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T B Freeman

Publications and source records attributed to T B Freeman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dopaminergic transplants in patients with Parkinson's disease: neuroanatomical correlates of clinical recovery.

For the past 15 years, patients with Parkinson's disease have participated in clinical trials evaluating the efficacy of intrastriatal dopamine transplants. Principally, two donor tissues have been employed, the chromaffin cells of the adrenal medulla and fetal ventral mesencephalon. The clinical response following each type of transplant has been variable. In general, the magnitude and the duration of the clinical response is greater with fetal dopaminergic neurons than with adrenal medullary grafts. Postmortem studies of patients receiving adrenal medullary grafts or fetal nigral implants provide a neuroanatomical framework for the clinical response. Adrenal grafts survive poorly following implantation into the striatum, but they are capable of inducing sprouting of host-derived fibers within a the caudate nucleus. In contrast, robust survival of fetal nigral implants can be achieved within the human brain which can provide extensive reinnervation to the parkinsonian striatum. These findings are strikingly similar to what has been seen in rodent and nonhuman primate models of PD. This paper describes the neuroanatomical correlates of dopamine brain grafting in humans and elucidates the pattern of changes seen in dopaminergic systems which are associated with clinical benefit.

Adrenal Medulla↗
PubMed1997

From transplants to gene therapy for Parkinson's disease.

The efficacy of fetal tissue transplants in the treatment of Parkinson's disease has been demonstrated preliminarily. However, results are short term, and have not been confirmed in prospective randomized controlled trials. Furthermore, although patients are improved, they remain severely disabled. There are several problems with the widespread clinical use of fetal tissue that make the use of molecular biological strategies more compelling. Several conceptual problems are shared by both fetal and molecular biological neuroreconstruction strategies. It is necessary to characterize the "dose" of the transplanted therapeutic agent as well as its volume of distribution. The symptoms that may improve following neuronal reconstruction are likely to be directly related to the somatotopic localization of the transplants; the duration of benefit should be long enough to be relevant in a chronic disease such as Parkinson's disease. Operative therapies that utilize gene therapy or other reconstructive neurosurgical techniques are likely to require novel clinical trial designs to demonstrate their efficacy.

Ethics, Medical↗
PubMed1997

Neural transplantation as an experimental treatment modality for cerebral ischemia.

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.

Animals↗
PubMed1997

Hyperactivity and hypoactivity in a rat model of Huntington's disease: the systemic 3-nitropropionic acid model.

The present study proposes the use of systemic 3-nitropropionic acid (3-NP) treatment in rats as a model of Huntington's disease (HD). The systemic 3-NP model involves chronic injection of low dose intraperitoneal (i.p.) injections of 3-NP to rats once every 4 days over a period of time. Evidence from our experimental studies suggests that manipulating the number of injections can result in either increased nocturnal spontaneous locomotor activity (hyperactivity) or nocturnal akinesia (hypoactivity) [1]. For example, two injections of 3-NP (using the treatment of one injection every 4 days) result in hyperactivity, while four injections or more of 3-NP lead to hypoactivity [1]. The locomotor activity is recorded by Digiscan locomotor activity monitors [11]. The observation of these two types of locomotor activity is unique since no excitotoxin model has replicated a two-stage progression of a HD-like behavioral alteration. Most studies using excitotoxins like quinolinic acid (QA) and kainic acid (KA) have only reproduced the hyperactivity stage [4,5,7]. With the systemic 3-NP model, investigations into at least two stages of the disease are made possible. This allows for better assessment of intervention strategies such as neural transplants across different stages of the disease. The systemic 3-NP rat model is believed to be an improved animal model of HD.

Animals↗
PubMed1997

Testis-derived Sertoli cells have a trophic effect on dopamine neurons and alleviate hemiparkinsonism in rats.

Neural tissue transplantation has become an alternative treatment for Parkinson's disease (PD) and other neurodegenerative disorders. The clinical use of neural grafts as a source of dopamine for Parkinson's disease patients, although beneficial, is associated with logistical and ethical issues. Thus, alternative graft sources have been explored including polymer-encapsulated cells and nonneural cells (that is, adrenal chromaffin cells) or genetically modified cells that secrete dopamine and/or trophic factors. Although progress has been made, no current alternative graft source has ideal characteristics for transplantation. Emerging evidence suggests the importance of trophic factors in enhancing survival and regeneration of intrinsic dopaminergic neurons. It would be desirable to transplant cells that are readily available, immunologically accepted by the central nervous system and capable of producing dopamine and/or trophic factors. Sertoli cells have been shown to secrete CD-95 ligand and regulatory proteins, as well as trophic, tropic, and immunosuppressive factors that provide the testis, in part, with its "immunoprivileged" status. The present study demonstrated that transplantation of rat testis-derived Sertoli cells into adult rat brains ameliorated behavioral deficits in rats with 6-hydroxydopamine-induced hemiparkinsonism. This was associated with enhanced tyrosine hydroxylase (TH) immunoreactivity in the striatum in the area around the transplanted Sertoli cells. Furthermore, in vitro experiments demonstrated enhanced dopaminergic neuronal survival and outgrowth when embryonic neurons were cultured with medium in which rat Sertoli cells had been grown. Transplantation of Sertoli cells may provide a useful alternative treatment for PD and other neurodegenerative disorders.

Animals↗
PubMed1996

Functional fetal nigral grafts in a patient with Parkinson's disease: chemoanatomic, ultrastructural, and metabolic studies.

A patient with Parkinson's disease received bilateral fetal human nigral implants from six donors aged 6.5 to 9 weeks post-conception. Eighteen months following a post-operative clinical course characterized by marked improvement in clinical function, this patient died from events unrelated to the grafting procedure. Post-mortem histological analyses revealed the presence of viable grafts in all 12 implant sites, each containing a heterogeneous population of neurons and glia. Approximately 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir) neurons were found. A greater number of TH-ir grafted neurons were observed in the right (128,162) than the left (81,905) putamen. Grafted TH-ir neurons were organized in an organotypic fashion. These cells provided extensive TH-ir and dopamine transporter-ir innervation to the host striatum which occurred in a patch-matrix fashion. Quantitative evaluations revealed that fetal nigral grafts reinnervated 53% and 28% of the post-commissural putamen on the right and left side, respectively. Grafts on the left side innervated a lesser area of the striatum, but optical density measurements were similar on both sides. There was no evidence that the implants induced sprouting of host TH-ir systems. Electron microscopic analyses revealed axo-dendritic and occasional axo-axonic synapses between graft and host. In contrast, axo-somatic synapses were not observed. In situ hybridization for TH mRNA revealed intensely hybridized grafted neurons which far exceeded TH mRNA expression within residual host nigral cells. In addition, gamma-amino butyric acid (GABA)-ergic neurons were observed within the graft that formed a dense local neuropil which was confined to the implant site. Serotonergic neurons were not observed within the graft. Cytochrome oxidase activity was increased bilaterally within the grafted post-commissural putamen, suggesting increased metabolic activity. In this regard, a doubling of cytochrome oxidase activity was observed within the grafted post-commissural putamen bilaterally relative to the non-grafted anterior putamen. The grafts were hypovascular relative to the surrounding striatum and host substantia nigra. Blood vessels within the graft stained intensely for GLUT-1, suggesting that this marker of blood--brain barrier function is present within human nigral allografts. Taken together, these data indicate that fetal nigral neurons can survive transplantation, functionally reinnervate the host putamen, establish synaptic contacts with host neurons, and sustain many of the morphological and functional characteristics of normal nigral neurons following grafting into a patient with PD.

Carrier Proteins↗
PubMed1996

Cyclosporine-A increases locomotor activity in rats with 6-hydroxydopamine-induced hemiparkinsonism: relevance to neural transplantation.

BACKGROUND: The immunosuppressant cyclosporine-A (CsA) is the primary drug for neural transplantation in Parkinson's disease. However, little is known of its direct effects on movement disorders. Our previous observation of increased locomotor activity in normal rats injected with CsA prompted us to investigate further the effects of CsA on hemiparkinsonian rats. METHODS: We examined the effects of CsA with 6-hydroxydopamine-induced hemiparkinsonism. The animals were randomly assigned to either intraperitoneal injections of CsA (15 mg/kg) or olive oil (the vehicle used for CsA) for 32 days. All animals were tested using the elevated body swing test, and the spontaneous and the amphetamine-induced rotational tests prior to and following the 32-day drug regimen. RESULTS: As revealed by the elevated body swing test, CsA-treated rats had significantly higher mean percent contralateral (to the lesion) swings compared to their pretreatment level (p < 0.01) or to vehicle-treated rats at posttreatment (p < 0.005). In the spontaneous rotational test, CsA-treated rats displayed ipsilateral (to the lesion) rotations which were significantly higher than their pretreatment rotational behavior (p < 0.005) or the posttreatment rotational behavior of olive oil-treated rats (p < 0.0001). Similarly, CsA-treated rats displayed significantly more amphetamine-induced ipsilateral rotations compared to their or the olive oil-treated rats pretreatment level (p < 0.05). CONCLUSION: Our present observations extend our previous findings on motor alterations produced by CsA on normal rats to hemiparkinsonian rats. These results taken together would suggest that CsA may interact with the locomotor effects observed following neural transplantation with adjunctive CsA immunosuppression.

Animals↗
PubMed1996

Fetal nigral transplantation as a therapy for Parkinson's disease.

