Faculty Bibliography

BACKGROUND:Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p19q status. METHODS:We analyzed 412 histologic oligodendroglial tumors with use of 1p19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p19q was performed. Polysomy was defined as >2 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS). RESULTS:In our cohort, 333 tumors (81%) had 1p19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p19q loss had significantly better PFS and OS than did the group with 1p19q maintenance (p < 0.0001 each). Patients with 1p19q loss and polysomy showed significantly shorter PFS survival than patients with 1p19q co-deletion only (p-<0.0001), but longer PFS and OS than patients with 1p19q maintenance (p < 0.01 and p<0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% of polysomic cells. Polysomy had no prognostic significance on progression-free or overall survival in patients with 1p19q maintenance. CONCLUSIONS:The presence of polysomy in oligodendroglial tumors with co-deletion of 1p19q predicts early recurrence and short survival in patients with 1p19q co-deleted tumors.

Vision relies on both specific knowledge of visual attributes, such as object categories, and general brain states, such as those reflecting arousal. We hypothesized that these phenomena independently influence recognition of forthcoming stimuli through distinct processes reflected in spontaneous neural activity. Here, we recorded magnetoencephalographic (MEG) activity in participants (N = 24) who viewed images of objects presented at recognition threshold. Using multivariate analysis applied to sensor-level activity patterns recorded before stimulus presentation, we identified two neural processes influencing subsequent subjective recognition: a general process, which disregards stimulus category and correlates with pupil size, and a specific process, which facilitates category-specific recognition. The two processes are doubly-dissociable: the general process correlates with changes in criterion but not in sensitivity, whereas the specific process correlates with changes in sensitivity but not in criterion. Our findings reveal distinct mechanisms of how spontaneous neural activity influences perception and provide a framework to integrate previous findings.

Dynamic functional connectivity captures temporal variations of functional connectivity during MRI acquisition and it may be a suitable method to detect cognitive changes in Parkinson's disease. In this study, we evaluated 118 patients with Parkinson's disease matched for age, sex and education with 35 healthy control subjects. Patients with Parkinson's disease were classified with normal cognition (n = 52), mild cognitive impairment (n = 46), and dementia (n = 20) based on an extensive neuropsychological evaluation. Resting state functional MRI and a sliding-window approach were used to study the dynamic functional connectivity. Dynamic analysis suggested two distinct connectivity 'States' across the entire group: a more frequent, segregated brain state characterized by the predominance of within-network connections, State I, and a less frequent, integrated state with strongly connected functional internetwork components, State II. In Parkinson's disease, State I occurred 13.89% more often than in healthy control subjects, paralleled by a proportional reduction of State II. Parkinson's disease subgroups analyses showed the segregated state occurred more frequently in Parkinson's disease dementia than in mild cognitive impairment and normal cognition groups. Further, patients with Parkinson's disease dementia dwelled significantly longer in the segregated State I, and showed a significant lower number of transitions to the strongly interconnected State II compared to the other subgroups. Our study indicates that dementia in Parkinson's disease is characterized by altered temporal properties in dynamic connectivity. In addition, our results show that increased dwell time in the segregated state and reduced number of transitions between states are associated with presence of dementia in Parkinson's disease. Further studies on dynamic functional connectivity changes could help to better understand the progressive dysfunction of networks between Parkinson's disease cognitive states.

Deficits of convergence and accommodation are common following traumatic brain injury, including mild traumatic brain injury, though the mechanism and localization of these deficits have been unclear and supranuclear control of the near-vision response has been incompletely understood. We describe a patient who developed profound instability of the near-vision response with inability to maintain convergence and accommodation following mild traumatic brain injury, who was identified to have a structural lesion on brain MRI in the pulvinar of the caudal thalamus, the pretectum, and the rostral superior colliculus (SC). We discuss the potential relationship between post-traumatic clinical near-vision response deficits and the MRI lesion in this patient. We further propose that the MRI lesion location, specifically the rostral superior colliculus, participates in neural integration for convergence holding, given its proven anatomic connections with the central mesencephalic reticular formation (cMRF) and C-group medial rectus motoneurons in the oculomotor nucleus which project to extraocular muscle non-twitch fibers specialized for fatigue-resistant, slow, tonic activity such as vergence holding.

Sensory neurons of the peripheral nervous system are critical in health and disease. Sensory neurons derived from induced pluripotent stem (iPS) cells are now being used increasingly for in vitro models of neuropathy, pain, and neurotoxicity. DNA methylation is critical for neurodevelopment and has been implicated in many neuronal diseases, but has not been examined in iPS-derived sensory neurons. In order to better characterize the iPS-derived sensory neuron model, we have undertaken a genome-wide DNA methylation study on the cells from human iPS to iPS-derived sensory neurons during differentiation through reduced representation and bisulfite sequencing. We report decreasing DNA methylation with iPS-derived sensory neuronal differentiation that is reflected in increasing numbers and proportions of hypomethylated individual CpGs and regions, as well as lowered DNMT3b expression. Furthermore, genes with changes in DNA methylation near their TSS suggest key pathways that may be involved in iPS-derived sensory neuronal differentiation. These findings provide insights into sensory neuronal differentiation and can be used for further in vitro modelling of disease states.