Alzforum thanks Sam Gandy, Soong Ho Kim, and Effie Mitsis at Mount Sinai School of Medicine for preparing this meeting summary, edited by Tom Fagan.
Identifying injuries that might lead to chronic traumatic encephalopathy or other neurodegenerative pathologies, and then treating those injuries, are two major challenges for those in the traumatic brain injury field. Both were addressed at Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies, a Keystone symposium held 26 February-2 March 2012. Kaj Blennow, University of Gothenburg, Sweden, has performed studies on CSF biomarkers to identify and monitor neuronal injury in amateur boxers. He reported that after a bout, CSF levels of neurofilament light (NFL), tau, GFAP, and S100B increased in boxers who received more than 15 punches, reflecting acute axonal and glial damage. This was despite the boxers wearing head protection, not being knocked out, and sparring only a small number of rounds. The CSF NFL reached five times higher after a bout than after over three months' rest, and the severity correlated with the number of blows suffered. Interestingly, Blennow and colleagues detected no change in the levels of these CSF biomarkers in amateur soccer players after 15-30 headings or in Swedish military officers after repeated blast exposure from the firing of heavy weapons during training (see slides).
Kevin Wang, University of Florida, Gainesville, showed examples of candidate blood-based protein biomarkers for TBI. He and his colleagues selected UCH-L1 (cell body injury), GFAP (glial injury), and SBDP150 (axonal injury), among others, as potential acute markers, while testing SBDP120 (axonal injury), MBP-fragment (demyelination), and MAP2 (dendritic injury) as sub-acute markers. They detected UCH-L1 in the CSF and serum of TBI patients, and their levels in the first 24 hours post-injury correlated with clinical outcome. UCH-L1 stayed elevated beyond 24 hours in CSF, but normalized in serum. UCH-L1 can be used as a biomarker of neuronal loss in aneurismal subarachnoid hemorrhage, based on a previous study, said Wang (see Lewis et al., 2010). Wang’s data suggest that tau is vulnerable to calpains and caspase-3 under acute and sub-acute TBI conditions, and tau fragments might be potential contributors to CTE.
Using a human Aβ knock-in mouse model, which does not overexpress APP, Milos Ikonomovic, University of Pittsburgh, Pennsylvania, showed that simvastatin treatment after CCI injury lowered Aβ levels, suppressed microglial activation, reduced hippocampal synaptic and neuronal loss, and restored hippocampus-dependent cognitive function (see slides). Mark Burns, Georgetown University, Washington, D.C., reported that APP accumulated in damaged axons as soon as 30 minutes post-TBI (CCI). Additionally, TBI triggered APP processing and production of Aβ monomers and soluble Aβ oligomers. DAPT (a γ-secretase inhibitor) treatment of TBI mice blocked abnormal increases in Aβ40 at 24 hours post-injury, dramatically reduced lesion volume, and rescued spatial learning and fine motor coordination at one month post-injury. However, CCI also caused global dendritic spine loss 24 hours after injury, even on the uninjured side of the brain, and DAPT treatment did not suppress it.
Fernando Gomez-Pinilla, University of California, Los Angeles, showed that FPI mice treated with a curcumin derivative exhibited more BDNF production, reduced oxidative stress (less 4-HNE), and increased availability of ATP (enhanced AMPK activity) compared with untreated FPI mice. A DHA supplement also counteracted the effects of FPI by restoring BDNF and CamKII levels and hippocampus-dependent cognitive function, said Gomez-Pinilla. In contrast, low DHA diet or diets high in calories (fructose or saturated fats) attenuated BDNF function and triggered more anxiety-like behavior in both sham and FPI mice, compared to DHA-fed controls. Besides a proper diet, exercise may benefit TBI since voluntary exercise caused an epigenetic change on the BDNF gene in rodents, which led to more BDNF mRNAs and protein production in the hippocampus (see slides).
- Keystone: Traumatic Brain Injury—Epidemiology and Characteristics
- Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy
- Keystone: Metabolic and Axonal Dysfunction in Traumatic Brain Injury
- Keystone: TBI—Learning From Markers, Models, and Diseases
- Lewis SB, Wolper R, Chi YY, Miralia L, Wang Y, Yang C, Shaw G. Identification and preliminary characterization of ubiquitin C terminal hydrolase 1 (UCHL1) as a biomarker of neuronal loss in aneurysmal subarachnoid hemorrhage. J Neurosci Res. 2010 May 15;88(7):1475-84. PubMed.