Parkinson’s disease (PD) is a slowly-progressive disease which ultimately robs its victims of voluntary motor control. The disease manifests itself as a series of symptoms which include "bradykinesia, rigidity, tremor, and impairment of postural reflexes (Fitzgerald, 1992:215)". It is a result of a loss of neurons in the substantia nigra pars compacta (SNpc). Chemotherapy, in the form of drugs such as levodopa and carbidopa, has been effective in alleviating many of the symptoms in the early stages of PD; however, with increasing losses in the number of cells in SNpc, such therapy becomes more and more ineffective. New therapies, using selegiline (deprenyl) and antioxidants (tocopherol or Vitamin E) focus on halting the progression of the disease by potentially salvaging surviving SNpc cells (Ahlskog, 1990).

A more aggressive approach in the treatment of PD has surfaced in recent years. Researchers are experimenting with the prospects of transplanting tissue directly into the afflicted areas of the central nervous system (CNS) of PD patients. In both animal models of PD and humans, marginally successful transplants have been performed using adrenal chromaffin cells and fetal neurons. Genetically-altered, dopamine-producing tissues are currently being proposed as an alternative in transplant therapy of PD. As techniques become more refined, such "brain-grafting" may be the panacea for not only PD, but also for other debilitating diseases such as Huntington’s disease and Alzheimer’s disease.

According to Fitzgerald (1992:215), the "cardinal pathological feature [of PD] is loss of neurons from the substantia nigra". Most of this loss occurs in the SNpc, of which approximately 80% of these neurons are lost before symptoms of PD appear. There is also a significant, but less substantial, loss of the substantia nigra pars reticularis (SNpr). The substantia nigra, or "black substance," is located in the "most ventral part of the tegmentum" of the midbrain. Its pigmentation is derived from neuromelanin, a pigment that is "produced during the synthesis of dopamine (Fitzgerald, 1992:115)". Neurons from the substantia nigra project to the corpus striatum (caudate nucleus and putamen) via the nigrostriatal pathway. Loss of these neurons results in decreased dopamine release to the corpus striatum. Consequently, patients present with a host of symptoms mentioned previously. Two more symptoms may also be present, but are less common: oculomotor dyskinesia, in which "saccadic movements of the eyes toward the selected targets are found to be both delayed and slow; and dementia, which sometimes occurs many years into the disease (Fitzgerald, 1992:216)".

Although the administration of levodopa and carbidopa alleviate many symptoms of PD in its earlier stages, such drugs do not halt the progression of the disease. It is now the goal of researchers to replace such lost tissue using transplant of catecholamine-producing tissues, which theoretically will pump a new source of dopamine into the dopamine-starved striatum. One technique is exploring the autologous transplant of adrenal chromaffin cells into the caudate nucleus. The results of the first of such transplants were published in 1987 by Madrazo et. al. They reported "dramatic improvement in motor deficits following cerebral transplantation in two patients with [PD]". Because of its ability to produce large quantities of catecholamines, Madrazo et. al. chose the adrenal medulla as the transplant tissue. According to Ahlskog (1990):

"When removed from the influence of the adrenal cortex, synthesis patterns change, and the adrenal medulla produces increased quantities of dopamine".

Researchers in the United States have likewise attempted adrenal medulla transplants, but with much less remarkable results. Ahlskog (1990) states:

"...there has been a general inability to replicate the dramatic results initially reported for adrenal transplantation. Patients have either failed to improve or at best have improved to a mild or moderate extent".

Immunohistochemical investigation of operated sections of the patient’s brain after autopsy revealed tyrosine hydroxylase (TH)-immunoreactive cells present within the graft site. TH is an enzyme involved in the conversion of tyrosine into dopamine. The authors proposed that these TH-immunoreactive cells may be viable grafted chromaffin cells based on the following criteria:

1) That cells "were clearly located within the graft site, and their morphology cannot be confused with the TH-immunoreactive neurons located within the host striatum". 2) These cells "clustered in a manner typical of grafted cells and unlike the cytoarchitectural arrangement seen in the intrinsic host population (Kordower et. al., 1991)".

