Patients with multiple system atrophy-parkinsonism show more severe and more widespread cognitive dysfunctions than patients with multiple system atrophy-cerebellar ataxia. Our results also indicate that cognitive dysfunction in patients with multiple system atrophy-parkinsonism may be associated with prefrontal involvement.

Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.

Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of ''rejuvenated'' induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8ab T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) a chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8ab T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8ab T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.

Objective: To determine whether apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values can detect early pathological involvement in multiple system atrophy (MSA), and be used to differentiate MSA-P (multiple system atrophy if parkinsonian features predominate) from Parkinson's disease (PD). Methods: We compared ADC and FA values in the pons, cerebellum and putamen of 61 subjects (20 probable MSA patients, 21 age matched PD patients and 20 age matched healthy controls) using a 3.0 T magnetic resonance system. Results: ADC values in the pons, cerebellum and putamen were significantly higher, and FA values lower in MSA than in PD or controls. These differences were prominent in MSA lacking dorsolateral putaminal hyperintensity (DPH) or hot cross bun (HCB) sign. In differentiating MSA-P from PD using FA and ADC values, we obtained equal sensitivity (70%) and higher specificity (100%) in the pons than in the putamen and cerebellum. In addition, all patients that had both significant low FA and high ADC values in each of these three areas were MSA-P cases, and those that had both normal FA and ADC values in the pons were all PD cases. Our diagnostic algorithm based on these results accurately diagnosed 90% of patients with MSA-P. Conclusion: FA and ADC values detected early pathological involvement prior to magnetic resonance signal changes in MSA. In particular, low FA values in the pons showed high specificity in discriminating MSA-P from PD. In addition, combined analysis of both FA and ADC values in all three areas was more useful than only one.