Fetal nigral grafts have been demonstrated to survive, secrete dopamine, form synaptic connections with host neurons, and reverse behavioral disturbances in experimental models of parkinsonism. These findings suggest that fetal nigral grafting may be a useful therapy for patients with Parkinson's disease (PD). Recent preliminary clinical trials of transplantation in PD have shown increased striatal fluorodopa uptake (measured using positron emission tomography) and clinical benefit in some patients. An autopsy study of one patient who had received fetal nigral transplants demonstrated robust graft survival and striatal reinnervation, with no evidence of host-derived sprouting or immune rejection. The development of a successful clinical transplantation program depends on a careful consideration of the transplantation variables and the related long-term risks and benefits to the patients.

Female↗
PubMed1996

CNS immunological modulation of neural graft rejection and survival.

Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD), has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transplantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell suspension and stereotaxically injected intraparenchymally into a rat lesion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarly, studies on nonhuman primate models of PD provide considerable support for neural transplantation of DA neurons as an experimental clinical procedure for the treatment of PD. To this end, experimental clinical trials have been centered upon transplantation of the embryonic ventral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most patients with marked increases in fluorodopa uptake (indicating graft survival) have been immunosuppressed. Furthermore, immune reactions have been observed in rats xenografted with human embryonic tissue. Of note, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of grafts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neural tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting cells. To circumvent these obstacles, several methods have been suggested including the use of immunosuppressants such as Cyclosporine-A, transplantation of autografts, polymer-encapsulated DA-secreting cells, co-culturing and co-transplantation of DA-secreting cells with microcarrier beads, with Sertoli cells, or with fragments of a monoclonal antibody that can mask the MHC class I antigens, and genetically modifying cells that can withstand CNS immune reactions. Some of these techniques allow transplantation of allograft (same species transplantation), or even xenograft (cross species transplantation) without immunosuppression of the recipient. We discuss recent CNS immunosuppression techniques that pose some promise for enhanced survival of neural grafts. When possible, advantages and disadvantages of each method are presented. Hopefully, such critical analysis of different immunosuppression techniques will produce innovated ideas that will lead to a better understanding of CNS immune response and its modulatory function on graft rejection and survival.

Adrenal Medulla↗
PubMed1996

Free radical damage and oxidative stress in Huntington's disease.

Bioenergetic defects and oxidative stress may be critical links in an excitotoxic mechanism of neuronal death. Oxidative stress, a condition describing the production of oxygen radicals beyond a threshold for proper antioxidant neutralization, has been implicated as a pathologic condition in several neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. In addition, oxygen radicals are known to be important mediators in acute pathologies, in the theory of senescence, cancer, as well as our healthy immune system. Although free radicals may have a special chemical nature which allows them to perform important cellular functions, they are a damaging entity whose reactivity may play a part in the development of cellular compromises that can kill a neuron. In this review, the free radicals in biological systems, the defense systems against them, and the damaging interactions, i.e., oxidative stress, which they confer are discussed. The descriptions provided raise the hypothesis that an imbalance between the production and removal of radicals would be abrasive on a neuron. Accordingly, the neurodegeneration initially caused by gene mutation in Huntington's disease may be further worsened by free radical damage underlied by oxidative stress. This article reviews existing data on the free radical damage and the oxidative stress, which are primarily directed towards Parkinson's disease and Alzheimer's disease, and whenever possible relates such mechanisms to Huntington's disease.

Alzheimer Disease↗
PubMed1995

Behavioral pathology induced by repeated systemic injections of 3-nitropropionic acid mimics the motoric symptoms of Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurons, especially the intrinsic neurons of the striatum, and characterized by involuntary abnormal choreiform movements and progressive dementia. With the discovery of the gene underlying HD, genetic therapy may be the next logical step towards finding a cure, but no such treatment is currently available. Animal models that closely mimic the neurobiological and clinical symptoms of the disease may offer an alternative approach for the development of new therapies. We report that systemic administration of 3-nitropropionic acid, an inhibitor of the mitochondrial citric acid cycle, results in a progressive locomotor deterioration resembling that of HD. We further demonstrate that manipulating the time course of 3-nitropropionic acid injections leads to sustained hyperactivity (early HD) or hypoactivity (advanced HD). These data suggest that this animal model can be used to test experimental treatments for HD across different stages of the disease.

Animals↗
PubMed1995

Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.

BACKGROUND: Trials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinson's disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum. METHODS: We studied a 59-year-old man with advanced Parkinson's disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 6 1/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods. RESULTS: After transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brain, each of the large grafts appeared to be viable. Each was integrated into the host striatum and contained dense clusters of dopaminergic neurons. Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. Ungrafted regions of the putamen showed sparse dopaminergic innervation. We could not identify any sprouting of host dopaminergic processes. CONCLUSIONS: Grafts of fetal mesencephalic tissue can survive for a long period in the human brain and restore dopaminergic innervation to the striatum in patients with Parkinson's disease. In the patient we studied, clinical improvement and enhanced fluorodopa with uptake on PET scanning were associated the survival of the grafts and dopaminergic reinnervation of the striatum.

Brain Tissue Transplantation↗
PubMed1995

Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

Adult↗