Grant Number:	1R01CA289833-01A1 Interpret this number
Primary Investigator:	Hattangadi-Gluth, Jona
Organization:	University Of California, San Diego
Project Title:	Mechanisms of Radiation-Induced Neurocognitive Decline (MIND): Longitudinal Study of Imaging Biomarkers and Risk and Resilience Factors Underlying Cognitive Phenotypes in Patients with Glioma
Fiscal Year:	2025

Abstract While radiotherapy (RT) is a mainstay in the treatment of glioma, most patients will experience radiation-induced neurocognitive decline due to injury to critical brain tissue. The pathogenesis of radiation-induced neurocognitive decline is not well understood and the potential risk factors for neurocognitive decline including tumor-related, other treatment-related, and patient-specific parameters are unclear. In this proposal, designed to respond directly to RFA PAR-21-329 on neurotoxicity of cancer therapies, we will perform a prospective longitudinal study to clinically characterize RT-associated cognitive decline using a novel patient-centered approach (cognitive phenotyping), uncover the mechanisms underlying these changes using quantitative multimodal imaging (MMI), and identify risk and resilience factors that moderate the relationship between RT-induced brain injury and cognitive decline. This work will guide future interventions for cognitive-sparing radiotherapy that aim to optimize neurocognitive outcomes in patients with glioma. Specific Aims: 1. To characterize neurocognitive heterogeneity and identify cognitive phenotypes in glioma patients before and longitudinally after RT. 2: To analyze mechanisms underlying radiation-induced cognitive decline by measuring MMI biomarkers of structural and microstructural damage and vascular sufficiency over time. 3: To identify tumor-, treatment-, and patient-related factors (including demographic, cerebrovascular health, and social determinants of health; SDH) that impact a patient’s vulnerability to RT-induced brain injury and increase risk for cognitive decline. Study Design: We will prospectively enroll adult patients with glioma receiving fractionated partial brain radiotherapy on an open longitudinal, observational study (NCT05576103) with total target accrual of n=250. We will recruit English and Spanish-speaking patients who are diverse in race, ethnicity, and socioeconomic class from a broad geographical region. Patients will undergo standard of care clinical MRI, including diffusion, 3D volumetric, and perfusion imaging along with comprehensive neurocognitive, mood, and quality of life assessments at discrete endpoints: baseline (pre-RT); 3-, 6-, 12-months post-RT, then yearly for up to 5 years. Socio-demographic, clinical, tumor-related, and treatment variables will be collected, along with assessments of tumor progression. Cognitive phenotypes and MMI signatures of brain health will be derived pre-RT and their trajectories will be measured up to 5 years post-RT. Finally, risk and resilience factors related to vascular health and SDH will be explored as potential moderators of RT-induced brain injury and cognitive decline. This study has strong implications for public health because it will identify modifiable factors which impact treatment-related cognitive decline in patients with glioma. This study also strives to improve representation of minority patients in clinical trials, which will increase generalizability and the clinical impact of our findings.





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