Adrenal Medullary Tissue Research Articles

Grafting of perfused adrenal medullary tissue into the caudate nucleus of patients with Parkinson's disease

The authors report results obtained in 20 severely affected patients with Parkinson's disease (Grade IV or V) who received an autotransplant of perfused adrenal medullary tissue. This study seems to indicate that these autoimplants can improve the parkinsonian symptomatology and induce amelioration in the patients' performance of routine activities. All the symptoms analyzed showed improvement, although it differed in intensity and time of onset. Moreover, this improvement was accompanied by a reduction in the daily intake of L-dopa, with discontinuance of dopamine agonists and amantadine. A number of medical complications were encountered, including three deaths, probably related to performing abdominal surgery in seriously affected parkinsonian patients who were unable to tolerate the discontinuance of their medication. The transient psychiatric disorders observed appeared to be related to the postoperative dose of L-dopa and/or anticholinergic agents administered, and diminished or disappeared when the doses were reduced. The reasons for improvement, which was bilateral, remain unknown, although one cause may be the surgical trauma (minicaudotomy) together with the implantation of adrenal medullary tissue, which may promote the sprouting of surviving dopaminergic fibers. Moreover, in this series, perfusion of adrenal medulla increased the capacity for revascularization of the tissue and may have reduced the damaging effects of warm ischemia on the cells. This, together with the existence of fenestrated vessels, could hypothetically have served as an access point for drugs, and if the implanted cells were viable, they might have served to store and manufacture different factors and/or transmitters. These results as well as those of other groups justify the development of a controlled international clinical trial.

Stereotaxic Implantation of Autologous Adrenal Medulla Into Caudate Nucleus in Four Patients With Parkinsonism

Four patients with levodopa-responsive parkinsonism (aged 26, 35, 45, and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days, during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case, the stereotaxic implantation missed the basal ganglia, resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases, a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.

Adrenal medullary “ribbon” grafts in non-human primates: transplant method

A novel stereotaxic method permits the transplantation of autologous adrenal medullary tissue into the brain parenchyma in longtailed macaques. Long, narrow “ribbons” of intact medullary tissue are drawn into a 19-gauge needle by suction and deposited in the caudate, putamen or substantia nigra without collapsing their linear conformation. Methods of dissection, preparation of medullary ribbons, stereotaxic insertion, and chronic intracerebroventricular treatment are described in detail. The ribbon method consistently yields a large amount of viable adrenal tissue after the 4–8 week survival times tested. Although further development is necessary before this method can be applied in humans, the results suggest that autologous adrenal tissue may be viable when transplanted in human parkinsonian patients according to these methods.

Four Forms of Tyrosine Hydroxylase Are Present in Human Adrenal Medulla

Alternative splicing can result in up to four forms of human tyrosine hydroxylase (HTH) mRNA (mRNAHTH). In the adrenal gland, a major site of catecholamine biosynthesis, the presence of all four mRNAHTH forms is controversial. In the present study, postmortem human adrenal medullary tissue was analyzed for the presence of multiple forms of HTH protein by blot immunolabeling. Electrophoretic transfers were developed with affinity-purified rabbit anti-HTH antibodies raised against peptides that reproduced the unique amino acid sequences predicted by the four mRNAHTH forms. All four of the predicted HTH protein forms were present in the adrenal glands from a diverse sample population.

Intraputaminal Infusion of Nerve Growth Factor to Support Adrenal Medullary Autografts in Parkinson's Disease

Experimental studies in rodents show that beta-nerve growth factor can increase the survival, neurite outgrowth, and functional effect of grafts of adrenal chromaffin cells to the basal ganglia. We, therefore, have begun to investigate whether treatment with nerve growth factor might also increase the functional effect of autografts of adrenal medullary tissue in patients with Parkinson's disease. Previous studies have shown that stereotactic implantation of adrenal tissue pieces produces a transient functional improvement that lasts for a few months. This report describes a trial of grafting of adrenal chromaffin tissue into the putamen, supported by infusion of nerve growth factor. The patient is a 63-year-old woman with a 19-year history of Parkinson's disease, now complicated by on-off phenomena and drug-induced hyperkinesia, despite optimized medical management. The left adrenal gland was removed, and the medulla was dissected into 1- to 2-mm3 pieces in a solution containing nerve growth factor purified from mouse submandibular gland. Pieces were implanted in six tracts 3 to 4 mm from a previously placed cannula in the left putamen. Through the cannula, nerve growth factor was infused for 23 days for a total dose of 3.3 mg. Clinical assessment consisted of global ratings for rigidity and/or hypokinesia and for drug-induced hyperkinesia. Measures of gait and fine-motor control were also made. The motor readiness potential and auditory evoked potentials were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

