Can endogenous stem cells be stimulated to repair the degenerating brain?
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Animals↗
Biomedical subjects
R A Barker
Publications and source records attributed to R A Barker.
Profile of cognitive progression in early Huntington's disease.
OBJECTIVE: To examine the pattern of cognitive decline in early Huntington's disease (HD). METHODS: The authors studied 61 patients with mild to moderate HD who had at least three annual neuropsychological assessments using the Core Assessment Program for Intracerebral Transplantation in Huntington's Disease short battery. A subset of 34 patients had additional neuropsychological tests, and another subset of 21 patients was assessed annually on the Cambridge Neuropsychological Test Automated Battery. Neuropsychological measures that changed significantly over time were submitted to a multiple analysis of covariance to explore associations with demographic and neurologic indices. RESULTS: Patients showed a progressive impairment in attention, executive function, and immediate memory, with timed tests of psychomotor skill being particularly sensitive to decline. In contrast, general cognition, semantic memory, and delayed recall memory were relatively unaffected. CONCLUSION: The profile of cognitive performance shows selective and progressive dysfunction of attention and executive function in patients with mild to moderate HD, consistent with frontostriatal pathology at this stage of disease.
Adult↗
Stem cells and neurological disease.
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Humans↗
How common is dementia with Lewy bodies?
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Aged↗
Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington's disease.
Transplantation of human fetal central nervous system tissue has been shown to be of benefit in Parkinson's disease, and is currently being explored as a therapeutic option in Huntington's disease. The success of a neural transplant is dependent on a number of factors, including the requirement that donor cells are harvested within a given developmental window and that the cell preparation protocols take account of the biological parameters identified in animal models. Although many of the criteria necessary for a successful neural transplant have been defined in animal models, ultimately they must be validated in human studies, and some issues can only ever be addressed in human studies. Furthermore, because neural transplantation of human fetal tissue is limited to small numbers of patients in any one surgical center, largely due to practical constraints, it is crucial that tissue preparation protocols are clearly defined and reproducible, so that (i) multicenter trials are possible and are based on consistent tissue preparation parameters, and (ii) results between centers can be meaningfully analyzed. Here we describe the preparation of human fetal striatum for neural transplantation in Huntington's disease, and report on the validation of a method for estimating the developmental stage of the fetus based on direct morphometric measurements of the embryonic tissue.
Algorithms↗
Alpha Gal is widely expressed in embryonic porcine stem cells and neural tissue.
Fetal porcine neural xenografts are an alternative to human fetal tissue for cell based treatments of a number of neurodegenerative conditions but are currently limited by host immunological rejection. The expression of a major immunological epitope, Galalpha1-3Galbeta1-4GlcNAcbeta-R (alphaGal) was determined on stem cells and primary cells derived from E26 porcine fetal brains. alphaGal was detected on the majority of neural stem cells and cells from primary cell suspensions. The expression of this epitope paralleled the binding of human IgG and IgM to the cells, a binding that was significantly reduced with anti-alphaGal depleted human serum. This study demonstrates that alphaGal expression is extensive in embryonic porcine neural cells and will be of relevance to any clinical trials using this tissue.
Animals↗
The genetic basis of Parkinson's disease.
Although the mechanisms underlying neurodegeneration in Parkinson's disease are not fully understood, considerable evidence suggests that genetic factors can influence susceptibility to the disease. In this article, we critically review this evidence and examine studies estimating patterns of inheritance. In a few families, Parkinson's disease is clearly inherited in a Mendelian fashion, and in some of these the disease causing genes have already been identified. Possible pathogenic mechanisms by which these genes cause Parkinson's disease are discussed. Further candidate genes and systematic efforts to identify genes influencing susceptibility to the disease in general are also summarised. The identification of such susceptibility genes will eventually enable us to more accurately classify this complex disease.
Chromosome Aberrations↗
Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475.
OBJECTIVES: Huntington's disease (HD) is an inherited autosomal dominant condition in which there is a CAG repeat expansion in the huntingtin gene of 36 or more. Patients display progressive motor, cognitive, and behavioural deterioration associated with progressive cell loss and atrophy in the striatum. Currently there are no disease modifying treatments and current symptomatic treatments are only partially effective in the early to moderate stages. Neural transplantation is effective in animal models of HD and offers a potential strategy for brain repair in patients. The authors report a safety study of unilateral transplantation of human fetal striatal tissue into the striatum of four patients with HD. SUBJECTS AND METHODS: Stereotaxic placements of cell suspensions of human fetal ganglionic eminence were made unilaterally into the striatum of four patients with early to moderate HD. All patients received immunotherapy with cyclosporin A, azathioprine, and prednisolone for at least six months postoperatively. Patients were assessed for safety of the procedure using magnetic resonance imaging (MRI), regular recording of serum biochemistry and haematology to monitor immunotherapy, and clinical assessment according to the Core Assessment Protocol For Intrastriatal Transplantation in HD (CAPIT-HD). RESULTS: During the six month post-transplantation period, the only adverse events related to the procedure were associated with the immunotherapy. MRI demonstrated tissue at the site of implantation, but there was no sign of tissue overgrowth. Furthermore, there was no evidence that the procedure accelerated the course of the disease. CONCLUSIONS: Unilateral transplantation of human fetal striatal tissue in patients with HD is safe and feasible. Assessment of efficacy will require longer follow up in a larger number of patients.
Adult↗
Neurodegeneration: a failure of neuroregeneration?
