Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy

Barrett D Allen; Yasaman Alaghband; Eniko A Kramár; Ning Ru; Benoit Petit; Veljko Grilj; Michael S Petronek; Casey F Pulliam; Rachel Y Kim; Ngoc-Lien Doan; Janet E Baulch; Marcelo A Wood; Claude Bailat; Douglas R Spitz; Marie-Catherine Vozenin; Charles L Limoli

doi:10.1093/neuonc/noac248

Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy

Neuro Oncol. 2023 May 4;25(5):927-939. doi: 10.1093/neuonc/noac248.

Authors

Barrett D Allen¹, Yasaman Alaghband¹, Eniko A Kramár², Ning Ru¹, Benoit Petit³, Veljko Grilj³, Michael S Petronek⁴, Casey F Pulliam⁴, Rachel Y Kim¹, Ngoc-Lien Doan¹, Janet E Baulch¹, Marcelo A Wood², Claude Bailat⁵, Douglas R Spitz⁴, Marie-Catherine Vozenin³, Charles L Limoli¹

Affiliations

¹ Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA.
² Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
³ Laboratory of Radiation Oncology, Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
⁵ Institute of Radiation Physics/CHUV, Lausanne University Hospital, Lausanne, Switzerland.

Abstract

Background: Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes.

Methods: Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements.

Results: The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels.

Conclusions: Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.

Keywords: FLASH radiotherapy; medulloblastoma; neurocognition; synaptic integrity; vascular sparing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms* / etiology
Brain Neoplasms* / radiotherapy
Child
Disease Models, Animal
Female
Humans
Male
Mice
Radiotherapy / adverse effects
Radiotherapy Dosage

Abstract

Publication types

MeSH terms

Grants and funding