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T J Collier

Publications and source records attributed to T J Collier.

At least 19 recordsLinked to original sources
PubMed2005

A rapid access cardiology service for chest pain, heart failure and arrhythmias accurately diagnoses cardiac disease and identifies patients at high risk: a prospective cohort study.

OBJECTIVE: To conduct a one year follow up study of patients seen in a combined rapid access chest pain, arrhythmia and heart failure clinic. METHODS: Local general practitioners, accident and emergency department clinicians and other hospital clinicians were invited to refer patients with a new presentation of chest pain, palpitations and suspected cardiac-induced breathlessness to the rapid access cardiology clinics at Charing Cross Hospital, London, on a one-stop, no appointment basis. Consent to be followed up by a postal questionnaire one year later was sought from all patients attending between 1 November 2002 and 31 October 2003. RESULTS: 1223 patients were seen in the 12 month study period. 940 (77%) consented to one year follow up. 216 (23%) patients had a diagnosis of definite cardiac, 621 (66%) of not cardiac and 103 of possible cardiac disease (11%). 98% of patients diagnosed "not cardiac" did not receive a diagnosis of cardiac disease over the following 12 months. Of patients with diagnosed definite cardiac disease, one year cardiac mortality was 7 of 216 (3%), compared with an age- and sex-matched expected cardiac mortality of 0.9% (standardised mortality ratio 3.5, 95% confidence interval (CI) 1.4 to 7.2). For patients with an initial diagnosis of possible or not cardiac disease, cardiac mortality at one year was 0.3% compared with an expected cardiac mortality of 0.4% (standardised mortality ratio 0.8, 95% CI 0.1 to 2.8). CONCLUSIONS: A rapid access cardiology clinic accurately diagnoses and risk stratifies patients into those with cardiac disease at high risk of cardiac death and those without significant cardiac disease.

Adolescent↗
PubMed2004

Rapid access arrhythmia clinic for the diagnosis and management of new arrhythmias presenting in the community: a prospective, descriptive study.

OBJECTIVE: To investigate whether a rapid access approach is useful for the evaluation of patients with symptoms suggestive of a new cardiac arrhythmia. DESIGN: Prospective, descriptive study. SETTING: Secondary care based rapid access arrhythmia clinic in West London, UK. PARTICIPANTS: Patients referred by their general practitioner or the emergency department with symptoms suggestive of a new cardiac arrhythmia. MAIN OUTCOME MEASURES: Number of patients with a newly diagnosed significant arrhythmia. Number of patients with diagnosed atrial fibrillation. Number of eligible, moderate, and high risk patients treated with warfarin. RESULTS: Over a 25 month period 984 referrals were assessed. The mean age was 55 years (range 20-90 years) and 56% were women. The median time from referral to assessment was one day. A significant cardiac arrhythmia was newly diagnosed in 40% of patients referred to the RAAC. The most common arrhythmia was atrial fibrillation, with 203 new cases (21%). Of these, 74% of eligible patients over 65 were treated with warfarin. Other arrhythmias diagnosed were supraventricular tachycardias (127 (13%)), conduction disorders (43 (4%)), and non-sustained ventricular tachycardia (21 (2%)). Vasovagal syncope was diagnosed for 53 patients (5%). The most frequent diagnosis was symptomatic ventricular and supraventricular extrasystoles (355 (36%)). CONCLUSION: A rapid access arrhythmia clinic is an innovative approach to the diagnosis and management of new cardiac arrhythmias in the community. It provides a rapid diagnosis, stratifies risk, and leads to prompt initiation of effective treatment for this population.

Adult↗
PubMed2001

Diminished survival of mesencephalic dopamine neurons grafted into aged hosts occurs during the immediate postgrafting interval.