Evidence suggests that the brain, like many other tissues, is in a state of dynamic equilibrium. It has an endogenous population of stem cells that proliferate in response to environmental and pharmacological manipulations and that can replace cells lost in some experimental lesions. However, the fact remains that neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterised by continuous loss of neurons that are not replaced. In this hypothesis, we postulate that a primary deficit in neural stem-cell proliferation; migration, or differentiation, or both, might contribute to net cell loss and neuronal circuit disruption in these disorders. Experimental validation of this hypothesis would not only substantially advance understanding of the pathogenesis of these diseases, but could also have profound implications for future treatment of these incurable disorders.
Animals↗
Cellular and molecular aspects of striatal development.
The striatum is a key component of the basal ganglia and there is considerable evidence that it has an important role in motor, cognitive and limbic functions. However, very little is known about how this forebrain structure develops. This review considers the role of cellular and molecular mechanisms involved in the development of the striatum, and the potential application of this knowledge to the understanding of the pathology and treatment of primary disease of this structure.
Animals↗
Death of dopaminergic neurons in vitro and in nigral grafts: reevaluating the role of caspase activation.
Caspases are cysteine proteases involved in apoptotic cell death, and pharmacological caspase inhibition has been demonstrated to prevent neuronal cell death in certain experimental paradigms. In this study, the role of caspase-1 and -3 in the death of dopaminergic neurons derived from the E14 rat ventral mesencephalon (VM) has been examined in two model systems using peptide caspase inhibitors. First, cell death was induced in vitro by withdrawing serum after 2 days. Different doses of caspase-1 (IL-1beta converting enzyme) and caspase-3 inhibitors (Ac-DEVD-cmk) were added to the medium at the time of serum withdrawal, and the ability of the inhibitors to promote dopaminergic neuronal survival and prevent activation of caspase-3 was assessed at 7 days. Immunostaining using tyrosine hydroxylase (TH) and cleaved caspase-3 antibodies demonstrated that caspase-1 and -3 inhibitors reduce caspase-3 activation as well as overall cell death. This did not, however, improve the survival of TH-positive neurons, although it did appear to promote their maturation. The second paradigm investigated the effects of these inhibitors in the 6-hydroxydopamine rat model of PD, and similarly, addition of caspase-1 or -3 inhibitor during tissue preparation or immediately prior to grafting of VM tissue did not promote dopaminergic neuronal survival. These results demonstrate that the reduction of apoptotic cell death by pharmacological inhibition of caspase-1 and -3 does not increase dopaminergic neuronal survival in these paradigms and suggest either that caspase-3 activation is not the major determinant of dopaminergic neuronal death in vitro and in grafts or that the ability of caspase inhibitors to rescue cells depends upon the degree of apoptotic stress. This implies that strategies to improve dopaminergic cell survival in clinical programmes of transplantation for PD will need to target other pathways of cell death.
Animals↗
Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells.
Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised. In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/macrophages, immunoglobulin M and complement could be demonstrated to varying degrees. Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral grafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neurodegenerative conditions such as Parkinson's disease are discussed.
Animals↗
Mechanisms of cognitive set flexibility in Parkinson's disease.
Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.
Cognition↗
Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands.
We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.
Attention↗
Getting to the heart of dementia.
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3-Iodobenzylguanidine↗
Prospects for the treatment of Parkinson's disease using neurotrophic factors.
Parkinson's disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of alpha-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific 'dopaminotrophic' effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.
Animals↗
A role for complement in the rejection of porcine ventral mesencephalic xenografts in a rat model of Parkinson's disease.
Vascularized whole organ discordant xenografts placed in the periphery are rejected by a rapid "hyperacute" process that involves preformed antibody binding to the xeno-antigens on the donor endothelial cells with complement activation. In the CNS, xenografts are classically thought to be rejected more slowly by a T-cell-dependent process. We now report that xenografts of embryonic porcine ventral mesencephalic tissue in the 6-hydroxydopamine-lesioned, nonimmunosuppressed rat induce both a humoral and a cell-mediated response. Over the first 10 d after implantation, the xenografts matured with identifiable TH neurons and pig-specific neurofilament fibers extending along host white matter tracts. During this period of time, IgM and complement binding were observed within the graft, as well as a CD8 cellular infiltrate, leading to rejection of the transplant over the next 25 d. These intracerebral xenografts were not associated with an early systemic antibody response. A role for complement in this rejection process was further investigated using cobra venom factor (CVF), which systemically depleted the rats of complement for 7 d. CVF treatment, when given in the period immediately before and after grafting, delayed but did not prevent the cellular immune response induced by the graft, demonstrating that xenografted neural tissue can activate the humoral arm of the rejection process, in particular the complement cascade. This suggests that interventions targeting this aspect of the immune rejection process may be of great importance for the future development of xenotransplantation for neurodegenerative conditions.
Adrenergic Agents↗
Porcine neural xenografts: what are the issues?
The allografting of embryonic neural tissue into the CNS of animals with experimental lesions and patients with neurodegenerative conditions has shown that this tissue survives, makes and receives synapses, and ameliorates behavioural deficits without inducing a significant rejection process. There are though, major problems with the use of aborted human tissue in clinical programmes of transplantation which has lead to the search for alternative sources of cells, including embryonic porcine tissue. However there are two major issues relating to the use of this tissue: (a) the risk of zoonotic infection especially with porcine endogenous retroviruses (PERVs); and (b) the loss of the tissue to an immunologically based rejection process, and it is this latter issue that forms the basis of this chapter. The rejection of neural xenografts has clearly been shown to involve T cell-directed processes although there is now increasing evidence that complement and humoral immune mediators may also play a role. This suggests that transgenic pigs expressing regulators of the human complement cascade may offer an advantage over normal porcine tissue in any clinical neural xenograft programmes. However the extent to which these different immune processes are interdependent, and the contribution of each of them to the actual loss of the grafted tissue is currently unresolved.
Animals↗