Journal
BRAIN
Volume 141, Issue -, Pages 459-471Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx339
Keywords
traumatic brain injury; microglia; minocycline; neurodegeneration; positron emission tomography
Categories
Funding
- Wellcome Trust-GlaxoSmithKline Translational Medicine Training Programme
- UK National Institute for Health Research (NIHR)
- MS Society of Great Britain
- Progressive MS Alliance
- Medical Research Council (MRC)
- GlaxoSmithKline
- Imperial College Healthcare Trust Biomedical Research Centre
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- VINNOVA
- Torsten Soderberg foundation
- NIHR
- Medical Research Council [G0700995, MR/N008219/1, MR/L022141/1, MR/K501013/1, MR/N026934/1, MR/N026063/1, 1116129, MC_U120097115, G0900897] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10022, NIHR-RP-011-048] Funding Source: researchfish
- MRC [MC_U120097115, MR/L022141/1, MR/N026063/1, G0700995, G0900897, MR/N026934/1, MR/N008219/1] Funding Source: UKRI
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Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using C-11-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, C-11-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater C-11-PBR28 binding. Minocycline reduced 11 C-PBR28 binding (mean Delta white matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.
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