The survival rate of dopamine (DA) neurons in mesencephalic grafts to young adult rats is poor, estimated at 5-20%, and even poorer in grafts to the aged striatum. Grafted cells die in young adult rats during the first 4 days after implantation. The present study was undertaken to determine whether the decreased survival of DA neurons in grafts to aged rats is (1) due to additional cell death during the immediate postgrafting interval or (2) due to protracted cell loss during longer postgrafting intervals. We compared survival rates of tyrosine hydroxylase-immunoreactive (THir) neurons in cell suspension grafts to young adult (3 months) and aged (24 months) male Fischer 344 rats at 4 days and 2 weeks after transplantation. At 4 days after grafting, mesencephalic grafts within the aged rat striatum contain approximately 25% of the number of THir neurons in the same mesencephalic cell suspension grafted to young adult rats. This corroborates the decreased survival of grafted DA neurons we have demonstrated previously at 10 weeks postgrafting. THir neurons in grafts to the intact striatum possessed a significantly shorter "long axis" than their counterparts on the lesioned side. No significant differences in the number of apoptotic nuclear profiles or total alkaline phosphatase staining between mesencephalic grafts to young and aged rats were detectable at 4 days postgrafting. In summary, the present study indicates that the exaggerated cell death of grafted DA neurons that occurs following implantation to the aged striatum occurs during the immediate postgrafting interval, timing identical to that documented for young adult hosts.

Age Factors↗
PubMed2001

Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.

Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNFalpha-induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNFalpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNFalpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNFalpha-treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNFalpha-induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNFalpha receptor 1 (p55, R1) and TNFalpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNFalpha treatment. These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD.

Animals↗
PubMed2001

A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease.

Neural progenitor cells potentially provide a limitless, on-demand source of cells for grafting into patients with Parkinson's disease (PD) if the signals needed to control their conversion into dopamine (DA) neurons could be identified. We have recently shown that cytokines which instruct cell division and differentiation within the hematopoeitic system may provide similar functions in the central nervous system. We have shown that mitotic progenitor cells can be isolated from embryonic rat mesencephalon and that these cells respond to a combination of interleukin-1, interleukin-11, leukemia inhibitory factor, and glial cell line-derived neurotrophic factor yielding a tyrosine hydroxylase-immunoreactive (THir) phenotype in 20-25% of total cells. In the present study, 24 clonal cell lines derived from single cells of mesencephalic proliferation spheres were examined for their response to the cytokine mixture. The clone yielding the highest percentage of THir neurons (98%) was selected for further study. This clone expressed several phenotypic characteristics of DA neurons and expression of Nurr1. The response to cytokines was stable for several passages and after cryopreservation for several months. When grafted into the striatum of DA-depleted rats, these cells attenuated rotational asymmetry to the same extent as freshly harvested embryonic DA neurons. These data demonstrate that mesencephalic progenitor cells can be clonally expanded in culture and differentiated in the presence of hematopoietic cytokines to yield enriched populations of DA neurons. When transplanted, these cells provide significant functional benefit in the rat model of PD.

Animals↗
PubMed2000

Oligodendrocyte-type 2 astrocyte-derived trophic factors increase survival of developing dopamine neurons through the inhibition of apoptotic cell death.

Survival of embryonic dopamine (DA) neurons is extremely low (5-20%) following transplantation. Strategies to increase this survival are critical to the future of transplantation for Parkinson's disease. We demonstrate here that a factor(s) released from striatal oligodendrocyte-type 2 astrocytes (SO2A) greatly improves the survival and phenotype expression of mesencephalic DA neurons in culture while simultaneously decreasing the presence of apoptotic nuclear profiles, as detected by the TUNEL method and bisbenzamide/tyrosine hydroxylase double labeling. This SO2A-derived trophic factor(s) has minimal effects on glia and no effect on nondopaminergic mesencephalic neurons. The developmental period during which this SO2A trophic effect occurs (E14-18) coincides with the period when mesencephalic grafts are undergoing the highest rates of apoptosis, i.e., immediately following implantation. Therefore, SO2A-derived trophic factor(s) offers great potential for the augmentation of grafted DA neuron survival.

Animals↗
PubMed2000

Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity.

