{"doi":"10.1093/neuonc/noac248","title":"Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy","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.","journal":"Neuro-Oncology","year":2022,"id":236675,"datarank":0.635115975689589,"base_score":4.23410650459726,"endowment":4.23410650459726,"self_citation_contribution":0.635115975689589,"citation_network_contribution":0.0,"self_endowment_contribution":0.635115975689589,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":68,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":857668,"name":"Yasaman Alaghband","orcid":"0009-0000-5305-7965","position":1,"is_corresponding":false},{"id":497186,"name":"Enikö A. Kramár","orcid":"0009-0003-2279-7743","position":2,"is_corresponding":false},{"id":509551,"name":"Ning Ru","orcid":"0009-0003-8965-5387","position":3,"is_corresponding":false},{"id":232791,"name":"Benoît Petit","orcid":"0009-0003-9397-4583","position":4,"is_corresponding":false},{"id":656468,"name":"Veljko Grilj","orcid":"0000-0001-6573-8063","position":5,"is_corresponding":false},{"id":393432,"name":"Michael S. Petronek","orcid":"0000-0001-7581-1172","position":6,"is_corresponding":false},{"id":393435,"name":"Casey Pulliam","orcid":"0000-0002-1509-894X","position":7,"is_corresponding":false},{"id":858355,"name":"Rachel Y Kim","orcid":null,"position":8,"is_corresponding":false},{"id":857669,"name":"Ngoc-Lien Doan","orcid":"0000-0002-4901-621X","position":9,"is_corresponding":false},{"id":294087,"name":"Janet E. Baulch","orcid":"0000-0002-1078-6946","position":10,"is_corresponding":false},{"id":509552,"name":"Marcelo A. Wood","orcid":"0000-0003-2029-4176","position":11,"is_corresponding":false},{"id":232798,"name":"Claude Bailat","orcid":"0000-0002-0386-4782","position":12,"is_corresponding":false},{"id":297605,"name":"Douglas R. Spitz","orcid":"0000-0002-1254-8765","position":13,"is_corresponding":false},{"id":232801,"name":"Marie‐Catherine Vozenin","orcid":"0000-0002-2109-8073","position":14,"is_corresponding":false},{"id":232800,"name":"Charles L. Limoli","orcid":"0000-0002-1321-4142","position":15,"is_corresponding":false},{"id":286121,"name":"Barrett D. 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