Abstract & Commentary
Source: Gaura V, et al. Striatal neural grafting improves cortical metabolism in Huntington’s disease patients. Brain. 2004;127:65-72.
The prospects for therapy in Huntington’s disease (HD) are rapidly improving. A number of discoveries about disease pathogenesis have been made that have targeted abnormalities in gene transcription, as well as energy metabolism, as potential therapeutic targets. Nevertheless, another potential treatment is to use striatal neural grafts. HD has for 15 years been considered a disease potentially amenable to cell therapy. A characteristic of the disease is that there are reductions in glucose metabolism as assessed by positron emission tomography (PET). It is detected initially in the striatum but then progresses into the cerebral cortex as the disease worsens. The cortical hypometabolism has been attributed to dysfunction of the cortico-striato-thalamo-cortical loops induced by the striatal disease. Another possibility, however, is that it may be related directly to some loss of cortical neurons within the cerebral cortex.
The rationale for neural grafting in HD differs from that in Parkinson’s disease (PD) because grafted neurons in HD have to substitute completely for degenerated cells in the striatum, whereas they are expected to provide innervation only in PD. In rodents, as well as nonhuman primates, striatal xenografts and allografts implanted into the lesioned striatum have been shown to survive, integrate into the host brain circuitry, and improve motor and cognitive functions. Like normal striatal neurons, grafted cells receive topographically organized cortical inputs and establish efferent projections to appropriate striatal targets. These include the globus pallidus and substantia nigra pars reticulata. Previous studies have shown that the reconstruction of neural circuitry can be physiologically active and can at least partially normalize the metabolic hypoactivity in the extrapyramidal neuronal system induced by striatal degeneration.
Gaura and associates have been studying fetal striatal allografts for many years. They carried out a pilot study, reported approximately 2 years ago in the Lancet. At that time, they noted that a number of patients had shown stabilization and even clinical improvement. The present report is a follow-up on these patients. They note that of the 5 patients who were initially grafted, the clinical improvement in 3 of the patients was associated with the reduction in the striatal and cortical hypometabolism. That demonstrated the grafts were able to restore function of the striatal-cortical loops. Conversely, in 2 patients who did not improve by the grafts, the striatal and cortical hypometabolism progressed over the 2-year follow-up period.
These results are very encouraging. They suggest that fetal striatal grafts can survive and function. They appear to have physiological effects that result in improved glucose metabolism that were accompanied by clinical improvements. Interestingly, the outcome of the patients with regard to both clinical improvement and clinical worsening was directly reflected by the cortical and striatal metabolism on PET scans, suggesting that this is a useful indicator for following the outcome of striatal allografts. — M. Flint Beal
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.