The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20-30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD-ir) neurons. A single treatment with CsA protected GAD-ir neurons from 3NP toxicity at lower (0.2 or 1.0 microM), but not at higher (5.0 microM) doses. Similar findings were seen when the cultures were treated twice with cyclosporin. In vivo experiments used the Lewis rat model of Huntington's disease (HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injections to disrupt the blood-brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP-lesioned rats displayed significantly more dopamine-and adenosine-3;, 5;-monophosphate-regulated phosphoprotein (DARPP32-ir) neurons ipsilateral to BBB disruption compared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second experiment, stereological counts of DARPP32-ir neurons revealed that CsA protected striatal neurons in a dose-dependent manner following bilateral disruption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) but not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32-ir striatal neurons relative to vehicle-treated 3NP-lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant protection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by protecting vulnerable neurons from the primary pathological event observed in HD.

Animals↗
PubMed2000

Striatal trophic activity is reduced in the aged rat brain.

Our previous studies demonstrated that the survival of a mesencephalic graft was reduced in aged animals suggesting an age-related decline in target-derived neurotrophic activity. We tested this hypothesis by examining dopamine (DA) and trophic activities from the striatum of intact or unilateral 6-hydroxydopamine (6-OHDA) lesioned rats of increasing age. Fisher 344 rats were 4, 12, 18, and 23 months old (m.o.) at sacrifice. Half the animals had received unilateral 6-OHDA lesions of the mesostriatal DA pathway 8 weeks earlier. Striatal tissue punches were analyzed for DA, homovanillic acid (HVA), and DA activity (HVA/DA) using HPLC. The remainder of the striatal tissue was homogenized to generate tissue extracts which were added to E14.5 ventral mesencephalic cultures to test trophic activity. In the non-lesioned animals, striatal DA was reduced and striatal DA activity was increased in the 18 and 23 m.o. animals relative to the 4 and 12 m.o. animals. Striatal trophic activity was inversely related to age. In the lesioned animals, striatal DA ipsilateral to 6-OHDA infusion was below detection limits while the contralateral striatum exhibited age-related changes in DA similar to those seen in the non-lesioned animals. In 4 m.o. lesioned rats, striatal trophic activity ipsilateral to 6-OHDA infusion was elevated by 26% relative to the contralateral side. The ipsi/contra-lateral differences in striatal trophic activity were reduced in 12 m.o. animals and absent in the 18 and 23 m.o. groups. These data suggest that advancing age is associated with a reduction in striatal DA as well as trophic activity. Moreover, the aged striatum loses its ability to biochemically and trophically compensate for DA reduction and therefore may represent a more challenging environment for the survival, growth, and function of a fetal graft.

Aging↗
PubMed2000

Time course of apoptotic cell death within mesencephalic cell suspension grafts: implications for improving grafted dopamine neuron survival.

The vast majority ( congruent with 90%) of embryonic mesencephalic dopamine (DA) neurons die following transplantation to the striatum. Recent reports indicate that at least a subpopulation of grafted cells undergo apoptotic cell death at early times following implantation. This study examines the temporal pattern and magnitude of apoptotic cell death following the implantation of mesencephalic cell suspension grafts. Two techniques, a modified terminal deoxynucleotide-mediated nucleotide end labeling (TUNEL) technique and cresyl violet staining, are used to assess apoptotic cell death by detection of its biochemical and morphological identifiers, respectively. Male, Fischer 344 rats were examined at 1, 4, 7, and 28 days following implantation of embryonic day 14 (E14) ventral mesencephalic cells to the DA-denervated striatum. Results indicate that the overwhelming majority of apoptotic cell death occurs within the first 7 days after transplantation. However, the impact of the apoptosis that occurs over the first week following grafting only appears to limit grafted tyrosine hydroxylase-immunoreactive (THir) neuron survival during the first 4 days. No significant differences between the survival rates of THir neurons at 4 days after grafting and at 28 days after grafting were found. Therefore, it appears that the critical interval during which an estimated 90% of grafted DA neurons die is during the first 4 days postimplantation and that a major contributor to this cell death is apoptosis.

