Neural correlates of abnormal sensory discrimination in laryngeal dystonia

AbstractAberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder

CD8-targeted PET Imaging of Tumor Infiltrating T cells in Patients with Cancer: A Phase I First-in-Human Study of

There is a need for in vivo diagnostic imaging probes that can noninvasively measure tumor infiltrating CD8+ leukocytes. Such imaging probes could be used to predict early response to cancer immunotherapy, help select effective single or combination immunotherapies, and facilitate the development of new immunotherapies or immunotherapy combinations. This study was designed to optimize conditions for performing CD8 PET imaging with 89Zr-Df-IAB22M2C and determine if CD8 PET imaging could provide a safe and effective non-invasive method of visualizing the whole body biodistribution of CD8+ leukocytes. Methods: We conducted a phase 1 first-in-human PET imaging study using an anti-CD8 radiolabeled minibody, 89Zr-Df-IAB22M2C, to detect whole body and tumor CD8+ leukocyte distribution in patients with metastatic solid tumors. Patients received 111 MBq of 89Zr-Df-IAB22M2C followed by serial PET scans over a 5-7-day period. A two-stage design included a dose-escalation phase and a dose-expansion phase. Biodistribution, radiation dosimetry, and semi-quantitative evaluation of 89Zr-Df-IAB22M2C uptake were performed in all patients. Results: 15 subjects with metastatic melanoma, non-small cell lung cancer, and hepatocellular carcinoma were enrolled. No drug-related adverse events or abnormal laboratory results were noted except for a transient increase in anti-drug antibodies in 1 subject. 89Zr-Df-IAB22M2C accumulated in tumors and CD8-rich tissues (e.g. spleen, bone marrow, nodes) with maximum uptake at 24-48 hours post injection and low background activity in CD8-poor tissues (e.g. muscle and lung). Radiotracer uptake in tumors was noted in 10/15 subjects, including 7/8 subjects on immunotherapy, 1/2 subjects on targeted therapy, and 2/5 treatment naïve subjects. In three patients with advanced melanoma or hepatocellular carcinoma on immunotherapy, post-treatment CD8 PET/CT scans demonstrated increased 89Zr-Df-IAB22M2C uptake in tumor lesions, which correlated with response. Conclusion: CD8 PET imaging with 89Zr-Df-IAB22M2C is safe and has the potential to visualize the whole-body biodistribution of CD8+ leukocytes in tumors and reference tissues, and may predict early response to immunotherapy