Microstructural Cerebellar Injury Independently Associated With Processing Speed in Adult Patients With Primary Brain Tumors: Implications for Cognitive Preservation.

PURPOSE: The cerebellum's role in posttreatment neurocognitive decline is unexplored. This study investigated associations between cerebellar microstructural integrity using quantitative neuroimaging biomarkers and neurocognition among patients with primary brain tumors receiving partial-brain radiation therapy (RT). METHODS AND MATERIALS: In a prospective trial, 65 patients underwent volumetric brain magnetic resonance imaging, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment before RT and at 3, 6, and 12 months after RT. Delis-Kaplan Executive Function System-Trail Making (D-KEFS-TM) visual scanning and number and letter sequencing and Wechsler Adult Intelligence Scale, Fourth Edition, coding were used to evaluate PS. The cerebellar cortex and white matter (WM) and supratentorial structures subserving the previously mentioned cognitive domains were autosegmented. Volume was measured within each structure at each time point along with diffusion biomarkers (fractional anisotropy and mean diffusivity) in WM structures. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If associated, cerebellar biomarkers were evaluated as independent predictors of cognitive scores controlling for domain-specific supratentorial biomarkers. RESULTS: Left (P = .04) and right (P < .001) cerebellar WM volume declined significantly over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Smaller left cerebellar cortex volume was associated with worse D-KEFS-TM number (P = .01) and letter (P = .01) sequencing scores. A smaller right cerebellar cortex volume correlated with worse D-KEFS-TM visual scanning (P = .02) and number (P = .03) and letter (P = .02) sequencing scores. Greater right cerebellar WM mean diffusivity, indicating WM injury, was associated with worse D-KEFS-TM visual scanning performance (P = .03). Associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers. CONCLUSIONS: Injury to the cerebellum as measured with quantitative biomarkers correlates with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Efforts to preserve cerebellar integrity may preserve PS.

Dose-Dependent Atrophy in Bilateral Amygdalae and Nuclei After Brain Radiation Therapy and Its Association With Mood and Memory Outcomes on a Longitudinal Clinical Trial.

PURPOSE: Amygdalae are bilateral, almond-shaped structures located anterior to the hippocampi, critical to limbic system functions of emotional processing and memory consolidation. The amygdalae are heterogeneous, composed of multiple nuclei with distinct structural and functional properties. We prospectively assessed associations between longitudinal changes in amygdala morphometry, including component nuclei, and functional outcomes in patients with primary brain tumors receiving radiation therapy (RT). METHODS AND MATERIALS: On a prospective longitudinal trial, 63 patients underwent high-resolution volumetric brain magnetic resonance imaging and testing for mood (Beck Depression Inventory and Beck Anxiety Inventory), memory (Brief Visuospatial Memory Test-Revised [BVMT] Total Recall and Delayed Recall; Hopkins Verbal Learning Test-Revised [HVLT] Total Recall and Delayed Recall), and health-related quality-of-life outcomes (Functional Assessment of Cancer Therapy-Brain Social/Family Well-Being and Emotional Well-Being) at baseline and 3, 6, and 12 months after RT. Amygdalae, including 8 nuclei, were autosegmented bilaterally using validated techniques. Linear mixed-effects models assessed longitudinal change in amygdalae and nuclei volumes and associations with dose and outcomes. Wilcoxon rank sum tests compared amygdala volume change between patient groups with worse and more stable outcomes at each time point. RESULTS: Atrophy was found in the right amygdala at 6 months (P = .001) and the left amygdala at 12 months (P = .046). A higher dose was associated with atrophy of the left amygdala (P = .013) at 12 months. The right amygdala showed dose-dependent atrophy at 6 months (P = .016) and 12 months (P = .001). Worse BVMT-Total, HVLT-Total, and HVLT-Delayed performance was associated with smaller left lateral (P = .014, P = .004, and P = .007, respectively) and left basal (P = .034, P = .016, and P = .026, respectively) nuclei volumes. Increased anxiety at 6 months was associated with greater combined (P = .031) and right (P = .007) amygdala atrophy. Greater left amygdala atrophy (P = .038) was noted in patients with decreased emotional well-being at 12 months. CONCLUSIONS: Bilateral amygdalae and nuclei undergo time- and dose-dependent atrophy after brain RT. Atrophy in amygdalae and specific nuclei was associated with poorer memory, mood, and emotional well-being. Amygdalae-sparing treatment planning may preserve neurocognitive and neuropsychiatric outcomes in this population.

Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNß Expression Increases Neonatal Sensitivity to Endotoxemia.

Sepsis is a major cause of neonatal morbidity and mortality. The current paradigm suggests that neonatal susceptibility to infection is explained by an innate immune response that is functionally immature. Recent studies in adults have questioned a therapeutic role for IFNß in sepsis; however, the role of IFNß in mediating neonatal sensitivity to sepsis is unknown. We evaluated the transcriptional regulation and expression of IFNß in early neonatal (P0) and adult murine models of endotoxemia (IP LPS, 5 mg/kg). We found that hepatic, pulmonary, and serum IFNß expression was significantly attenuated in endotoxemic neonates when compared to similarly exposed adults. Furthermore, endotoxemia induced hepatic p65/NFκB and IRF3 activation exclusively in adults. In contrast, endotoxemia induced immunotolerant p50/NFκB signaling in neonatal mice without evidence of IRF3 activation. Consistent with impaired IFNß expression and attenuated circulating serum levels, neonatal pulmonary STAT1 signaling and target gene expression was significantly lower than adult levels. Using multiple in vivo approaches, the source of hepatic IFNß expression in endotoxemic adult mice was determined to be the hepatic macrophage, and experiments in RAW 264.7 cells confirmed that LPS-induced IFNß expression was NFκB dependent. Finally, treating neonatal mice with IFNß 2 h after endotoxemia stimulated pulmonary STAT1 signaling and STAT1 dependent gene expression. Furthermore, IFNß treatment of endotoxemic neonatal animals resulted in significantly improved survival following exposure to lethal endotoxemia. In conclusion, endotoxemia induced IFNß expression is attenuated in the early neonatal period, secondary to impaired NFκB-p65/IRF3 signaling. Pre-treatment with IFNß decreases neonatal sensitivity to endotoxemia. These results support further study of the role of impaired IFNß expression and neonatal sensitivity to sepsis.