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Introduction: In 2019, we published the results of a Phase IIb randomized controlled trial of putaminal encapsulated porcine choroid plexus cell (termed NTCELL®) administration in patients with Parkinson's disease. This study failed to meet its primary efficacy end-point of a change in UPDRS part III score in the 'off' state at 26-weeks post-implant. However, a number of secondary end-points reached statistical significance. We questioned whether with longer follow-up, clinically significant improvements would be observed. For this reason, we decided to follow-up all patients periodically to week 104. Herein, we report the results of this long-term follow-up., Methods: All 18 patients included in the original study were periodically re-assessed at weeks 52, 78 and 104 post-implant. At each time-point, motor and non-motor function, quality of life and levodopa equivalent daily dose was assessed using a standardized testing battery., Results: At week 104, no significant differences in UPDRS part III scores in the 'off' state were observed in any of the treatment groups compared to baseline. Only a single serious adverse event - hospitalisation due to Parkinson's disease rigidity not responding to changes in medications - was considered potentially related to the implant procedure. There was no evidence of xenogeneic viral transmission., Conclusion: Un-blinded, long-duration follow-up to week 104 post-implantation showed no evidence that putaminal NTCELL® administration produces significant clinical benefit in patients with moderately advanced Parkinson's disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Individuals with Parkinson's disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson's disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.

Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy., (© 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The aim of stem cell therapy for Parkinson's disease (PD) is to reconstruct local synapse formation and/or induce the release of dopamine and cytokines from grafted cells in the putamen. Fetal ventral-midbrain cells are reported to relieve the neurological symptoms of PD patients. However, not only embryonic stem cells (ESCs), but also induced pluripotent stem cells (iPSCs) are expected to provide an alternative donor cell population because of their capacity for self-renewal and pluripotency. A protocol to generate dopaminergic (DA) neurons from ESCs and iPSCs has been developed, and human ESCs were proven to function in the brain of rat and monkey PD models. The next step will be the isolation of DA neurons as a donor cell population for a safe and efficient transplantation.

Background: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial., Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression., Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort., Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Background: Attempts at cell-based dopamine replacement therapy in Parkinson disease (PD) have included surgical implantation of adrenal medullary, fetal mesencephalic, and cultured human mesencephalic tissue grafts. Trials involving putamenal implantation of human retinal pigment epithelial (RPE) cells in PD have also been performed. Neuropathologic findings in humans undergoing RPE cell implantation have not heretofore been reported. We describe the brain autopsy findings from a subject enrolled in a clinical trial of RPE cells in gelatin microcarriers for treatment of PD, and suggest factors which may have impacted cell survival., Methods: A 68-year-old man underwent bilateral surgical implantation of 325,000 RPE cells in gelatin microcarriers (Spheramine) but died 6 months after surgery. The left cerebral hemisphere was examined. Routine postmortem formalin fixation was performed and standard, as well as immunohistochemical methods used to highlight senile plaque and Lewy body pathologic changes, iron deposition, cellular inflammation, and reactive astrocytosis in implant regions. Manual cell counts were done of RPE cells., Results: Hematoxylin-eosin and alpha-synuclein immunostains confirmed the diagnosis of PD. Needle tracts with matrix material and RPE cells were observed in the context of local inflammatory and astrocytic reactive change. A total of 118 cells were counted (estimated 0.036% survival)., Conclusions: Retinal pigment epithelial cells are seen in human brain 6 months postimplantation, but overall survival of implanted cells appeared poor.

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA-specific functions, we used multiple [(11)C]-labeled positron emission tomography (PET) tracers, including [beta-(11)C]L-3,4-dihydroxyphenylalanine (L-[beta-(11)C]DOPA, DA precursor ligand), [(11)C]-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(11)C]beta-CFT, DA transporter ligand) and [(11)C]raclopride (D(2) receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L-[beta-(11)C]DOPA (M-1:41%, M-2:61%) and [(11)C]beta-CFT (M-1:31%, M-2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M-2 induced reduced [(11)C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell-based therapies against PD.

