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

Soumya Unnikrishnan; Roshan Karunamuni; Mia A Salans; Suma Gudipati; Alexander S Qian; Justin Yu; Michael Connor; Minh-Phuong Huynh-Le; Michelle D Tibbs; Gretchen Hermann; Anny Reyes; Alena Stasenko; Tyler M Seibert; Carrie R McDonald; Jona A Hattangadi-Gluth

doi:10.1016/j.ijrobp.2023.05.026

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

Int J Radiat Oncol Biol Phys. 2023 Nov 15;117(4):834-845. doi: 10.1016/j.ijrobp.2023.05.026. Epub 2023 May 24.

Authors

Affiliations

¹ University of California San Diego School of Medicine, La Jolla, California; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
² Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
³ Radiation Oncology, The Brooklyn Cancer Center, Brooklyn, New York.
⁴ Department of Psychiatry, University of California San Diego, La Jolla, California.
⁵ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California; Department of Psychiatry, University of California San Diego, La Jolla, California.
⁶ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California. Electronic address: jhattangadi@health.ucsd.edu.

PMID: 37230430
DOI: 10.1016/j.ijrobp.2023.05.026

Abstract

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.