title: Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction.
abstract: Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose-response relationship between the number of blast-related mild TBIs and uptake of (18)F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast-related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans.
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.affiliation: VA Jamaica Plain, Department of Neurology, Boston University School of Medicine, Jamaica Plain, MA 02130, USA.
authors.forename: Bertrand R
authors.initials: BR
authors.lastname: Huber
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Cross
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Richards
authors.affiliation: Department of Radiology, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Minoshima
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Pagulayan
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
authors.forename: Kole D
authors.initials: KD
authors.lastname: Meeker
authors.affiliation: Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA. Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Petrie
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
authors.affiliation: Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System (VA Puget Sound), Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA. Department of Medicine, University of Washington, Seattle, WA 98195, USA. Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. dgcook@u.washington.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001753:Blast Injuries / Q000150:complications* / Q000503:physiopathology*; D001924:Brain Concussion / Q000209:etiology; D002526:Cerebellar Diseases / Q000209:etiology* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D000076122:Disks Large Homolog 4 Protein; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005911:Gliosis / Q000150:complications / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D013569:Synapses / Q000473:pathology; D014728:Veterans
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D019788:Fluorodeoxyglucose F18; D051528:Guanylate Kinases; D005947:Glucose