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

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Confabulation following rupture of posterior communicating artery

In this study we report a patient, MG, who following rupture of left posterior communicating artery exhibited an amnesic-confabulatory syndrome. Neuropsychological examination showed severe impairment on episodic memory tasks, which were marred by florid but plausible and semantically appropriate confabulation. Performance on tasks involving various kinds of semantic knowledge was normal or only mildly impaired. Performance on tasks traditionally considered sensitive to frontal dysfunction was severely impaired with the exception of Cognitive Estimates where MG's performance was completely normal. There was no evidence of structural (CT scan) or metabolic (SPECT) damage to the frontal lobe. It is argued that tasks traditionally considered sensitive to frontal dysfunction are not specifically implemented by cognitive resources based on frontal structures. MG's confabulation is discussed in terms of a possible disruption of cognitive functions involved in the control of the subjective experience of feeling of remembering

Dissection and preparation of human primary fetal ganglionic eminence tissue for research and clinical applications

Here, we describe detailed dissection and enzymatic dissociation protocols for the ganglionic eminences from the developing human brain to generate viable quasi-single cell suspensions for subsequent use in transplantation or cell culture. These reliable and reproducible protocols can provide tissue for use in the study of the developing human brain, as well as for the preparation of donor cells for transplantation in Huntington’s disease (HD). For use in the clinic as a therapy for HD, the translation of these protocols from the research laboratory to the GMP suite is described, including modification to reagents used and appropriate monitoring and tissue release criteria

Neocortical morphometry in Huntington's disease: Indication of the coexistence of abnormal neurodevelopmental and neurodegenerative processes

Huntington's disease (HD) is an inherited, autosomal dominant disorder that is characteristically thought of as a degenerative disorder. Despite cellular and molecular grounds suggesting HD could also impact normal development, there has been scarce systems-level data obtained from in vivo human studies supporting this hypothesis. Sulcus-specific morphometry analysis may help disentangle the contribution of coexisting neurodegenerative and neurodevelopmental processes, but such an approach has never been used in HD. Here, we investigated cortical sulcal depth, related to degenerative process, as well as cortical sulcal length, related to developmental process, in early-stage HD and age-matched healthy controls. This morphometric analysis revealed significant differences in the HD participants compared with the healthy controls bilaterally in the central and intra-parietal sulcus, but also in the left intermediate frontal sulcus and calcarine fissure. As the primary visual cortex is not connected to the striatum, the latter result adds to the increasing in vivo evidence for primary cortical degeneration in HD. Those sulcal measures that differed between HD and healthy populations were mainly atrophy-related, showing shallower sulci in HD. Conversely, the sulcal morphometry also revealed a crucial difference in the imprint of the Sylvian fissure that could not be related to loss of grey matter volume: an absence of asymmetry in the length of this fissure in HD. Strong asymmetry in that cortical region is typically observed in healthy development. As the formation of the Sylvian fissure appears early in utero, and marked asymmetry is specifically found in this area of the neocortex in newborns, this novel finding likely indicates the foetal timing of a disease-specific, genetic interplay with neurodevelopment

In vivo evidence for the selective subcortical degeneration in Huntington's disease.

Although Huntington's disease is largely considered to be a subcortical disease, there is no clear consensus on whether all deep grey matter loss is a direct downstream consequence of the massive degeneration of the medium-size spiny neurons in the striatum. Our aim was to characterise in vivo such preferential degeneration by analysing various distinct diffusion imaging measures including mean diffusivity, anisotropy, fibre orientation (using the information of the principal diffusion direction) and white matter tractography. All results converged to demonstrate the selective degeneration of connections in subcortical grey and white matter, degeneration which was likely to originate with the death of the striatal medium-size spiny neurons. Indeed, we found a significant increase of MD and FA in all the subcortical grey matter structures involved in the cortico-striato-thalamo-cortical loops. The atypical striatal and pallidal increase of FA was concurrent to a decrease of the dispersion of the fibre orientation, unambiguously characterising a preferential loss of connections along specific radiating directions from these structures while some others are comparatively spared. Analysis of striatal and pallidal white matter tracts revealed that striato-pallidal projections were the most affected. The ability of DTI to uncover the impact of such neurodegenerative disease on some specific neuronal/axonal populations is a further step towards the future definition of a surrogate marker of this disease. Beyond Huntington's disease, we prove here that diffusion imaging technique, associated to adequate methodological analyses, can provide insight into any neurodegenerative disorder for which some neuronal populations or connections are selectively targeted over others

Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington's disease mutation in peripheral lymphocytes

The search for peripheral markers of neurodegenerative diseases aims at identifying molecules that could help in monitoring the effects of future therapeutics in easily accessible cells. Here we focused on the involvement of the endocannabinoid system in Huntington's disease (HD). We assayed peripheral lymphocytes from HD patients and healthy controls, and found that the activity of the fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide (AEA), was dramatically decreased (down to less than 10%) in HD compared to healthy subjects. Concomitantly, the endogenous levels of AEA were approximately 6-fold higher in HD versus healthy lymphocytes, while the other elements of the endocannabinoid system were not affected by HD. Low FAAH activity in HD lymphocytes was not due to down-regulation of protein expression, but rather to blockage of enzyme activity by a cytosolic and irreversible inhibitor. Finally, pre-HD patients showed defective FAAH activity, as did the brain of HD patients compared with healthy controls. Taken together, our data indicate that FAAH activity in lymphocytes mirrors some of the metabolic changes which take place in the brain, it is a measurable non-genetic peripheral marker that segregates with the HD mutation, and it might serve as a target to test chemicals active on the widespread toxic effects of the mutant protein