Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG. These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. .

Objectives: Screening tests of global cognition detect racial differences in scores even after adjustment for educational attainment. Differential educational environments in adolescence may affect individual cognitive function. This study examines the impact of high school educational quality on late-life cognition among community-dwelling older adults. Methods/design: Data were collected from community-dwelling individuals from the Philadelphia Healthy Brain Aging (PHBA) cohort at the University of Pennsylvania Health System. The present analysis included subjects from the PHBA over the age of 55 years without a diagnosis of Parkinson's disease or dementia, who had attended high school in the City of Philadelphia. Cognition was assessed using the Montreal Cognitive Assessment (MoCA); clinical information was abstracted from the subject's electronic health record. High school information was obtained from the Philadelphia Board of Education. After univariable correlations were defined, we performed stepwise multiple linear regression models to determine the most significant predictors of late-life cognitive status. Results: A total of 130 subjects meeting inclusion criteria were included in the analysis. Years of education, race, educational level, school district, and financial status were all positively associated with MoCA. Significant negative associations included composite vascular risk, attendance at highly segregated schools, and historical poverty status. In stepwise multiple linear regression modeling, the impact of race on cognition remained significant when educational attainment was added to the model but was no longer significant once segregation status was added. Conclusions: This work suggests that academic and community factors beyond years of education have a marked impact on late-life cognition. KEYWORDS cognition, dementia, healthy aging, mild cognitive impairment, quality of education 1 | INTRODUCTION In an aging population, cognitive impairment is a major driver of both health-related quality of life (HRQOL) and health-care costs. Even before the diagnosis of dementia, individuals with subjective cognitive complaints report worse quality of life; 1-3 care partners of these individuals experience higher levels of anxiety and burnout. 4,5 As individuals progress from subjective complaints to mild cognitive impairment to dementia, health utilization and cost increase dramatically. In the United States alone, the monetary cost of dementia care, including both direct costs such as physician visits and medications, and also indirect costs such as informal care by spouses and children, was estimated at $236 billion in 2016. 6 Even conservative estimates assuming a plateau or decline in dementia prevalence acknowledge a doubling of inflation-adjusted care costs by 2040. 7 Additionally, on detailed neuropsychological testing and in advanced imaging studies,

Introduction Apathy is a common, troublesome symptom in Parkinson’s disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. Methods Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson’s Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥ 1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. Results Of 132 PD patients 12.1% (N=16) scored in the apathetic range at baseline. A total of 19.6% (N=26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR=3.56; 95% CI=1.09–11.62; p=0.04). Conclusions A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia.

BACKGROUND Low health literacy (HL) indicates a limited ability to understand and use basic information to make appropriate healthcare decisions. While low HL is associated with higher morbidity, mortality, and healthcare costs in multiple chronic conditions, little is known about HL and its associations in Parkinson’s disease (PD). METHODS Cross-sectional study of non-demented adults with PD participating in the National Parkinson Foundation Parkinson’s Outcomes Project at the University of Pennsylvania. Subjects were administered two brief HL assessments—the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF), a word-recognition test, and the Newest Vital Sign (NVS), a test of literacy, numeracy and understanding of health information—as well as demographic and clinical questionnaires. Adverse outcomes included falls in the 3 months preceding the study visit, and hospital admissions, emergency room visits, infections, or injuries in the preceding year. Caregiver burden was measured using the Multidimensional Caregiver Strain Index. RESULTS 168 subjects completed both HL screens (mean 65.8 years, 65.5% male, 65.2% Hoehn & Yahr Stage 2). Using the REALM-SF, 97.6% of subjects had adequate HL. Using the NVS, however, 29.8% had low HL, which was associated with older age, lower education, male gender, greater disease severity, and poorer cognition. Low HL was associated with hospital admission and increased caregiver burden. CONCLUSIONS Low HL is common and associated with greater caregiver burden and a higher likelihood of hospitalization in patients with PD. Since HL is associated with both disease severity and adverse outcomes, it may be an important, modifiable contributor to morbidity.

Background Parkinsonian signs are common, non-specific findings in older adults and associated with increased rates of dementia and mortality. It is important to understand which motor outcomes are associated with parkinsonian signs. Objectives To determine the role of parkinsonian signs on fall rates among older adults. Methods We conducted a longitudinal study of primary care patients from the University of Pennsylvania Health System. Adults over 55 years were assessed at baseline through surveys and a neurological examination. We recorded falls over the following 2 years. Parkinsonian signs were defined as the presence of 2 of 4 cardinal signs. Incident falls were compared between subjects with and without parkinsonian signs, and modified Poisson regression used to adjust for potential confounders in the relationship between parkinsonian signs and falls. Results 982 subjects with a mean age of 68 (s.d. 8.8) years participated. 29% of participants fell and 12% exhibited parkinsonian signs at baseline. The unadjusted RR for falls among individuals with parkinsonian signs was 1.36 (95% CI 1.05–1.76, p=0.02). After adjusting for age, cognitive function, urinary incontinence, depression, diabetes, stroke and arthritis, individuals with parkinsonian signs were still 38% more likely to fall than those without parkinsonian signs (RR 1.38, 95% CI 1.04–1.82; p=0.03). Falls among those with parkinsonian signs were more likely to lead to injury (53% vs 37%; p=0.04). Conclusions Parkinsonian signs are a significant, independent risk factor for falls. Early detection of this clinical state is important in order to implement fall prevention programs among primary care patients.