Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

作者：Gregory Scott, Henrik Zetterberg, Amy Jolly, James H. Cole, Sara De Simoni, Peter O Jenkins, Claire Feeney, David R. Owen, Anne Lingford‐Hughes, Oliver Howes, Maneesh C. Patel, Anthony P. Goldstone, Roger N. Gunn, Kaj Blennow, Paul M. Matthews, David Sharp · 发表于：Brain · 年份：2017 · DOI：10.1093/brain/awx339 · 被引用次数：231 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Traumatic Brain Injury and Neurovascular Disturbances、Neurogenesis and neuroplasticity mechanisms

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 11C-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, 11C-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 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite 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...