However, Kordower et. al. (1991) also recognize the fact that these TH-immunoreactive cells, which were only seen in a few sections, were not tested for chromagranin A-binding, a marker for adrenal chromaffin cells. Furthermore, cells had "atypical morphological profiles, often displaying cuboidal somata and long neuritic processes". However, the authors explain that such morphological characteristics do not rule out the possibility that these TH--immunoreactive cells are indeed surviving adrenal chromaffin cells. They argue that it is "well-established...that the morphology of adrenal chromaffin cells is dependent on their environment".

The question still remains as to whether or not this patient showed improvement as a direct result of the implanted adrenal chromaffin cells. The authors suggest, that while the TH--immunoreactive cells located within the graft site may indeed be surviving adrenal chromaffin cells, too few cells were seen at autopsy to account for such a marked improvement. Rather, they "suggest that the enhanced TH-immunoreactive fiber network seen adjacent to the graft site is more likely responsible for the improvement seen in [their] patient (Kordower et.al., 1991)". To explain this, they turned to findings in research of animal models of PD. Freed et.al. (1991) report that "adrenal medulla grafts produce alterations in host dopaminergic systems even if the grafts do not survive". For instance in one study:

...a localized increase in TH-immunoreactive neurites [or "sprouting"] was reported following implantation of adrenal medulla, control tissues such as adipose tissue and sciatic nerve, and even cavitation without tissue implantation (Freed et.al., 1991).

immunohistochemical studies of sections of the brain of another PD patient after autopsy who received an adrenal medulla autograft to the caudate nucleus again revealed inconclusive results. The 53 year-old patient exhibited no improvements in PD symptoms and died 4 months after the transplant. While monoclonal antibodies to chromagranin A revealed intense granular staining in the graft site, "no chromagranin A-positive neurites or processes were seen (Hurtig et.al., 1989)". The authors also report that in animal studies involving rats with denervated striatum, behavioral recovery in the animals was correlated with a down-regulation of D2 (dopamine) receptors following transplantation of embryonic substantia nigra. Such data also correlate with those of the authors’ study, in that tissue sections closest to the site of implant of adrenal medulla also showed a decrease in density of both D1 and D2 receptors for dopamine and a subsequent increase in [H3]-mazindol binding. [H3]-mazindol binding indicates DA uptake sites. An increase in [H3]- mazindol binding is indicative of a high degree of DA utilization. The authors suggest that these data may reveal a "connection between the transplants and the regulation of the DA receptors". Nonetheless, due to an absence of TH--immunoreactivity within the region of the graft, it seems that "the viable chromaffin cells were producing neither an outgrowth of dopaminergic neurites nor sufficient DA to cause receptor down-regulation (Hurtig et.al., 1989)".

Another avenue researchers have chosen is the transplantation of fetal substantia nigra cells into the striatum of the host diagnosed with PD. There are obvious advantages to the use of fetal neurons that adrenal chromaffin cells lack. Both have the potential to produce the neurotransmitter DA. However, the immature neurons from the fetus have the added potential of secreting "co-transmitter and trophic substances, extend neurites, form synapses, and exhibit regulated neuronal activity (Freed et.al., 1991)". These advantages are not without limitations:

First, there are the practical problems in obtaining human tissues, legal and ethical issues, and immunological obstacles. Second, there is almost certainly a limitation in the degree of integration of these grafts into the host brains in that transplanted neurons do not become completely affected and the complete nigro-striatal-nigral circuitry cannot be re-established (Freed et.al., 1991).

Nonetheless, Freed, et.al. (1990) have reported in two publications favorable results after transplantation of fetal mesencephalic dopamine-producing cells into the caudate and putamen of a 52 year-old patient with PD. Fetal cells were transplanted "along 10 needle tracks in the caudate and putamen...[with] no reduction in motor function peri-operatively". The needle tracks were separated by a distance of approximately 4 mm, based on the fact that animal studies have shown extensive reinnervation from dopamine neurites that grew many millimeters in length. Twelve months after surgery, the patient showed improvements in many areas of PD:

He has shown increases up to 42% in speed of rapid alternating movements and in hand movements through space.... The patient can walk 17% faster than before surgery and is "on" about 86% of the time. His walking speed after the first dose of drugs in the morning has improved 37%.... His speech has improved in volume and clarity, he has regained the ability to whistle, and his chronic constipation has resolved (Freed, 1990).