Background: Human retinal pigment epithelial (RPE) cells produce levodopa and can be isolated from postmortem human eye tissue, grown in culture, and implanted into the brain attached to microcarriers. These implants ameliorated the motor deficits in rodent and nonhuman primate models of Parkinson disease., Objective: To evaluate the safety and efficacy of unilateral implantation of human RPE cells attached to gelatin microcarriers into the putamen contralateral to the more symptomatic side of patients with Parkinson disease., Design: Open-label pilot study., Setting: A tertiary referral center for movement disorders., Patients: Six patients with advanced Parkinson disease., Interventions: We performed stereotactic intrastriatal implantation of approximately 325,000 RPE cells on microcarriers., Main Outcome Measure: Change from baseline to 12 months in the Unified Parkinson's Disease Rating Scale motor subscore with the patients in the practically defined off state (not taking antiparkinsonian medications for at least 12 hours overnight)., Results: The implants were well tolerated. We observed an average improvement of 48% at 12 months after implantation in the Unified Parkinson's Disease Rating Scale motor subscore with the patient in the off state, which was sustained through 24 months. Improvement was also observed in activities of daily living, quality of life, and motor fluctuations. No off-state dyskinesias were observed., Conclusions: Implants of human RPE cells attached to gelatin microcarriers appear to be safe and well tolerated, and they improved motor symptoms in patients with Parkinson disease. On the basis of these results, a randomized, double-blind, placebo-controlled study has been initiated.

In this study, a modified infusion procedure and a novel infusion device designed for use in humans (Clinical Device B) were evaluated for delivery of recombinant adeno-associated virus (AAV2) to brain. The device is composed of 1.2 m of fused silica inserted through a 24.6-cm surgical steel cannula designed to fit a standard Leksell clinical stereotaxic frame and micro-infusion syringe pump. AAV2 encoding the human aromatic l-amino acid decarboxylase gene (AAV-hAADC-2) was infused into the putamen of 4 normal rhesus monkeys as a supportive study for a clinical trial in Parkinson's disease (PD) patients. Two infusion protocols were tested: a ramped procedure (slow stepwise increases in rate from 0.2 muL/min to 1 muL/min), thought to be essential for convection-enhanced delivery (CED), and a non-ramped infusion at a constant rate of 1 muL/min. The primary endpoints were safety evaluation of the infusion procedures and assessment of transgene expression at 5.5 weeks post-infusion. Clinical observations after vector infusions revealed no behavioral abnormalities during the study period. No differences in gross pathology with either the ramped or non-ramped infusion procedure were observed. Histopathology of the putamen was comparable with both procedures, and revealed only minimal localized inflammatory tissue reaction along the needle track in response to cannula placement and vector infusion. AADC immunohistochemistry demonstrated that vector was distributed throughout the putamen, with no significant difference in volume of immunostaining with either infusion procedure. Serum antibody levels against AAV2 vector exhibited a minor increase after infusion. These results validate the clinical utility of this new infusion device and non-ramped infusion conditions for intraputamenal gene therapy, and have the potential to impact a number of human diseases in which delivery of therapeutics to brain is indicated.

Fetal ventral mesencephalon (VM) transplantation has been reported to improve parkinsonian symptoms. Animal studies show that cografting of striatal tissue increases the survival of dopamine neurons. Whether or not VM and striatum cografting could ameliorate motor dysfunction in a Parkinson's disease (PD) patient was explored in this study. The patient was a 53-year-old male who had presented with symptoms of tremor, rigidity and bradykinesia for 11 years. He had been treated with L-dopa and had progressive deterioration of symptoms even with the daily dosage of L-dopa increased to 900 mg per day. Before transplantation, his PD symptoms were scored with Unified Parkinson's Disease Rating Scale (UPDRS) and video recordings. The influx constant (ki) of the [18F] 6-fluoro-L-dopa uptake in the striatum was measured by positron emission tomography (PET) imaging. The fetal VM and the lateral part of the lateral ganglionic eminence (LGE) were cografted into the right putamen and, one week later, fetal VM alone was transplanted into the left putamen. After the transplantation, the patient's UPDRS score improved from 128 to 62 at 6 months and to 24 at 22 months during the "off" phase. The score of daily living disability improved from 35 to 18 at 6 months and to 10 at 22 months post transplantation. Twenty-two months after grafting, "off" phases were almost absent, and the freezing had totally disappeared. The [18F] 6-fluoro-L-dopa PET studies were performed 1 month before and 21 months after transplantation. The ki for [18F] 6-fluoro-L-dopa was decreased by 15% in the right caudate and 5% in the left caudate, both of which did not have any ventral mesencephalic grafts. However, the ki was increased by 35%, in the left non-cografted putamen, and by 58% in the right cografted putamen. In conclusion, cografting the fetal VM and the LGE in the putamen may improve the motor function of PD patients.

Object: The aim of this study was to estimate the impact of stereotactic pallidal surgery on the binding potential of dopamine D2 receptors in patients with advanced Parkinson disease (PD)., Methods: Six patients with advanced PD (three men and three women; mean age 56.7 +/- 9.8 years, Hoehn and Yahr stage 3.3 +/- 1.1/3.9 +/- 1.2 [on/off scores], mean +/- standard deviation) underwent stereotactic pallidal surgery. One underwent right posteroventral pallidotomy (PVP), one received left PVP, three were treated with deep brain stimulation (DBS) of the left globus pallidus internus (GPi), and one with bilateral DBS of the GPi. The binding potential of the dopamine D2 receptors of these patients was determined before and after surgery by using positron emission tomography scanning with 11C-nemonapride and it was compared with the value in eight healthy volunteers. The authors also examined whether changes in the D2 receptor binding potential were correlated with the clinical outcome. The clinical symptoms, especially those in the off state, were significantly improved after surgery. Preoperatively, the D2 receptor binding potential in the putamen was elevated by 27% (p < 0.01) and that in the thalamus was 29% lower than that in controls (p < 0.01). The D2 receptor binding potential in the putamen and thalamus returned to control levels after surgery. The preoperative level of the D2 receptor binding potential in the anterior cingulate cortex was comparable to that of controls, but it declined significantly after surgery, whereas the D2 receptor binding potential in other regions of both hemispheres showed no significant changes after surgery. Although the D2 receptor binding potential did not correlate with the Hoehn and Yahr stage, the Schwab and England score, or the Unified PD Rating Scale (UPDRS) score, a positive correlation was seen between the percent improvement rate of the total UPDRS score in the off state and the percentage change of the D2 receptor binding potential in the putamen (r = 0.773, p = 0.0417 according to the Pearson linear correlation)., Conclusions: The altered dopamine D2 receptor binding potential in the putamen might play a crucial role in clinical improvement after PVP or DBS of the GPi in advanced PD.

The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson's Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

Object: There is growing evidence to indicate that tissue transplantation can potentially be a restorative neurosurgical treatment for patients with Parkinson disease (PD). In this study the authors investigated the clinical effect of unilateral intrastriatal grafting of autologous sympathetic neurons in patients with PD., Methods: Four patients with PD who had been observed for 1 year after graft placement of autologous sympathetic neurons were selected for an analysis of the effect of that procedure. Sympathetic ganglion tissue was endoscopically excised from the thoracic sympathetic trunk and grafted into the unilateral caudate head and putamen of the PD patients. No changes were made in the patients' preoperative regimens of antiparkinsonian medications, and clinical evaluations were made principally according to those established by the Core Assessment Program for Intracerebral Transplantation Committee. Whereas the sympathetic neuron grafts failed to affect clinical scores reflecting the patients' motor performance, which was evaluated during either the "on" or "off' phases, the grafts significantly increased the duration of the levodopa-induced on period with consequent reduction in the percentage of time spent in the off phase. This beneficial effect may be explained by the results of the present in vitro experiment, which show that human sympathetic neurons have the ability to convert exogenous levodopa to dopamine and to store this synthesized dopamine., Conclusions: Sympathetic neuron autografts were found to improve performance status in patients with PD by reducing the time spent in the off phase. This clearly indicates that sympathetic ganglion tissue, the use of which involves few ethical issues, can be an efficacious donor source in cell transplantation therapy for PD. Further studies are needed to determine whether the grafts may provide long-lasting clinical benefits.

Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

Clinical studies report symptomatic benefit in most fetal neurotransplantation treated Parkinson's disease patients. The underlying mechanism is incompletely explained. We investigated whether neural connections between host and transplanted tissue are established. Two Parkinson's disease patients with clinically excellent outcome after transplantation were studied with functional magnetic resonance imaging. A repetitive motor task that provided robust stimulation in the contralateral putamen in volunteers activated graft bearing regions of putamen in patients. In response to contralateral motor tasks, activation was recorded consistently in left putamen in patient 1 and in right putamen in patient 2. Functional magnetic resonance imaging suggests that neuronal rewiring contributes to the functioning of neurotransplants in vivo in humans.

Five parkinsonian patients who had received implants of human embryonic mesencephalic tissue unilaterally in the striatum 10-56 months earlier were grafted with tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18-24 months. After 12-18 months, PET showed a mean 85% increase in 6-L-[18F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: 'on-off' fluctuations virtually disappeared, movement speed increased, and L-dopa could be withdrawn in one patient and reduced by 70% in the other. The improvement in one patient was moderate. Two patients with atypical features, who responded poorly to the first graft, worsened following the second transplantation. These findings indicate that sequential transplantation in patients does not compromise the survival and function of either the first or the second graft. Moreover, putamen grafts that restore fluorodopa uptake to normal levels can give improvements of major therapeutic value.

Six patients with advanced Parkinson's disease have been grafted with human fetal neuronal cells. This clinical work is based on the technique originally described by the groups of Lund, Sweden and Créteil, France, with which we closely collaborate. A first group of 3 patients was grafted between 1995 and 1996, with neuronal tissue obtained from same-day abortions. We have observed bilateral improvement of motor functions after unilateral transplantation into the putamen. One patient had a second graft, into the heterolateral putamen, one year after the first one. Another group of 3 patients was operated between 1997 and 1998, and received grafts of hibernated tissue, in order to facilitate the technical organization of the transplantation procedure. Altogether, these clinical results are encouraging, but the technical and ethical limitations related with the use of human fetal tissue prompted us to develop alternative solutions, such as the use of xenografts and the transplantation of genetically modified cells.

Object: In recent years, fetal mesencephalic tissue transplant for the treatment of Parkinson's disease (PD) has been demonstrated to hold promise, but potential complications related to growth of allograft tissue have not been well described. This report explores the development and possible causation of a fatal cyst arising from a fetal transplant in the brain., Methods: The authors report the case of a 52-year-old woman who underwent bilateral putamenal fetal mesencephalic allograft transplant for PD at another hospital. Twenty-three months later she presented to the authors' institution in a coma. Admission computerized tomography and magnetic resonance (MR) studies revealed a contrast-enhancing mural nodule and associated large cyst arising from the left putamen and causing brainstem compression. Despite surgical decompression of the cyst, the patient did not regain consciousness. Biopsy and autopsy specimens were obtained, along with an analysis of the cyst fluid. Genotyping of the nodule and the patient's peripheral lymphocytes by using polymerase chain reaction-based microsatellite analysis was also performed. Biopsy samples and autopsy histopathological studies showed inflammatory cells, hemosiderin-laden macrophages, and astrocytosis. Scattered neurons and multiple rests of choroid plexus were also noted. The cyst had a thin wall and contained liquid that was identical in composition to cerebrospinal fluid (CSF). Genotyping demonstrated the presence of alleles in the nodule DNA that were not present in lymphocytic DNA, indicating that the nodule contained allograft tissue., Conclusions: The authors hypothesize that the choroid plexus tissue contained in the allograft resulted in CSF production and cyst formation at the transplant site, ultimately leading to the patient's herniation syndrome. The clinical history and large size of the mural nodule indicate slow growth of this allograft site and cyst over time. This case demonstrates that unusual patterns of tissue growth can occur in the brain after fetal tissue transplant and emphasizes the need for long-term monitoring of posttransplant patients by means of MR imaging. Cell sorting should be considered to ensure transplant of pure neuronal and astroglial populations.

