No abstract

No abstract

Bilateral ibotenic acid lesions of the anteromedial neostriatum produce neuropathological and behavioral changes in rats that are characterized by locomotor hyperactivity and severe maze learning impairments, which can be viewed as analogous to changes seen in Huntington disease. Grafts of fetal striatal neurons, implanted either into the lesioned striatum or into the denervated globus pallidus, reduced both the learning impairments and the locomotor hyperactivity, probably via different mechanisms. The results demonstrate the capacity of neural implants for functional neuronal replacement and promotion of functional recovery after damage to a maijor telencephalic structure participating in complex cognitive and motoric behaviors.Neurodegenerative diseases in man represent neuropathological conditions where rather selective and anatomically restricted neuronal damage results in characteristic and often severe behavioral deterioration. There is accumulating evidence from experimental work in rodents that intracerebral implants of fetal aminergic neurons at least to some degree can substitute, both anatomically and functionally, for lost intrinsic pathways in the brain. This is based, in particular, on results obtained with grafts of mesencephalic dopamine neurons in rats with lesions that mimic the dopamine deficiency in patients with Parkinson disease (1, 2) and with grafts of basal forebrain cholinergic neurons in rats with lesions that reproduce the cholinergic deficit in patients with dementia of the Alzheimer type (3-5). In these types of experimental lesions the primary damage is confined to such types of neurons, operating with acetylcholine or a monoamine as their transmitter, which normally act as tonic regulatory or level-setting systems in the brain. Hence, it is conceivable that the functional effects of grafted dopaminergic and cholinergic neurons could be mediated via a relatively nonspecific tonic release of the transmitter into their local environment.Huntington chorea is characterized by a massive neuronal degeneration, particularly in the neostriatum, accompanied by motor dyskinesias and progressive mental deterioration. In rats, injections of excitotoxic amino acids, such as kainic acid or ibotenic acid (IA), into the caudate-putamen (CPu) are capable of producing neuropathological and neurochemical changes in the basal ganglia that resemble those seen in Huntington disease (6-8). The behavioral changes seen in rats with excitotoxic neostriatal lesions are, by necessity, only of a correlative nature compared to the human disease. Thus, the rats with lesions do not, for example, exhibit any overt involuntary movements, typically seen in Huntingtonian patients. However, when the excitotoxic lesion involves the anteromedial neostriatum, which is the region most closely corresponding to the head of the caudate nucleus in man, the rats do develop a hyperactivity syndrome combined with substantial impairments in learning and memory (9-13), which can be viewed as analogous to the cardinal beha...

Expanded neural precursor cells provide an attractive alternative to primary fetal tissue for cell replacement therapies in neurodegenerative diseases. In this study we transplanted epigenetically propagated human neural precursor cells into a rat model of Huntington's disease. Neural precursors survived transplantation and large numbers differentiated to express neuronal antigens, including some that expressed DARPP-32, indicating a mature striatal phenotype had been adopted. Neuronal fibers from the grafts projected diffusely throughout the host brain, although there was no evidence that outgrowth was specifically target directed. This study supports the contention that propagated human neural precursors may ultimately be of use in therapeutic neural transplantation paradigms for diseases such as Huntington's disease.

Background: Huntington’s disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. Methods: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntington’s Disease Network’s (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol. Results: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn-35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on anti-dyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease. Conclusions: The unparalleled collection of clinical data and biomaterials within the EHDN’s REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments.