Can human fetal cortical brain tissue transplant (up to 20 weeks) sustain its metabolic and oxygen requirements in a heterotopic site outside the brain? A study of 12 volunteers with Parkinson's disease.
BACKGROUND: Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases from Parkinson's to Huntington's disease. Stereotactic placement of dopaminergic neurons in the caudate-putamen (striatum), is being attempted in centers of excellence and has proved to be beneficial. Basic research using cell transplantation indicates that structural development mechanisms seen in immature brains, i.e., fetal brains, can also function in the adult brain. The adult brain consumes 15% of the resting cardiac output for its metabolic needs. While most human tissues can sustain an anaerobic assault for a few minutes up to 30 minutes, a sudden total lack of oxygen supply to the brain cells in an adult will render the person unconscious within five to ten seconds. Our team has been working on the problem of human fetal tissue response to antigenic assault for the last two decades. In the present series, 12 patients with prolonged histories of Parkinsonism, who were not responding to anti-Parkinsonian drugs, and could not afford costly stereotactic surgery or deep brain stimulation and other modalities of recent Parkinson's disease treatment, were enrolled in the study. MATERIALS AND METHOD: After obtaining proper informed consents from the patients or their guardians and from the multidisciplinary ethical committee, the patients, varying in age from 45 to 75 years and suffering for many years with Parkinsonism, were enrolled in the heterotopic brain tissue transplant programme. We followed standard antiseptic, aseptic and premedication protocols, after selecting a proposed site of transplantation of the brain in the axillary fold of the skin, under local infiltration anaesthesia. In an adjacent OR, a fetus was collected from a consenting patient undergoing hysterotomy and ligation (before 20 weeks), under general anaesthesia. Within a minute of hysterotomy, the fetal brain tissue was dissected, and under the guidance of the operative microscope, 1 g of fetal cortical brain tissue was dissected and weighed in an electronic machine. The tissue was collected from around 1 cm of the frontal opercula of the developing human fetal brain and grafted in the already dissected and prepared subcutaneous site in the axilla and the skin was closed. Hematological parameters (Hgb; total count, Tc; differential count, Dc; erythocyte sedimentation rate, ESR) were estimated sequentially up to one month. A small portion of the transplanted tissue was retrieved after one to two months, and a serial histological study was done along with a clinical assessment of the disease condition as per the specifications of the Unified Parkinson's Disease Rating Scale. The results were matched with the pre-transplant ratings of the individual cases. Presenting dyskinesia was also rated (0-4), on the basis of objective criteria assessment like walking, putting on a coat, lifting a cup to drink, etc. RESULTS AND ANALYSIS: Initially 30 patients suffering from advanced Parkinson's disease (PD) were approached after getting the necessary clearance from the institutional multidisciplinary ethical committee; however, we have been able to arrange transplantation in only 12 cases so far. These patients were evaluated at the pre- and one month post-transplant period by the Unified Parkinson's Disease Rating Scale (0-108) and the minimum score was 40 in the motor portion of the unified scale at the pre-transplant state. Evaluation of the patients after one month revealed mild improvement of the pre-transplant scoring (up to 33.3%) in 41.6% of the cases, and moderate improvement (up to 66.6%) in another 41.6% of the cases. While 16.8% of the cases did not show any improvement from the basal score, i.e., the pre-transplant score, there was a definite sense of well being and rise in weight (2-4 pounds) noted in each case and there was also a reduction of the L-Dopa dosage in 75% of the cases. There was also a 58.3% improvement in the bradykinesia scoring from the pre-transplant level. What is intriguing is the survival, growth and proliferation of the grafted fetal brain tissue in the HLA- and sex-randomized adult axilla without any immunosuppressive support. Not a single histological study of the fetal brain tissues after removal from the axilla showed any signs of graft vs. host or inflammatory reaction (Figures 1-9) but there were features of growth of the transplanted cortical brain tissue along with its different components like neurogenesis, gliogenesis, early neovascularisation and angiogenesis, etc. There was also no systemic leucocytosis or lymphocytosis. DISCUSSION AND CONCLUSION: Histological evidence at the transplanted tissue site suggests that fetal cortical brain tissue can sustain life in sex-randomized, HLA-randomized adult hosts, without the support of immuno-suppressive drugs and the tacit support of the blood-CSF and blood-brain barrier and other specific requirements of adult brain cells in the skull. Whether the clinical improvement in PD is transient or long lasting is presently under investigation along with basic questions like, is it due to transplanted fetal dopaminergic or non-dopaminergic neurons or is it the growth factors and the cytokine mediated hitherto unknown reactions causing the clinical improvement.