Studies in nonhuman primates with experimental parkinsonism have shown that intrastriatal cografts of autologous adrenal medulla and peripheral nerve yield greater behavioral improvement and graft survival than do adrenal medulla grafts alone. To test these observations, five patients with advanced Parkinson's disease were selected to receive unilateral intrastriatal adrenal medulla-intercostal nerve cografts. They were evaluated using the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol. Three of these patients also underwent quantitative motor testing for the measurement of upper limb bradykinesia (movement time; MT). Following right flank adrenalectomy, cografts consisting of small fragments of adrenal medullary tissue and minced intercostal nerve were stereotaxically implanted into three targets in the right striatum using computerized tomography guidance. Surgery was uneventful and postoperative magnetic resonance imaging revealed accurate placement of the grafts. No morbidity was encountered. Results of 24 months of clinical and quantitative motor assessments postoperatively are reported. Total UPDRS motor scores in the "off" state improved from a mean preoperative score of 39.5 to 32.1 at 3, 29.7 at 6, 27.6 at 9, 28.5 at 12, 31.4 at 18, and 26.5 at 24 months after surgery. Total timed motor test scores during the "off" state improved 17.9% at 6, 23.3% at 9, 18.2% at 12, 38.2% at 18, and 34.9% at 24 months postoperatively compared to baseline. Movement time showed statistically significant improvement (repeated measures ANOVA, P < 0.05) in the left arm (contralateral to surgery) in all three patients tested. These results indicate that stereotaxic intrastriatal implantation of autologous adrenal medulla-peripheral nerve cografts can be performed safely and clinical improvement from this procedure is sustained for a period of 24 months. The clinical improvement was paralleled by improvement in objective, quantitative motor testing.

Transplantation of autologous sympathetic ganglion was performed in 35 patients with Parkinson's disease. Approximately half the patients showed improvement of parkinsonian symptoms over the 3 years following transplantation. The patients showed amelioration of bradykinesia and gait disturbance, but tremor and muscle rigidity were not improved by transplantation. The other half of the patients did not show amelioration after transplantation. No serious complications were encountered, though mild ptosis was observed in all patients. The mechanism of improvement of symptoms might be the release of dopamine from the grafted sympathetic ganglion. Transplantation of autologous sympathetic ganglion can be a therapeutic modality for Parkinson's disease.

Fundamental pathological and neurochemical changes in Parkinson's disease are loss of midbrain dopamine neurons that innervate the caudate and putamen. In an effort to replenish the striatal dopaminergic innervation, fetal mesencephalic tissue containing dopamine cells was implanted into the unilateral putamen in two patients with severe Parkinson's disease. The tissue was obtained from three fetuses with gestational ages of 7 to 9 weeks. The cell suspension was stereotactically injected into the unilateral putamen using 5 needle trajectories. Postoperative immune suppression was not performed. Clinical improvement appeared after 2 months. Both patients showed improvement according to the Activities of Daily Living Scale during the off and practically-defined off state 9 and 14 months after surgery. The motor scores of the Unified Parkinson's Disease Rating Scale improved during the off and practically-defined off state 9 and 14 months after surgery. Dyskinesia and off state were shorter and less severe than before the transplantation. Although the long-term effects need to be ascertained, our short-term observation in these two patients with unilateral transplantation is encouraging and justifies further research trials in selected patients.

The first results on functional effects induced by embryonic nigral grafts in the rat model of Parkinson's disease (PD) were reported in the late 70 s. It took another 10 years before the first publications on PD patients demonstrated clinical and neuroradiological signs of improvement after the transplantation of allogeneic embryonic nigral grafts. Technical details as well as clinical results varied considerably in the first clinical studies. In the last years crucial questions have been identified, also because of increasing international cooperation, which represent a challenge jointly to basic and clinical scientists. The clarification of those questions related to scientific and ethical issues will determine which impact the transplantation of embryonic nigral dopamine neurons will have as a potential therapy for PD in clinical medicine.

Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine-rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6-L-[18F]-fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the "off" phase, and by a prolongation of the effect of a single dose of L-dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L-dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non-grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.

Patients with idiopathic Parkinson's disease who had become refractory to medical treatment underwent unilateral stereotactic transplantation of mesencephalic tissue obtained from 7- to 9-week-old postconception fetuses. Small pieces of tissue, less than 1 mm, were deposited in 9 sites in the putamen and 3 in the caudate. Patients were 4 men and 3 women and aged from 42 to 59 years (mean 50). Symptom durations were from 9 to 21 years (mean 14). The examinations were done at 3- to 4-month intervals pre- and postoperatively. Patients were examined for a minimum of 1 year postoperatively. The examinations consisted of neurological and general physical examinations, UCLA Parkinson's Disability Scale, Hoehn and Yahr rating and United Parkinson's Disease Rating Scale (PDRS), all in both 'on' and 'off' states. Video recordings and timed tests of a number of motor tests were performed. Patients also completed 7 consecutive days of hourly self-assessments prior to each visit. Fluorodopa PET scans were obtained pre- and 6 and 15 months postoperatively. The operations took place from mid-July 1992 to January 1993. Postoperative states have been free of complications. All have been on immunosuppressants. Levodopa was transiently decreased in the postoperative period, but raised to approximately the preoperative level thereafter. In late March 1993, 3 patients appeared to show modest improvement in the UCLA and UPDRS scales and in the patients' self-assessments.

The paper reports the results of adrenal medulla autotransplantations into the brain of parkinsonian patients performed up to now in many neurosurgical centers in the world. Different surgical techniques and methods of tissue preparation for transplantation are also reviewed. Core Assessment Program for Intracerebral Transplantation (CAPIT) is presented. This program was developed as an unified system for patients' diagnosis and evaluation of clinical signs and symptoms before and after transplantation. It enables direct comparison of the results obtained in different centers. Surgical risk depending on the method of operation is discussed. The mechanisms involved in functioning of adrenal medulla grafts are considered as well as the trials to improve graft survival and its activity in the host brain. The results of neuropathological studies from autopsy cases are also reported. The analysis of about 400 published cases shows moderate or marked clinical improvement due to adrenal medulla autotransplantation which was observed until 20 months postoperatively. The results indicate that the progress of Parkinson's disease becomes slower and the clinical symptoms are less severe. L-dopa doses might be decreased which is followed by the reduction of its side effects. The opinions from different neurosurgical centers evaluating adrenal medulla autografts vary depending on the results noticed after those neurotransplantations.

We report our preliminary results related to CT-guided stereotactic transplantation of foetal ventral mesencephalic cell suspension into the striatum of five patients with idiopathic Parkinson's disease. The mean age was 51 years, the evolution time of the disease ranged from 7 to 14 years, and all of them had motor complications associated with chronic L-dopa therapy. The patients were evaluated according to the Core Assessment Program for Intracerebral Transplantations (CAPIT) for one year before and three months after surgery. The postoperative clinical assessment demonstrated significant improvement of neurological symptoms and reduction of daily L-dopa dosage.

