Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimers disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuinl deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuinl all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
ObjectivePatients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH.MethodsOur study cohort was comprised of 51 primary age‐ and sex‐matched ICH patients with moderate‐sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes.ResultsAcute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high‐level PHE expansion.InterpretationAcute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short‐term outcomes.
BACKGROUND There are radiographic and clinical outcome differences between patients with deep and lobar intracerebral hemorrhage (ICH) locations. Pilot studies suggest that there may be functional coagulation differences between these locations detectable using whole blood coagulation testing. OBJECTIVE To confirm the presence of interlocation functional coagulation differences using a larger cohort of deep and lobar ICH patients receiving whole blood coagulation testing: thromboelastography (TEG; Haemonetics). METHODS Clinical and laboratory data were prospectively collected between 2009 and 2018 for primary ICH patients admitted to a tertiary referral medical center. Deep and lobar ICH patients receiving admission TEG were analyzed. Patients with preceding anticoagulant use and/or admission coagulopathy (using prothrombin time/partial thromboplastin time/platelet count) were excluded. Linear regression models assessed the association of ICH location (independent variable) with TEG and traditional plasma coagulation test results (dependent variable) after adjusting for baseline hematoma size, age, sex, and stroke severity. RESULTS We identified 154 deep and 53 lobar ICH patients who received TEG. Deep ICH patients were younger and had smaller admission hematoma volumes (median: 16 vs 29 mL). Adjusted multivariable linear regression analysis revealed longer TEG R times (0.57 min; 95% CI: 0.02-1.11; P = .04), indicating longer clot formation times, in deep compared to lobar ICH. No other TEG parameter or plasma-based coagulation differences were seen. CONCLUSION We identified longer clot formation times, suggesting relative coagulopathy in deep compared to lobar ICH confirming results from prior work. Further work is required to elucidate mechanisms for these differences and whether ICH location should be considered in future coagulopathy treatment paradigms for ICH.
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