Aspects of PET imaging relevant to the assessment of striatal transplantation in Huntington's disease.

Proper assessment of outcome in clinical trials of neural transplantation requires both biochemical and imaging indices of graft survival, and behavioural and physiological indices of graft function. For transplantation in Huntington's disease, a variety of ligands that are selective for striatal degeneration and graft-derived replacement are available, notably ligands of dopaminergic receptors on striatal neurons. However, the validity of such ligands is potentially compromised by adjunctive drug therapies (e.g. neuroleptics) given to patients in the course of normal clinical care. We review the present state of experimental and clinical understanding of the selectivity of available ligands for striatal imaging, their interaction with other drug treatments, and strategies for refining valid assessment protocols in patients.

The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset.

Huntington's disease is a genetically inherited neurodegenerative disorder for which currently there is no effective treatment or cure. In order to gauge the potential therapeutic benefits of neuroprotective or restorative treatments, it is necessary to create an animal model that is associated with readily measurable and long-lasting functional impairments. The undifferentiated neostriatum and limited behavioural repertoire of rodents have led to the extension of our investigations into the common marmoset. We have used quinolinic acid to create unilateral excitotoxic lesions of the caudate nucleus or the putamen in this small non-human primate. Following rigorous investigation of each monkey on a battery of behavioural tests, we found that the unilateral putamen lesion was associated with a contralateral motor impairment that persisted for at least 9 months and withstood repeated testing. However, the unilateral caudate nucleus lesion did not appear to be associated with any detectable motor deficit. The stability and the reproducibility of the unilateral putamen lesion in the marmoset provide a suitable tool for the investigation of potential treatments for neurodegenerative disorders that attack this region of the brain.

Neural tissue xenotransplantation: what is needed prior to clinical trials in Parkinson's disease? Neural Tissue Xenografting Project.

Embryonic allografted human tissue in patients with Parkinson's disease has been shown to survive and ameliorate many of the symptoms of this disease. Despite this success, the practical problems of using this tissue coupled to the ethical restrictions of using aborted human fetal tissue have lead to an exploration for alternative sources of suitable material for grafting, including xenogeneic embryonic dopaminergic-rich neural tissue. Nevertheless, xenografted neural tissue itself generates a number of practical, ethical, safety, and immunological issues that have to be addressed prior to any clinical xenotransplant program. In this article we review these critical issues and set out the criteria that we consider need to be met in the development of our clinical xenotransplantation research programs. We advocate that these, or similar, criteria should be adopted and made explicit by other centers contemplating similar clinical trials.

Striatal tissue transplantation in non-human primates.

The caudate nucleus and putamen form part of a complex but topographically connected circuitry that links the cortex, the basal ganglia and the thalamus. Within this complex system lie a series of functionally and anatomically segregated loops that allow the concurrent processing of a wide range of cognitive and motor information (Alexander et al., 1986; Alexander and Crutcher, 1990). As a constituent of these loops it has been shown that the striatum is involved in movement initiation, response selection and attentional processes (Robbins and Brown, 1990; Alexander, 1994; Lawrence et al., 1998). Although it is the medium spiny GABAergic projection neurones that are primarily lost in HD, it is not sufficient merely to replace the GABA. Instead it is crucial for striatal tissue transplants to integrate with the host tissue in such a way that the cortico-striatal-thalamic circuitry is restored and is functional. Rodent studies have progressed a long way in establishing the principle that striatal grafts can, at least partially, restore function and integrate appropriately with the host (Dunnett and Svendsen, 1993; Björklund et al., 1994; Sanberg et al., 1998) but the limited behavioural repertoire and the undifferentiated striatum meant that it was inevitable that studies should progress into primate models. Anatomical tracing studies have demonstrated that motor, premotor and somatosensory cortical areas send corticostriatal projections primarily to the putamen region in primates, whereas the head and body of the caudate nucleus mostly receive efferent input from associative cortical areas (Kemp and Powell, 1970; Kunzle, 1975, 1977, 1978; Selemon and Goldman-Rakic, 1985). Based on such anatomical, and functional, studies Alexander and colleagues have proposed the existence of at least five cortico-striatal-thalamic loops including a motor, a dorsolateral-prefrontal and an orbito-frontal loop (Alexander et al., 1986). The concentration of motor inputs to the putamen region suggests a particular involvement of this structure in the motor loop. Indeed, unilateral lesions of the putamen disrupt motor performance in the marmoset and generate apomorphine-induced dyskinesias in larger primates (Burns et al., 1995; Kendall et al., 2000). The implantation of striatal grafts into marmosets that had previously received unilateral putamen lesions ameliorated some of the motor impairments, which suggested at least partial restoration of the motor loop. In support of this we found direct evidence of host-graft cortico-striatal connectivity using an anterograde tracer injected in the primary motor cortical region (Kendall et al., 1998a). In larger primates, with lesions of the caudate and putamen, striatal [figure: see text] allografts and xenografts have been shown to reduce apomorphine-induced dyskinesias (Isacson et al., 1989; Hantraye et al., 1992; Palfi et al., 1998). The mechanism by which dyskinesias are elicited is not fully understood but alterations in firing patterns within both segments of the globus pallidus have been identified during dyskinetic movements (Matsumura et al., 1995). It seems likely that it would actually require re-establishment of afferent connections between the implanted putamen and the globus pallidus as well as of functioning dopamine receptors within the graft for the reduction in the dyskinetic profile to be observed. Certainly there is evidence, from rodent studies and the marmoset study described here, that close proximity of the graft to the globus pallidus yields better functional recovery (Isacson et al., 1986). In addition, anatomical tracing studies in rats have demonstrated connections between the implanted tissue and the host globus pallidus (Wictorin et al., 1989b, 1990) However, the relationship between graft placement and functional recovery remains to be fully substantiated.

Functional integration of striatal allografts in a primate model of Huntington's disease.

Huntington's disease is an autosomal dominant, inherited disorder that results in progressive degeneration of the basal ganglia (especially the neostriatal caudate nucleus and putamen) and other forebrain structures and is associated with a clinical profile of movement, cognitive and psychiatric impairments for which there is at present no effective therapy. Neuropathological, neurochemical and behavioral features of the disease can all be reproduced in experimental animals by local injection of excitotoxic or metabolic toxins into the neostriatum. All these features of the disease can be alleviated, at least in rats, by transplantation of embryonic striatal tissue into the degenerated striatum, which was the basis for commencing the first clinical trials of striatal transplantation in Huntington's patients. However, although rat striatal xenografts may temporarily reduce apomorphine-induced dyskinesias in monkeys, there has been no demonstration that allograft techniques that work well in rats translate effectively to the much larger differentiated striatum of primates. Here we demonstrate good survival, differentiation and integration of striatal allografts in the primate neostriatum, and recovery in a test of skilled motor performance. Long-term graft survival in primates indicates probable success for clinical transplants in Huntington's disease; in addition, our data suggest that graft placement has a direct influence on the pattern and extent of functional recovery.

Neuronal cell transplantation for Parkinson's and Huntington's diseases.

The brain constitutes a privileged transplantation site. Under appropriate conditions neuronal tissues can survive transplantation into the damaged brain, integrate with the host, and alleviate functional impairments associated with neurological disease. The experimental techniques have been developed to the point of clinical application with demonstrable benefit in Parkinson's disease, and similar applications in Huntington's disease appear to be imminent. Nevertheless, present techniques require use of embryonic/fetal tissues which will limit the availability of donors for the foreseeable future. There is an active search for alternative sources of tissue that are equally effective but more readily available, including engineered cells, expanded stem/precursor cells, and xenografts.