{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:53:52Z","timestamp":1791579232424,"version":"4.3.4"},"reference-count":359,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Uniformed Services University of the Health Sciences MDO1 award","award":["HU00012320026"],"award-info":[{"award-number":["HU00012320026"]}]},{"award":["HU00012320026"],"award-info":[{"award-number":["HU00012320026"]}],"id":[{"id":"https:\/\/ror.org\/04r3kq386","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Veterans Affairs Office of Biomedical Laboratory Research and Development","award":["I01BX004896"],"award-info":[{"award-number":["I01BX004896"]}]},{"name":"Veteran Affairs Northwest Mental Illness Research, Education and Clinical Center"},{"name":"Congressionally Directed Medical Research TBI Psychological Health Research Program award","award":["HT94252310755"],"award-info":[{"award-number":["HT94252310755"]}]},{"name":"Department of Defense\/War United States Army Medical Research and Development Command award","award":["HT9245-23-1-055"],"award-info":[{"award-number":["HT9245-23-1-055"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exposure to blast waves without kinetic, penetrating, thermal, or toxic components causes a distinct form of traumatic brain injury, termed primary blast-induced TBI (pbTBI). Clinical manifestations of pbTBI span a wide spectrum, ranging from life-threatening intracranial hemorrhage, hyperemia, and delayed cerebral edema to mild and transient neurological symptoms without detectable structural abnormalities on routine imaging. At the mild end of the spectrum, symptoms after a single exposure may resolve quickly, yet repeated exposures\u2014even at very low levels, termed \u201csubconcussive\u201d\u2014can develop into post-concussive syndrome (PCS) or persistent post-concussive symptoms (PPCS) in a subset of individuals. Despite extensive studies, the molecular pathobiology linking primary blast exposure to delayed and sometimes chronic neurobehavioral deficits remains incompletely understood. A mechanistic framework connecting blast-wave physics to biomechanics to biological vulnerability may therefore help define exposure hazards, interpret clinical symptomatology, and guide diagnostic and therapeutic development. This review summarizes the physics of primary blast waves, the resulting biomechanical responses, and candidate biological substrates, emphasizing structures and interfaces with distinct acoustic impedances across anatomical, tissue, cellular, and molecular scales. We synthesize evidence supporting the hypothesis that the cerebral vasculature and endothelial cells represent critically vulnerable substrates of primary blast-wave injury, in part because the vascular tree constitutes the brain\u2019s largest and most widely distributed interface between compartments with different acoustic impedances. Across experimental and human studies, endothelial stress, vascular injury, and downstream neuroinflammation emerge as convergent molecular responses to primary blast exposure. Temporal dynamics are central to understanding pbTBI because many blast-induced processes unfold in sequential phases. These observations support conceptualizing pbTBI as a condition characterized by prominent cerebrovascular injury of varying severity with secondary consequences for neuronal signaling, network function, and behavior. Within this framework, cerebrovascular and neurovascular unit (NVU) dysfunction provides a parsimonious bridge between primary blast-wave exposure and chronic symptom trajectories, where vascular pathology may offer more accessible therapeutic targets than neuronal injury. Key knowledge gaps include identifying which physical component(s) of the blast are most injurious, establishing biologically meaningful dose\u2013response relationships at molecular and physiological levels, and defining windows of vulnerability during recovery that are relevant to repeated exposures. Addressing these gaps is essential for refining safety protocols, improving diagnostic specificity through mechanism-informed biomarkers, and developing evidence-based molecular and vascular therapeutic targets for pbTBI-associated conditions. Progress will require integrating waveform-aware dosimetry with longitudinal physiological and molecular monitoring across both preclinical and human cohorts. Such integration offers a practical path toward translating blast physics into actionable medical guidance for prevention, triage, and recovery management.<\/jats:p>","DOI":"10.3390\/ijms27114669","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"4669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Primary Blast-Induced Traumatic Brain Injury as a Risk Factor for (Cerebro)vascular Disorder: Clinical Manifestations, Blast Physics, Biomechanics, Pathobiology, and Critical Gaps"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-0098","authenticated-orcid":false,"given":"Denes V.","family":"Agoston","sequence":"first","affiliation":[{"name":"Department of Anatomy, Physiology and Genetic, School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-1546","authenticated-orcid":false,"given":"James S.","family":"Meabon","sequence":"additional","affiliation":[{"name":"Veterans Affairs Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/00005373-199602000-00007","article-title":"Causation, incidence, and costs of traumatic brain injury in the U.S. military medical system","volume":"40","author":"Ommaya","year":"1996","journal-title":"J. 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