High incidence of cardiopulmonary complications associated with implantation of adrenal medullary tissue into the caudate nucleus in patients with advanced neurologic disease

The purpose of our study was to examine the cardiopulmonary complications of a group of patients who had undergone implantation of adrenal medullary tissue into the caudate nucleus for treatment of neurologic disease. Prospective study with partially matched historical controls. Tertiary care community medical center. Seven patients with advanced Parkinson's disease and three patients with progressive supranuclear palsy underwent implantation of adrenal medullary tissue into the caudate nucleus. These patients were compared with respect to their cardiopulmonary complications with a control group who had undergone craniotomy and then compared with a control group who had undergone only abdominal surgery. In the study group, six patients developed major postoperative complications including development of large pleural effusions, lobar atelectasis, pneumonia, upper airway obstruction, and cardiac arrest. Three patients had minor complications including development of small pleural effusions, subsegmental atelectasis, purulent bronchitis, mild congestive heart failure, and atrial flutter/fibrillation. One patient had an unremarkable postoperative course. The first control group, whose only surgery was a craniotomy, had only one major complication. The second control group, the abdominal surgery control group, had one major and five minor complications. The particular neurologic disease, its severity, and the type of surgery performed appear to be causative factors in the high incidence of complications in the study group.

Differential Subcellular Distribution of p36 (the Heavy Chain of Calpactin I) and Other Annexins in the Adrenal Medulla

The annexins are a group of highly related Ca2(+)-dependent membrane-binding proteins that are present in a wide variety of cells and tissues. We have examined the subcellular distribution of five members of the annexin family in the adrenal medulla. Bovine adrenal medullary tissue was homogenized in buffers containing EGTA and fractionated on sucrose gradients. p36 (the large subunit of calpactin I) was found to be predominantly membrane associated, with approximately 20% present in fractions enriched in chromaffin granules. In contrast, lipocortin I was localized primarily to the cytosol, with only a small proportion found in plasma membrane-containing fractions. Like lipocortin I, endonexin I was found to be present almost entirely in the soluble fractions. The 67-kDa calelectrin was localized primarily to the plasma membrane fractions, with a small amount present in the chromaffin granule and cytoplasmic fractions. Synexin was present in both membranous and cytoplasmic fractions. p36 appeared to be a peripherally associated granule membrane protein in that it was dissociated from the membrane by addition of base and it partitioned with the aqueous phase when granule membranes were treated with Triton X-114. Antiserum against p10 (the small subunit of calpactin I) reacted with a protein of 19 kDa that is specifically localized in chromaffin granule membrane fractions. The differences in subcellular distributions of the annexins suggest that these proteins have distinct cellular functions. The finding that p36 is associated with chromaffin granule and plasma membrane fractions provides further support for a possible role of calpactin in exocytosis.

Characterization of muscarinic receptors of bovine adrenal chromaffin cells: Binding, secretion and anti-microtubule drug effects

1. Binding of [ 3H]QNB to adrenal membranes is saturable, specific and to a single class of receptors. 2. Tubulozole, and not other microtubule drugs, inhibits [ 3H]QNB binding. 3. Pretreating cultured chromaffin cells with oxotremorine, a muscarinic receptor agonist, has no effect on either basal, nicotine (10 μM) or K +-stimulated catecholamine release and failed to enhance secretion of submaximal concentrations of nicotine (3–5 μM). 4. These results confirm that binding of [ 3H]QNB is associated with muscarinic receptors on bovine adrenal medullary tissue. 5. These studies also demonstrate that although bovine adrenal chromaffin cells possess muscarinic receptors, these receptors do not appear to be coupled to secretory processes.

