Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI.

BACKGROUND: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. METHODS: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls. RESULTS: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates. CONCLUSIONS: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury.

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

Emergently planned exclusive hub-and-spoke system in the epicenter of the first wave of COVID-19 pandemic in Italy: the experience of the largest COVID-19-free ICU hub for time-dependent diseases.

BACKGROUND: Lombardy was the epicenter in Italy of the first wave of COVID-19 pandemic. To face the contagion growth, from March 8 to May 8, 2020, a regional law redesigned the hub-and-spoke system for time-dependent diseases to better allocate resources for COVID-19 patients. METHODS: We report the reorganization of the major hospital in Lombardy during COVID-19 pandemic, including the rearrangement of its ICU beds to face COVID-19 pandemic and fulfill its role as extended hub for time-dependent diseases while preserving transplant activity. To highlight the impact of the emergently planned hub-and-spoke system, all patients admitted to a COVID-19-free ICU hub for trauma, neurosurgical emergencies and stroke during the two-month period were retrospectively collected and compared to 2019 cohort. Regional data on organ procurement was retrieved. Observed-to-expected (OE) in-ICU mortality ratios were computed to test the impact of the pandemic on patients affected by time-dependent diseases. RESULTS: Dynamic changes in ICU resource allocation occurred according to local COVID-19 epidemiology/trends of patients referred for time-dependent diseases. The absolute increase of admissions for trauma, neurosurgical emergencies and stroke was roughly two-fold. Patients referred to the hub were older and characterized by more severe conditions. An increase in crude mortality was observed, though OE ratios for in-ICU mortality were not statistically different when comparing 2020 vs. 2019. An increase in local organ procurement was observed, limiting the debacle of regional transplant activity. CONCLUSIONS: We described the effects of a regional emergently planned hub-and-spoke system for time-dependent diseases settled in the epicenter of COVID-19 pandemic in Italy.