In a second publication, this same patient showed continued improvement up to fifteen months post-operatively. Freed et.al. (1992) report that at twelve months, drug therapy was changed so as to optimize the effects of the drugs. The patient was started on deprenyl, a monoamine oxidase inhibitor. Unfortunately, the began experiencing dystonia and freezing episodes. The authors interpreted these symptoms as the result of dopamine-agonist overdose. Subsequently, these agonist were reduced, which resulted in an "increase in walking speed before and after the first morning dose of drugs". (See Table 1 and Figure 1). In fact, at 15 months, walking speed after drug administration increased 53% of the preoperative level to 1 m/see, considered to be a normal walking speed (Freed et.al., 1992).

Freed et.al. (1992) suggest the importance of a drug schedule that coincides with possible changes in dopamine secretion from successful fetal tissue implants. Overdosing and under-dosing with dopamine agonist can worsen Parkinsonian symptoms if drugs are maintained at preoperative levels or decreased, respectively. However, as more experiments are performed, and researchers "work out the time course of growth of fetal implants,...a scheduled taper of drug therapy could be initiated in anticipation of transplantation effects".

Finally, researchers are exploring the possibility of using genetically-altered cells to use as transplant vectors in PD. Two techniques may be employed. One proposal is to modify fetal dopaminergic neurons by immortalizing them through the introduction of oncogenes so that they may be grown in tissue culture. Once raised, these functional neurons could then be implanted into host striatum. Another method involves the transfer of specific functional genes into a target cell, so that when implanted into the host, these cells will produce a functional protein, such as TH necessary in converting tyrosine into L-hydroxyphenylalanine (L-dopa). L-dopa would be effective in alleviating the symptoms of PD. Either available cortical cell lines or primary fibroblasts, as examples, could easily be modified this way and used in transplant therapy (Freed et.al., 1991).

The latter proposal has already been attempted in a rat model of PD. Using a retroviral vector, an entire rat TH cDNA was transferred into fibroblasts. Researchers found that these cells, later implanted into the caudate nuclei of rats with unilateral nigral lesions, indeed "expressed [TH] and secreted L-dopa in vitro". Those rats that received the implants of these altered fibroblasts showed a significant reduction in the characteristic rotational behavior of this animal model. In spite of such positive results, the authors contend that these immortalized fibroblasts may still have the potential to form tumors (Chen et.al., 1991).

While brain-grafting is still a new treatment in PD, its potential is broad and unlimited with respect to neurological disorders. Many more experiments must be performed before treatment becomes routine, and perhaps under the Clinton administration, such research may flourish without the legal red-tape.

Literature Cited:

Ahlskog, J. E. 1990. Parkinson’s disease: new treatment strategies. Comprehensive Therapy, 16(12):41-6.

Chen, L. S. et.al. 1991. Cellular replacement therapy for neurologic disorder: potential of genetically engineered cells. Journal of Cellular Biochemistry, 45:252-7.

Fitzgerald, M. J. T. Neuroanatomy: Basic and Clinical. London: Bailliere Tindall, 1992.

Freed, C. R. et.al. 1992. Improved drug responsiveness following fetal tissue implant for Parkinson’s disease. Neurochemistry International, 20: 321S-327S.

Freed, C. R. et.al. 1990. Transplantation of human fetal dopamine cells for Parkinson’s disease. Fetal Human Transplant, 47:505-12.

Freed, W. J. et.al. 1991. Brain grafts and Parkinson’s disease. Journal of Cellular Biochemistry, 45:261-7.

Hurtig, H. et.al. 1989. Postmortem analysis of adrenal-medulla-to caudate autograft in a patient with Parkinson’s disease. Annals of Neurology, 25(6):607-13.

Kordower, J. H. et.al. 1991. Putative chromaffin cell survival and enhanced host-derived TH-fiber innervation following a functional adrenal medulla autograft for Parkinson’s disease. Annals of Neurology, 29(4):405-12.