Monoaminergic neural transplants prevent learned helplessness in a rat depression model

Current theories of the etiology of depression implicate disturbances and imbalances in the junction of monoaminergic systems, particularly involving serotonin and norepinephrine. Neural transplantation is a potential approach towards restoring balanced functioning in the central nervous system. The purpose of the present study was to determine the utility of transplanting monoamine-producing cells into the brain to alleviate behavioral depression. Serotonin-containing pineal gland tissue, catecholamine-containing adrenal medullary tissue, a combination of both, and a control of striated muscle tissue were implanted into the frontal neocortex of adult rats. The ability of these grafts to prevent the development of learned helplessness, a widely accepted model for depression, was assessed 6–8 weeks following transplantation. The monoamine-containing transplants, but not the control transplants, were able to prevent the development of learned helplessness. Immunocytochemical and ultrastructural studies revealed that the grafted monoaminergic tissues survived and continued to produce high levels of monoamines. These results suggest that neural transplants may provide a long-term local source of monoamines as a potentially new approach for alleviating some forms of depression.

Carcinoid tumours of the appendix are different

The Journal of PathologyVolume 162, Issue 3 p. 189-190 EditorialFree Access Carcinoid tumours of the appendix are different Paul A. V. Shaw, Paul A. V. Shaw Department of Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.Search for more papers by this author Paul A. V. Shaw, Paul A. V. Shaw Department of Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.Search for more papers by this author First published: November 1990 https://doi.org/10.1002/path.1711620303Citations: 19AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Sjolund K, Sanden G, Hakanson R, Sundler R. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 1983; 85: 1120– 1130. 2 Godwin JD. Carcinoid tumors. An analysis of 2837 cases. Cancer 1975; 36: 560– 569. 3 Moertel CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumors of the appendix: treatment and proghosis. N Engl J Med 1987; 317: 1699– 1701. 4 Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12 year period. Acta Pathol Microbiol Scand Sect A 1976; 84: 322– 330. 5 Chejfec G., Falkmer S, Askensten U, Grimelius L, Gould VE. Neuroendocrine tumours of the gastrointestinal tract. Pathol Res Pract 1988; 183: 143– 154. 6 Lundqvist M, Wilander E. Subepithelial neuroendocrine cells and carcinoid tumours of the human small intestine and appendix. A comparative immunohistochemical study with regard to serotonin, neuron specific enolase and S100 protein reactivity. J Pathol 1986; 148: 141– 147. 7 Aubock L, Hofler H. Extraepithelial intraneural endocrine cells as starting points for gastrointestinal carcinoids. Virchows Arch A [Pathol Anat] 1983; 401: 17– 33. 8 Rode J, Dhillon AP, Papadaki L, Griffiths D. Neurosecretory cells of the lamina propria of the appendix and their possible relationship to carcinoids. Histopathology 1982; 6: 69– 79. 9 Kinsey WL, Shaw PAV. On the histogenesis of carcinoid tumours: evidence from the distribution of neuroendocrine cells in the normal appendix. J Pathol 1990; 161: 356A. 10 Lundqvist M,. Wilander E. A study of the histopathogenesis of carcinoid tumors of the small intestine and appendix. Cancer 1987; 60: 201– 206. 11 Cross SS, Hughes AD, Williams GT, Williams ED. Endocrine cell hyperplasia and appendiceal carcinoids. J Pathol 1988; 156: 325– 329. 12 Stanley MW, Cherwitz D, Hagen K, Snover DC. Neuromas of the appendix. A light microscopic, immunohistochemical and electron microscopic study of 20 cases. Am J Surg Pathol 1986; 10: 801– 815. 13 Lewin KJ, Ulich T, Yang K, Layfield L. The endocrine cells of the GI tract and their tumors. Part II. In: SC Sommers, PR Rosen, RE Fechner, eds. Pathology Annual, Volume 21, Part 2. Norwalk, CT: Appleton-Century-Crofts, 1986; 181– 215. 14 Lloyd RV, Blaivas M, Wilson BS. Distribution of chromogranin and S100 protein in normal and abnormal adrenal medullary tissues. Arch Pathol Lab Med 1985; 109: 633– 635. Citing Literature Volume162, Issue3November 1990Pages 189-190 ReferencesRelatedInformation

Host-graft relationships of isolated bovine chromaffin cells in rat periaqueductal grey