Animals↗
PubMed2000

Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatment.

Despite widespread use of the primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, there is a paucity of data concerning the relationship between striatal dopaminergic function and behavior over time. This study examines the relationship between markers of dopamine neuron integrity and dopaminergic metabolic activity in striatal subregions with the degree of parkinsonian disability in 32 monkeys treated with MPTP one year earlier. Based on the parkinsonian summary score during the month following MPTP treatment, each monkey was assigned to one of four severity categories. We called these categories "Severe", "Moderate", "Mild" and "Asymptomatic". Monkeys in the Severe category were behaviorally stable, and loss of dopamine concentration was greater than 98% in all subregions of striatum one year after MPTP treatment. This value was not significantly different from the level of depletion, reported previously, at one to two months after MPTP in Severe monkeys, and apparently this loss of striatal dopamine is beyond the level from which effective compensations can occur. The parkinsonian disabilities in monkeys of other severity groups (Moderate, Mild, Asymptomatic) improved significantly over the year, despite having mean dopamine depletion of 75-99% in different subregions of striatum at one to two months after MPTP treatment. At one year after MPTP treatment, the mean dopamine depletions in different subregions of caudate nucleus and putamen had diminished in Asymptomatics (21-81%), Milds (35-96%), and Moderates (86-97%). Dopamine loss in nucleus accumbens was relatively spared compared with most striatal subregions, yet in Severe monkeys the decrease in this region reached 96%. In addition, at one year after MPTP treatment, there was a significant linear relationship between parkinsonian behavioral severity category and dopamine concentration, and homovanillic acid concentration and homovanillic acid/dopamine ratio in the striatum. The re-establishment of dopamine levels and homovanillic acid/dopamine ratios was most pronounced in putamen, ventromedial caudate nucleus and nucleus accumbens. Thus the small difference in striatal dopamine loss that distinguishes monkeys with widely different behavior at one to two months after MPTP increases over time. We suggest that the milder the initial loss, the greater capacity there is for regeneration or sprouting of dopamine terminals, which is reflected in marked increases in dopamine levels and modest elevations of metabolic activity (homovanillic acid/dopamine ratio). With greater initial losses, there is less capacity to increase terminal density, which is reflected later by smaller increases in striatal dopamine levels and more marked increases in metabolic activity. It appears that 5-10% of normal striatal dopamine levels is sufficient for overtly normal motor performance in non-human primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Diminished viability, growth, and behavioral efficacy of fetal dopamine neuron grafts in aging rats with long-term dopamine depletion: an argument for neurotrophic supplementation.

We examined the behavioral and morphological correlates of the response to a single intrastriatal dispersed cell graft of fetal rat ventral mesencephalic tissue in male Fischer-344 rats of varying age (4, 17, and 24-26 months old) and history of mesostriatal dopamine (DA) depletion (1 or 14 months). Our goal was to determine the impact of advancing age and duration of DA depletion in the host on DA graft viability and function. The findings can be summarized as follows. (1) Fetal DA neuron grafts that were effective in completely ameliorating amphetamine-induced rotational behavior in young rats with short-term lesions were virtually without effect in aged rats with long-term lesions. Middle-aged rats with long-term lesions responded to these grafts with partial behavioral recovery. (2) Age of the host at the time of transplantation, and not duration of DA depletion, was the primary determinant of response to DA grafts. (3) Diminished efficacy of grafts in lesioned aging rats was related to decreased survival and neurite extension of transplanted DA neurons. (4) Co-grafts of DA neurons with Schwann cells as a source of neurotrophic support improved the behavioral outcome of grafts in aged lesioned rats. These findings support the view that the DA-depleted striatum of aged rats is an impoverished environment for survival, growth, and function of DA grafts. Consistent with this view, local supplementation of the neurotrophic environment of grafted DA neurons with products of co-grafted Schwann cells, a demonstrated source of neurotrophic activity for embryonic DA neurons, improved graft outcome.

