Claudia Mechi

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntingtons disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.

Fetal striatal grafting slows motor and cognitive decline of Huntington's disease

Objective To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntingtons disease (HD). Methods We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. Results Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [18F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [123I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. Conclusions Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.

Markers of JC virus infection in patients with multiple sclerosis under natalizumab therapy

Objective: To evaluate the frequency of JC polyomavirus (JCPyV) infection and anti-JCPyV antibodies in patients with multiple sclerosis under natalizumab therapy. Methods: Presence of anti-JCPyV antibodies and JCPyV DNA was analyzed in 39 patients with relapsing-remitting multiple sclerosis undergoing natalizumab therapy. Anti-JCPyV antibodies were evaluated in serum by a 2-step virus-like particle-based ELISA assay (Stratify), and JCPyV DNA was evaluated in peripheral blood mononuclear cells, plasma, and urine by quantitative PCR. The anti-JCPyV antibodies were evaluated in serum samples collected at the same time or later than those collected for DNA analysis. Results: JCPyV DNA was detected in 59% of patients, and anti-JCPyV antibodies were present in 67%. JCPyV DNA occurred more often in blood than in urine. Anti-JCPyV antibodies were observed in 70% of the JCPyV-infected patients, and JCPyV DNA was detected in 50% of the patients without anti-JCPyV antibodies. When JCPyV DNA was investigated in blood and urine the frequency of infection was higher than previously described. Conclusion: Under these experimental conditions, with respect to the observed frequency of JCPyV infection, the sensitivity of the anti-JCPyV antibody assay was lower than expected.

Susceptibility weighted MRI can help differentiating pathogenesis of white matter lesions in MS and CNS inflammatory vasculopathies.

cancelled 144 Poster presentation with discussion

I03 Magnetisation transfer MR imaging demonstrates degeneration of the subcortical and cortical grey matter in Huntington's disease

Purpose To investigate with magnetisation transfer (MT) MR imaging the microstructural changes of the residual brain subcortical and cortical grey matter (GM) in carriers of the Huntingtons disease (HD) gene and to preliminarily assess their correlation with the clinical features. Materials and methods 15 HD gene carriers with a range of clinical severity and 15 age and sex matched healthy controls underwent MT MR imaging on a 1.5T scanner. The MT ratio was measured automatically in several subcortical and cortical GM regions (striatal nuclei, thalami and the neocortex of the frontal, temporal, parietal and occipital lobes) using FMRIB Software Library tools. Results The MT ratio was significantly (p<0.05 with Bonferroni correction for multiple comparison) decreased in all subcortical structures but the putamen and diffusely in the cerebral cortex of HD carriers compared with controls. Close correlation was observed between the subcortical and cortical regional MT ratios and several clinical variables, including disease duration, motor disability and scores in timed neuropsychological tests. Conclusions MT imaging demonstrates degeneration of the subcortical and cortical GM in HD carriers and might serve along with volumetric assessment as a surrogate marker in future clinical trials of HD.