The transplantation of chromaffin cells from the adrenal medulla into pain modulatory regions of the CNS has previously been shown to reduce pain sensitivity, most likely via local release of neuroactive substances from the transplanted cells. The ready availability of bovine adrenal glands, as well as the high levels of opioid peptides produced by their chromaffin cells, make these glands a potentially valuable donor source for antinociception studies. However, the success of these xenografts depends on their ability to survive and integrate within the host CNS. The aim of the present study was to assess host-graft relationships of bovine chromaffin cells transplanted to the rat CNS. We have found that isolated bovine chromaffin cells survive for at least three months in the rat periaqueductal grey, with no evidence of immunological response following a short-term course of immunosuppressant treatment. In the early stages following transplantation, only minor pathology is found at the injection site, which apparently recovers completely at later stages. The host-graft borders are not well demarcated, in contrast to solid tissue grafts. Neuronal processes of host origin, forming numerous synapses with the transplanted bovine chromaffin cells, are apparent by three weeks following transplantation. Migration also occurs from the graft into the host parenchyma, as evidenced by individual chromaffin cells found near host parenchymal blood vessels. The clusters of chromaffin cells found in the graft itself are generally not very vascular, in contrast to solid tissue grafts. The chromaffin cell clusters are surrounded by blood vessels of the non-fenestrated CNS type at the host-graft border. It is likely that the small size of the graft does not require extensive angiogenesis. The lack of fenestrated peripheral-type endothelial capillaries, normally seen in adrenal medullary tissue grafts, may contribute to the survival of these xenografts in the rat brain.

Viability of adrenal chromaffin cells in the superior cervical ganglion of young adult and aged rats

Adrenal medullary tissue was autotransplanted to the superior cervical ganglion (SCG) of aged (26 months old) and young adult (3 months old) rats. Four and 20 weeks after operation, the viability of the transplants was evaluated using the formaldehyde-induced fluorescence (FIF) technique and tyrosine hydroxylase (TH) immunocytochemistry. Four weeks postgrafting, the transplant consisted of a densely-packed group of intensively fluorescent chromaffin cells in both age groups. The cells showed strong TH immunoreactivity and some of them were elongated, but only a few displayed short processes. At 20 weeks, most of the cells were spindle shaped and sent out fluorescent processes and a few of them were transformed toward ganglion-like cells. The results suggest that both young and old adrenal chromaffin cells are able to survive, produce neuronal processes and transform toward a neuronal phenotype in the rat superior cervical ganglion.

Therapy of Parkinson's Disease

Part 1 History of Parkinson's disease: the history of the medical therapy of Parkinson's disease. Part 2 Assessment, symptoms and sign, and basis of therapy: clinical rating scales and videotape analysis quantitative techniques of assessing motor disability therapies to extend duration of levodopa action magnetic resonance imaging and PET investigations of Parkinson's disease. Part 3 Pharmacologic agents: anticholinergic drugs in the treatment of Parkinson's disease amantadine in Parkinson's disease biochemical basis for levodopa therapy levodopa-based therapy levodopa infusion therapy long-acting levodopa preparations intracerebroventricular infusion of dopaminergic drugs dopamine agonists in Parkinson's disease the influence of bromocriptine on levodopa lisuride - a direct dopamine agonist in the treatment of Parkinson's disease pergolide. Part 4 Surgical approaches: stereotactic thalamotomies the effects of unilateral ventral-posterior medical pallidotoing in patients with Parkinson's disease and Parkinson's plus syndromes chronic high frequency thalamic stimulation in Parkinson's disease scientific basis for dopaminergic brain grafting transplantation of adrenal medullary tissue to brain in Parkinson's disease neurotransplantation. Part 5 Diet in therapy: dietary issues in the treatment of Parkinsonism management of late Parkinson's disease with L-Dopa - role of dietary protein redistribution. Part 6 Other therapeutic approaches: nondopaminergic therapy in Parkinson's disease treatment of autonomic nervous system disturbances in Parkinson's disease management of behavioral symptoms in Parkinson's disease treatment of depression in Parkinson's disease management of psychosis in Parkinson's disease electroconvulsive therapy in Parkinson's disease. (Part Contents).

Adrenal medullary implants in the rat spinal cord reduce nociception in a chronic pain model

Previous work in this laboratory has indicated that the transplantation of adrenal medullary tissue into the subarachnoid space of the rat spinal cord can reduce pain sensitivity to acute noxious stimuli, particularly following stimulation by nicotine. This most likely results from the stimulated release of opioid peptides and catecholamines from the transplanted chromaffin cells. However, chronic pain models may more closely resemble human clinical pain, and the arthritic rat model has been used for screening potential therapeutic strategies. The purpose of the present study was to assess the potential for adrenal medullary tissue implanted into the spinal subarachnoid space to alleviate chronic pain. Adrenal medullary tissue was implanted into adjuvant-in-duced arthritic rats, and changes in body weight and vocalization responses were monitored over the 10 week course of the disease. Results indicate that the severe weight reduction normally associated with this inflammatory arthritis was attenuated by adrenal medullary, but not control, implants. In addition, vocalizations were reduced in animals implanted with adrenal medullary, but not control tissue following nicotine stimulation. This reduction was blocked by the opiate antagonist, naloxone, and partially attenuated by the alpha-adrenergic antagonist, phentolamine. Together, these results suggest that the transplantation of adrenal medullary tissue into the subarachnoid space of the spinal cord may provide a local source of opioid peptides and catecholamines for the reduction of chronic pain.

Prolonged analgesia by enkephalinase inhibition in rats with spinal cord adrenal medullary transplants

Transplants of adrenal medullary tissue or isolated chromaffin cells into the spinal cord subarachnoid space has been shown to reduce pain sensitivity in rats. This analgesia probably results from the release of neuroactive substances, particularly opioid peptides, from the transplanted cells since it is induced by nicotinic stimulation of chromaffin cell receptors, and can be blocked by naloxone. However, this analgesia is short-lived, most likely due to the rapid hydrolysis of opioid peptides. The purpose of this study was to determine whether protection of opioid peptide hydrolysis by the potent enkephalinase inhibitor kelatorphan could prolong this analgesia. Results indicated that the intrathecal injection of kelatorphan in animals with either adrenal medullary or chromaffin cell implants significantly prolonged nicotine-stimulated analgesia. Pretreatment with naloxone completely eliminated this analgesia. These results suggest that it may be possible to induce long-term reductions in pain sensitivity using enkephalinase inhibitors following the transplantation of opioid peptide-producing cells into the CNS.

Adrenal Medullary Transplantation Into the Brain for Treatment of Parkinson's Disease: Clinical Outcome and Neurochemical Studies

Transplantation of adrenal medulla into the caudate nucleus as treatment for Parkinson's disease was performed in eight patients. Although our previous 6-month follow-up revealed early modest improvement, an extension of that follow-up to 1 year disclosed no additional gains in any patient. At the end of 1 year, only one patient could be categorized as moderately improved; three patients were mildly improved, and four patients were unimproved. The rationale for transplanting adrenal medulla was to reestablish a physiologic source of dopamine to the striatum. We measured cerebrospinal fluid (CSF) and plasma catecholamines and metabolites before and after transplantation. Conjugated dopamine (the predominant form of dopamine found in the CSF) and homovanillic acid (the major dopamine metabolite) were modestly and inconsistently increased in the CSF. Conjugated and free epinephrine and norepinephrine, as well as 3-methoxy-4-hydroxyphenylglycol concentrations were not increased in CSF after graft placement, an indication that the adrenal chromaffin cells were no longer producing high levels of these nondopamine catecholamines and metabolites. CSF cortisol concentrations were not increased after transplantation, compared with values from controls, consistent with low numbers of functioning adrenal cortical cells contaminating the graft (or poor survival). Posttransplantation CSF did not induce a neurotrophic effect in cell cultures of 15-day embryonic rat dorsal root ganglion or PC12 (rat pheochromocytoma) cell lines. Survival of samples of patients' adrenal medullary tissue for 2 weeks in tissue culture attested to the viability of the graft at the time of transplantation. The relative concentrations of dopamine to epinephrine or norepinephrine increased in these cultured adrenal medullary cells, presumably because of loss of the glucocorticoid influence on catecholamine synthesis. A wide variety of factors could have contributed to our failure to replicate the earlier impressive results of adrenal-to-brain transplantation reported by others. Continued transplantation studies in animal models of parkinsonism are necessary for better elucidation of these factors.

