The retinas of Alzheimer’s disease (AD) patients and transgenic AD animal models display amyloid beta deposits and degeneration of ganglion cells. Little is known, however, about the glial changes in the AD retina. The present study used a triple transgenic mouse model (3xTG-AD), which carries mutated human amyloid precursor protein, tau, and presenilin 1 genes and closely mimics the human brain pathology, to investigate retinal glial changes in AD. AD cognitive symptoms are known to begin in the 3xTG-AD mice at four months of age but plaques and tangles are not seen until six to twelve months. Müller cells in 3xTG-AD animals were GFAP-positive, indicating activation, at the earliest time point investigated, nine months. Astrocyte activation was also suggested in the 3xTG-AD mice by an apparent increase in size and process number. Another glial marker, S100, was expressed by astrocytes in both the non-transgenic (NTG) controls and 3xTG-AD retinas. Labeling was predominantly nuclear in nine month non-transgenic (NTG) control mice but was also seen in the cytoplasm and processes at 18 months of age. Interestingly, the nuclear localization was not as prominent in the 3xTG-AD retina even at nine months with labeling observed in astrocyte processes. The diffusion of S100 suggests the possible secretion of this protein, as is seen in the brain, with age and, more profoundly, associated with AD. Several dense, abnormally shaped, opaque structures were noted in all 3xTG-AD mice investigated. These structures, which were enveloped by GFAP and S100-positive astrocytes and Müller cells, were positive for amyloid beta, suggesting that they are amyloid plaques. Staining control retinas with amyloid showed similar structures in 30% of NTG animals but these were fewer in number and not associated with glial activation. The results herein indicate retinal glia activation in the 3xTG-AD mouse retina.

Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH-mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine.

Cutaneous histiocytoid carcinoma can occur as a primary tumor of the periocular region. Morphologically similar histiocytoid carcinomas arising as primary tumors of the breast have a predilection for orbital metastases. They can occasionally contain regions with prominent vacuolated cytoplasm and minimal nuclear atypia, which mimic benign histiocytic lesions. Differentiating nonneoplastic, primary neoplastic, and metastatic histiocytoid lesions involving the periorbita can be challenging for both the clinician and the pathologist, and this distinction has management implications. Herein, we present 3 cases to illustrate the challenges of diagnosing periocular histiocytoid carcinoma.