Background and Methods: Patients with Parkinson's disease tend to have a reduced response to levodopa after 5 to 20 years of therapy, with "on-off" fluctuations consisting of dyskinesia alternating with immobility. In an effort to modify the motor disability of advanced Parkinson's disease, we implanted embryonic mesencephalic tissue containing dopamine cells into the caudate and putamen of seven patients. Two patients received unilateral grafts in the caudate and the putamen on the side opposite the side with worse symptoms. Five patients received bilateral grafts implanted in the putamen only. In six of the seven patients, the fetal tissue was obtained from a single embryo with a gestational age of seven to eight weeks. The tissue was injected by means of 10 to 14 needle passes. There were no surgical complications. Four of the seven patients underwent immunosuppression with cyclosporine and prednisone., Results: All patients reported improvement according to the Activities of Daily Living Scale when in the on state 3 to 12 months after surgery (P < 0.01). Neurologic examination according to the Unified Disease Rating Scale showed that five of the seven patients improved when in the on state six months after surgery. The mean group Hoehn-Yahr score improved from 3.71 to 2.50 (P < 0.01). Computer and videotape testing in the home supported these findings. Fluctuations in clinical state were moderated, and periods of dyskinesia and off episodes were shorter and less severe than before implantation. Drug doses were reduced by an average of 39 percent (P < 0.01; maximum, 58 percent). The results of clinical evaluation and fluorodopa positron-emission tomography in one patient were compatible with transplant survival for as long as 46 months. Both immunosuppressed and nonimmunosuppressed patients improved., Conclusions: Fetal-tissue implants appear to offer long-term clinical benefit to some patients with advanced Parkinson's disease.

Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and [18F]6-L-fluorodopa ([18F]dopa). The uptake of [18F]dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen [18F]dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, [18F]dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of [18F]dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of [18F]dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which, balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.

Ventral mesencephalic tissue from aborted human fetuses (age, 6-7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1-year follow-up period. Clinical improvement was observed as a reduction of the time spent in the "off" phase and the number of daily "off" periods; a lessening of bradykinesia and rigidity during the "off" phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L-dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine-rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.

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)

12 patients with advanced Parkinson's Disease who had right caudate implantations of late stage foetal mesencephalon have been followed up for 1 to 2 years with extensive clinical and physiological assessments. Three patients failed to comply and were excluded. Seven of the remaining 9 patients showed substantial initial improvement which was well maintained in 4. Two of the 3 remaining patients of this group maintained lesser improvement. One returned to pre-operative state. Two patients with greatly advanced disease had only slight but brief improvement. A series of 24 matched patients have been treated and continue under investigation.

Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.

Autograft of adrenal medullary tissue into the striatum was performed stereotactically in 5 patients with severe Parkinson's disease. Two patients had suffered from side effects of L-dopa, and 3 were severely disabled without L-dopa preoperatively. After surgery, the dosage of L-dopa could be reduced in 1, and L-dopa could be withdrawn in 4 patients. The results of adrenal medullary tissue transplantation in Parkinson's disease are analyzed.

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.

Central nervous system transplantation currently is being investigated in numerous centers throughout the world. The concept of restoring lost neurological function by grafting neuronal or neuronal-like tissue into the CNS has the potential for revolutionizing the treatment of numerous neurological disorders. Parkinson's disease is the subject of the majority of CNS transplantation studies although the first human studies were disappointing. However, further refinements of technique and patient selection, and animal research using a newly developed primate model of parkinsonism, led to promising results reported from several centers. Despite this, numerous fundamental issues have yet to be resolved: (1) age of patient? (2) degree of disability of patient? (3) use of fetal or adrenal tissue? (4) caudate or putamen placement? and (5) open or stereotactic surgery? This report reviews the clinically significant results of nonhuman primate research and clinical studies, and addresses these unresolved issues.

Autologous adrenal medullary tissue was transplanted unilaterally to the putamen in two patients with severe Parkinson's disease. The first patient exhibited a transient, two-day improvement of motor performance in the limbs contralateral to the implantation site. He also had significantly longer episodes of normal function for about two months. The second patient reported a minor improvement of balance and gait, again lasting for two months. Electrophysiological studies of the motor readiness and auditory evoked potentials were consistent with increased catecholaminergic activity in the basal ganglia after transplantation in both patients. Positron emission tomography showed no postoperative alteration of receptor density in the putamen. No significant adverse effects of the transplantation were observed in the patients' performance on neurological and psychological tests or in their quantitative electroencephalogram and cerebral blood flow recordings. Immediately after the grafting, one patient showed transient signs of sympathetic hyperactivity, probably caused by release of catecholamines from the implanted tissue into the peripheral circulation. We conclude that catecholamine-rich cellular implants in the basal ganglia have transient beneficial effects in patients with severe Parkinson's disease.