Grafts and Growth Factors in CNS

In 1979, we presented the first evidence that grafts of fetal brain tissue to the adult central nervous system could counteract an experimentally induced neurological deficit. Using the unilaterally dopamine-denervated rat model of Parkinson's disease, it was first shown that fetal substantia nigra grafts were effective and, later, that adult adrenal medullary chromaffin tissue might be used as a possible substitute for fetal brain tissue. These observations led to the first clinical trials with chromaffin autografting in severe cases of Parkinson's disease, which were initiated at the Karolinska Hospital in 1982, and several years later to clinical trials with grafts of fetal dopamine neuroblasts obtained after early elective abortions. In parallel with the ongoing intense basic research aimed at optimizing grafting procedures and finding new possible clinical applications, there are now worldwide clinical trials of grafting procedures involving a large number of neurosurgical centers and a large number of patients. Here, I shall review our recent studies of grafts and growth factors as they relate to possible new therapeutic principles applicable not only to Parkinson's disease, but also to Alzheimer's senile dementia and possibly to spinal cord injury and other afflictions. Recent evidence suggests that cholinergic neurons in the brain, known to degenerate in Alzheimer's disease, depend on nerve growth factor. In one approach we have grafted genetically modified cell lines, designed to secrete large amounts of nerve growth factor, and demonstrated that they can rescue lesioned cholinergic neurons that would otherwise die. Nerve growth factor can also serve to enhance survival of, and promote fiber formation by, chromaffin grafts in experimental parkinsonism. Interestingly, a series of other growth factors, such as IGF-1, bFGF, aFGF, BDNF, TGF's, as well as their receptors, are now being cloned and in several cases shown to have interesting temporal and regional distributions as well as effects in the central nervous system. Our own studies using intraocular grafts suggest potent effects on fetal brain tissue growth of truncated IGF-1, bFGF, and aFGF. It thus appears as if neurosurgery is on the verge of entering a new era in which repair in the adult brain and spinal cord, once thought impossible in mammals, will become possible using growth factors and grafts.

Adrenal to caudate transplantation—postmortem study

A patient with Parkinson's disease who had undergone bilateral adrenal to caudate implantation by stereotactic technique came to autopsy. The implantation was shown to have produced minimal trauma and to have been well placed. Minimal surviving adrenal medullary tissue remained in the implanted coil, and no outgrowth of tissue into the striatum occurred.

The Relationship of Negative Schizophrenia to Parkinsonism

The positive-negative distinction of schizophrenia has emerged as a valid means of clarifying its heterogeneity. Despite evidence that the two symptom classes may reflect different dimensions of the disease, there is presently no integrated model for understanding of the pathophysiology of these symptoms and their co-occurrence in schizophrenia. We propose that negative phenomena of schizophrenia may be a variant of Parkinsonism. This view is supported by the overlap with Parkinsonism in terms of clinical features, neurochemistry, pharmacology, as well as neuroradiological and neuropathological aspects. As such, negative symptoms may be a manifestation of disease of the basal ganglia and constitute the core pathology in schizophrenia. Positive symptoms, conversely, may reflect an "accessory" process related to a compensatory increase in striatal and limbic dopamine activity following an injury to the dopaminergic system. In the present communication we present a series of studies that support the association of negative schizophrenia and Parkinsonism. Based on this evidence, we suggest that schizophrenic patients with prominent negative symptoms might be managed like patients with Parkinson's disease, namely, with dopaminergic drugs and MAO-B inhibitors. Finally, the association of negative schizophrenia with Parkinsonism raises the possibility that adrenal medullary tissue transplantation, which may benefit a selected group of Parkinsonian patients, may be a future promising therapy for refractory negative schizophrenia.

Multiloci Stereotactic Transplantation of Autologous Adrenal Medullary Tissue to the Putamen and Caudatum in Parkinson's Disease

Adrenal to striatum transplants may be effective, but many technical issues are still debated. A procedure whereby a number of grafts were stereotactically placed at the putamen and caudatum is reported. It enables grafting deep nuclei, such as the putamen, the most denervated structure in Parkinson's disease, and allows a widespread spatial distribution of multiple grafts within these huge targets, conceivably enhancing the local release of neurotransmitters at the site or in the vicinity of the denervated receptors. It also enables the use of a sizeable volume of tissue, presumably a crucial but as yet unknown factor. Although preliminary, the present data seem to warrant further clinical trials.