Alloimmunisation to Donor Antigens and Immune Rejection Following Foetal Neural Grafts to the Brain in Patients with Huntington's Disease

BACKGROUND: The brain is deemed “immunologically privileged” due to sparse professional antigen-presenting cells and lymphatic drainage, and to the blood-brain barrier. Although the actual extent of this privilege is controversial, there is general consensus about the limited need in intracerebral neural grafts for immunosuppressive regimens comparable to those used in other cases of allotransplantation. This has led over the past fifteen years to the use of either short-term or even no immunosuppression in most clinical trials with foetal neural transplant in patients with Parkinson's and Huntington's disease. METHODOLOGY/PRINCIPAL FINDINGS: We report biological demonstration of alloimmunisation without signs of rejection in four grafted patients out of 13 studied during the course of a clinical trial involving fetal neural transplantation in patients with Huntington's Disease. Biological, radiological and clinical demonstration of an ongoing rejection process was observed in a fifth transplanted patient. The rejection process was, however, fully reversible under immunosuppressive treatment and graft activity recovered within six months. CONCLUSIONS/SIGNIFICANCE: There had been, up to date, no report of documented cases that could have cast a doubt on those procedures. Our results underline the need for a reconsideration of the extent of the so-called immune privilege of the brain and of the follow-up protocols of patients with intracerebral grafts. It also suggests that some of the results obtained in past studies with foetal neural transplants may have been biased by an unrecognized immune response to donor cells

Human Mesenchymal Stem Cells Prolong Survival and Ameliorate Motor Deficit through Trophic Support in Huntington's Disease Mouse Models

We investigated the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in Huntington's disease (HD) mouse models. Ten weeks after intrastriatal injection of quinolinic acid (QA), mice that received hBM-MSC transplantation showed a significant reduction in motor function impairment and increased survival rate. Transplanted hBM-MSCs were capable of survival, and inducing neural proliferation and differentiation in the QA-lesioned striatum. In addition, the transplanted hBM-MSCs induced microglia, neuroblasts and bone marrow-derived cells to migrate into the QA-lesioned region. Similar results were obtained in R6/2-J2, a genetically-modified animal model of HD, except for the improvement of motor function. After hBM-MSC transplantation, the transplanted hBM-MSCs may integrate with the host cells and increase the levels of laminin, Von Willebrand Factor (VWF), stromal cell-derived factor-1 (SDF-1), and the SDF-1 receptor Cxcr4. The p-Erk1/2 expression was increased while Bax and caspase-3 levels were decreased after hBM-MSC transplantation suggesting that the reduced level of apoptosis after hBM-MSC transplantation was of benefit to the QA-lesioned mice. Our data suggest that hBM-MSCs have neural differentiation improvement potential, neurotrophic support capability and an anti-apoptotic effect, and may be a feasible candidate for HD therapy

Automatic segmentation of the striatum and globus pallidus using MIST: Multimodal Image Segmentation Tool

Accurate segmentation of the subcortical structures is frequently required in neuroimaging studies. Most existing methods use only a T1-weighted MRI volume to segment all supported structures and usually rely on a database of training data. We propose a new method that can use multiple image modalities simultaneously and a single reference segmentation for initialisation, without the need for a manually labelled training set. The method models intensity profiles in multiple images around the boundaries of the structure after nonlinear registration. It is trained using a set of unlabelled training data, which may be the same images that are to be segmented, and it can automatically infer the location of the physical boundary using user-specified priors. We show that the method produces high-quality segmentations of the striatum, which is clearly visible on T1-weighted scans, and the globus pallidus, which has poor contrast on such scans. The method compares favourably to existing methods, showing greater overlap with manual segmentations and better consistency

The neural substrates of script knowledge deficits as revealed by a PET study in Huntington's disease

Item does not contain fulltextIntroduction Previous neuropsychological investigations have suggested that both the prefrontal cortex and the basal ganglia are involved in the management of script event knowledge required in planning behavior. Methods This study was designated to map, the correlations between resting-state brain glucose utilization as measured by FDG-PET (positron emission tomography) and scores obtained by means of a series of script generation and script sorting tasks in 8 patients with early Huntington's disease. Results These patients exhibited a selectively greater impairment for the organizational aspects of scripts compared to the semantic aspects of scripts. We showed significant negative correlations between the number of sequencing, boundary, perseverative and intrusion errors and the metabolism of several cortical regions, not only including frontal, but also posterior regions. Conclusion Our findings suggest that, within the fronto-striatal system, the cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia. Highlights ► The correlation between resting-state brain glucose utilization and performance on script generation and sorting tasks was examined in Huntington's disease. ► A selectively greater impairment for the organizational aspects of scripts was observed. ► Significant negative correlations between script errors and the metabolism of several cortical frontal and posterior regions were found. ► The cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia

Distribution of grey matter atrophy in Huntington's disease patients: a combined ROI-based and voxel-based morphometric study.

The striatum, a subcortical structure, is the principal target of the neurodegenerative process in Huntington's disease (HD). The measurement of striatal atrophy using the bicaudate ratio on CT scanner images has therefore been used for years to assess disease progression, but this measure only takes into account unidimensional changes in the head of the caudate nucleus. Recently, voxel-based morphometry (VBM), which permits automated statistical comparisons of whole-brain MRI images, has been proposed to quantify striatal atrophy. However, VBM was not originally designed to study subcortical structures, and severe deep brain deformations that occur in HD may hamper the automatic processing of VBM. Here, we validate the use of the optimised protocol of VBM to quantify subcortical atrophy in HD by comparing results obtained with this method to those provided by manual segmentation of subcortical structures. We studied 20 patients with early HD and 12 controls matched for age, sex and handedness using an improved T1-weighted sequence that eased grey matter segmentation. Both manual and automated methods evidenced the dorso-ventral gradient of striatal atrophy, a loss of grey matter in the globus pallidus and the thalamus, and similar correlations between clinical scores and subcortical atrophy. Furthermore, we were able to detect with VBM grey matter loss in the substantia nigra, the hypothalamus, the amygdala, the insular cortex and the premotor and sensorimotor cortices. Finally, VBM provided results consistent with previous post mortem results and proved to be a sensitive biomarker capable of correctly managing subcortical distortions throughout HD patients' brains