. al. (1989). Pathogenesis of Dyskinesias in Parkinson’s Disease.Annals of Neurology; 25: 523-526.
16. Chase, T. N. et. al. (1989). Rationale for Continuous -Dopaminomimetic Therapy of Parkinson’s Disease. Neurology; 39: 7-10.
17. Scigliano, G. et. al. (1990). Mortality Associated with Early and Late Levodopa Therapy Initiation in Parkinson’s Disease. Neurology; 40: 265-269.
18. Bankiewicz, K. S. et. al. (1990). The Effect of Fetal Mesencephalon Implants on Primate MPTP-Induced Parkinsonism. J Neurosurgery; 72: 231-244.
19. Apuzzo, M. L. J. et. al. (1990). Utilization of Unilateral and Bilateral Stereotactically Placed Adrenomedullary-Striatal Autografts in Parkinsonian Humans: Rationale, Techniques, and Observations. Neurosurgery; 26: 746-757.
20. Lieberman, A. et. al. (1989). Adrenal Medullary Transplants as a Treatment for Advanced Parkinson’s Disease. Acta Neurol. Scand.; 126: 189-196.
21. Nakai, M. et. al. (1990). Autologous Transplantation of the Superior Cervical Ganglion Into the Brain of Parkinsonian Monkeys. J. Neurosurgery; 72: 91-95.
22.Wolff, J. A. et. al. (1989). Grafting Fibroblasts Genetically Modified to Produce L-Dopa in a Rat Model of Parkinson’s Disease. Proc. Nat’l. Acad. Sci., USA; 86: 9011-9014.
23.Carpenter, M. B. Core Text of Neuroanatomy (?). Scattered pages.
**I didn’t realize that I had so many sources until I typed them all out, but I swear I used them all! You should see how many I threw out!**