In the reports by Gallina et al., graft overgrowth was observed in all transplanted patients and as early as 4 months after surgery. The latter tissue growth had virtually ceased 9–10 months after transplantation. BMN 673 chemical structure However, the grafts had enlarged aberrantly and were not confined to the surgical target sites. In fact, they encompassed regions of the white matter within the overlying cortex and ventral striatum. Hypermetabolic activity was demonstrated by FDG-PET 6–9 months after surgery but had decreased by 12 months after transplantation. Changes in D1 receptor binding varied between patients,
which correlated with limited improvement, if any [21,52]. One additional MRI report showed large cysts and well-delimited masses in one patient 10 years after transplantation [45]. The very first post-mortem study of a transplanted HD-affected brain was conducted in a patient who died 18 months after transplantation of causes unrelated to the procedure.
This study provided the initial proof of concept that solid foetal striatal grafts could survive in a human HD brain [42,53] (Table 3). In this find more patient, most grafts survived (six out of 10), with three localized in the right putamen, two in the left putamen as well as one in the anterior limb of the internal capsule. The majority of transplants could be identified macroscopically. Using immunohistochemical staining, the grafts exhibited a compartmentalized organization with the formation of striatal patchy areas known as p-zones, as well as areas lacking a striatal phenotype (non p-zones) [54]. Large and medium-sized neurones were predominantly seen in the p-zones of the grafts using typical striatal
markers such as dopamine receptor-related phosphoprotein 32 kDa (DARPP-32), calretinin, acetylcholinesterase (AChE), calbindin, enkephalin and substance P. Interneurones positively stained for choline acetyltransferase (ChAT), NADPH-diaphorase (NADPH-d) and parvalbumin were also detected within p-zones. Non p-zones were largely devoid of these markers but were richer in glial fibrillary acidic protein (GFAP)-positive astrocytes. Human leucocyte antigen-DR (HLA-DR), a marker for PAK6 macrophages and microglia, was rarely found in the transplant but was abundantly expressed in the host brain. There was no perivascular cuffing or T-cell infiltration, as visualized with CD4 and CD8. mHtt inclusions within the grafted tissue were not detected [42]. One additional case from the Freiburg University cohort provided a description of graft status at early time interval following transplantation [22] (Table 3). In that report, the authors confirmed the presence of three putaminal and two caudate grafts per hemisphere. DARPP-32-positive neurones, as visualized by immunohistochemistry, were found within the grafted tissue and were interspersed with calretinin- and somatostatin-positive interneurones.