Aging↗
PubMed1999

Therapeutic potential of nerve growth factors in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative syndrome which primarily affects dopamine-producing neurons of the substantia nigra, resulting in poverty and slowness of movement, instability of gait and posture, and tremor at rest in individuals with the disease. While symptoms of the disease can be effectively managed for several years with available drugs, the syndrome is progressive and the efficacy of standard drugs wanes with time. One experimental approach to therapy is to use natural and synthetic molecules which promote survival and growth of dopaminergic neurons, so-called 'neurotrophic factors', to stabilise the diminishing population of dopaminergic neurons and stimulate compensation and growth in these cells. In this review, we examine the available evidence on 29 molecules with neurotrophic properties for dopaminergic neurons. The properties of these molecules provide ample reasons for optimism that a neurotrophic strategy can be developed that would provide a significant treatment option for patients with PD. While the search continues for even more specific, potent and long lasting agents, the single greatest challenge is the development of techniques for targeted delivery of these molecules.

Aged↗
PubMed1998

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons.

To enhance the current therapeutic benefit of dopamine (DA) neuron grafts in Parkinson's disease, strategies must be developed that increase both DA neuron survival and fiber outgrowth into the denervated striatum. Previous work in our laboratory has demonstrated that dopaminergic neurons grow to greater size when co-grafted with striatal cell suspensions and display extensive tyrosine hydroxylase-positive (TH+) projections, but no conclusion could be reached concerning enhancement of survival of grafted DA neurons. The aim of the present study was to characterize further the potential trophic effects of striatal co-grafts on grafted mesencephalic DA neuron survival. Unilaterally lesioned male Fischer 344 rats were grafted with either a suspension of mesencephalic cells or with both mesencephalic and striatal cell suspensions. Co-grafts were either mixed together or placed separately into the striatum. Lesioned rats receiving no graft served as controls. Rotational behavior was assessed following amphetamine challenge at 2 weeks prior to grafting and at 4 and 8 weeks following grafting. Only rats receiving co-grafts of nigral and striatal suspensions separated by a distance of 1 mm showed significant behavioral recovery from baseline rotational asymmetry. Both mixed and separate striatal co-grafts were associated with a doubling of DA neuron survival compared with solo mesencephalic grafts. In the mixed co-graft experiment, DA neurite branching appeared enhanced and TH-rich patches were observed, whereas with co-grafts that were separated, TH+ innervation of the intervening host striatum was increased significantly. These results provide the first evidence suggesting that nigral-striatal co-grafts, particularly those placed separately and in proximity to each other, increase both DA neuron survival and neurite extension from the mesencephalic component of the grafts.

Animals↗
PubMed1998

Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model.

The majority of investigations into the degree of restoration of neural circuitry following transplantation of the embryonic ventral mesencephalon to the striatum have focused upon the particular neurochemical subtypes of the fibers exchanged between graft and host. Visualization of neurites of specific neurotransmitter type while informative regarding the specificity of graft-host interactions, vastly underrepresents overall synaptogenesis as it may occur in the grafting situation. The present approach of using a molecular marker characteristic of all normal, functional synapses provides broader information about the synaptic remodeling that occurs after tissue grafting. Synaptophysin (SY), an integral membrane protein of the synaptic vesicle, is a reliable marker of nerve terminal differentiation. Immunohistochemical staining with antibodies directed against SY and the dopamine synthetic enzyme tyrosine hydroxylase (TH) was used to assess overall synaptic differentiation as well as the relationship between SY immunoreactivity and the distribution of grafted dopamine (DA) neurons and processes in mesencephalic grafts and mesencephalic-striatal co-grafts implanted in the striatum of MPTP-treated African green monkeys. Grafted embryonic cerebellar tissue was used as a comparison graft type that does not normally exchange prominent direct projections with striatum. Dense pericellular arrays of SY-positive terminals were associated with TH-positive neurons in mesencephalic grafts. In mixed mesencephalic-striatal co-grafts, TH-positive fiber patches within the striatal portion of the graft demonstrated a high degree of correspondence with SY immunoreactivity. In contrast, grafts of cerebellar tissue did not display the same pattern of prominent pericellular arrays of SY staining. These observations suggest that functional synapses are abundantly present within grafted mesencephalon, and that these contacts are enriched in areas of the graft occupied by DA neurons. Implantation of an inappropriate striatal target, the cerebellum, results in visibly diminished innervation. The pattern of SY labeling observed suggests that tissue grafts are extensively innervated, probably both from extrinsic and intrinsic sources, and that the pattern and density of this innervation corresponds to the appropriateness of the graft-host interaction.

Animals↗
PubMed1998

Differential regulation of astrocytic mRNAs in the rat striatum after lesions of the cortex or substantia nigra.

This study evaluates the time course of expression of three astrocytic mRNAs, glial fibrillary acidic protein (GFAP), apolipoprotein E (ApoE), and clusterin, in the rat striatum (ST) following a unilateral lesion of either the cortex (CX) or the substantia nigra (SN), using Northern blot and in situ hybridization analyses. We found that while there was a time-dependent increase in astrocytic GFAP mRNA in the deafferented ST following both the CX and the SN lesions, the time course of the response was different between the two lesion paradigms. Specifically, the increase in GFAP mRNA in striatal astrocytes after the SN lesion was rapid and transient returning to control levels by 10 days postlesion, while the response was long lasting and remained increased until at least 27 days after the CX lesion. In addition, the mRNA response for both ApoE and clusterin was differentially regulated in response to the two lesions. Specifically, both clusterin and ApoE mRNAs were rapidly increased in the ST following the CX lesion while both mRNAs remained unchanged following the SN lesion. Data from this study extend information derived from previous investigations on the multifunctional role of astrocytes in the response to brain injury. Specifically, our data support the notion that while the time course of the GFAP response in striatal astrocytes may vary between lesion paradigms, the upregulation of GFAP is part of a generalized response of reactive astrocytes to diverse brain injuries. By comparison, upregulation of the mRNAs for the lipoproteins clusterin and ApoE are lesion specific and may play a role in the transport of recycled myelin lipids from dying axons to actively growing axons and dendrites in reactive synaptogenesis.

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

Early gestational mesencephalon grafts, but not later gestational mesencephalon, cerebellum or sham grafts, increase dopamine in caudate nucleus of MPTP-treated monkeys.

The mechanism of the behavioral improvement observed in parkinsonian primates that receive intrastriatal transplants of fetal dopamine neurons has not been firmly established. Dopamine production by grafted neurons may be the basis of the behavioral recovery. Alternatively, stimulation of the host dopamine system by the transplant procedure itself may be central to the outcome. The present study examined whether dopamine concentration was raised in the caudate nucleus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate following grafting, and if so, whether the elevation was dependent on either (i) the introduction of the implantation cannula (sham), (ii) the brain region that was grafted, or (iii) the gestational age of fetal tissue that was grafted. Transplantation of early gestational age fetal ventral mesencephalon (embryonic days 40-50) was associated with significant elevation of caudate nucleus dopamine concentration to a mean of approximately 20% of control values in the vicinity (within 2 mm) of the graft, compared with more distant sites in the caudate nucleus. With early gestational age fetal ventral mesencephalon, the ratio of homovanillic acid/dopamine concentration near the graft site was normalized compared to the elevated value found in the caudate nucleus distant from the graft site. Grafts of later stage fetal ventral mesencephalon, or fetal cerebellum, or sham implantation did not increase dopamine concentration or lower homovanillic acid/dopamine ratio near the graft site. Biochemical and histochemical evidence suggests that host dopamine neurons terminating in the nucleus accumbens are not the source of the changes. Numerous tyrosine hydroxylase-positive neurons at the graft site were only observed in the MPTP-treated monkeys that received grafts of early gestational age fetal ventral mesencephalon. These data lend strong support to the hypothesis that dopamine derived from grafted dopamine neurons is the major basis for behavioral recovery observed following intrastriatal transplantation in our MPTP-treated monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