A Novel, Ultrasensitive Assay for Tau: Potential for Assessing Traumatic Brain Injury in Tissues and Biofluids

Abstract

Traumatic brain injury (TBI) is a cause of death and disability and can lead to tauopathy-related dementia at an early age. Pathologically, TBI results in axonal injury that is coupled to tau hyperphosphorylation, leading to microtubule instability and tau-mediated neurodegeneration. This suggests that the forms of this protein might serve as neuroinjury-related biomarkers for diagnosis of injury severity and prognosis of the neurological damage prior to clinical expression. We initially determined whether we could detect tau in body fluids using a highly sensitive assay. We used a novel immunoassay, enhanced immunoassay using multi-arrayed fiberoptics (EIMAF) either alone or in combination with rolling circle amplification (a-EIMAF) for the detection of total (T) and phosphorylated (P) tau proteins from brains and biofluids (blood, CSF) of rodents following controlled cortical impact (CCI) and human patients post severe TBI (sTBI). This assay technology for tau is the most sensitive to date with a detection limit of approximately 100 ag/mL for either T-tau and Ptau. In the rodent models, T-tau and P-tau levels in brain and blood increased following CCI during the acute phase and remained high during the chronic phase (30 d). In human CSF samples, T-tau and P-tau increased during the sampling period (5-6 d). T-tau and P-tau in human serum rose during the acute phase and decreased during the chronic stage but was still detectable beyond six months post sTBI. Thus, EIMAF has the potential for assessing both the severity of the proximal injury and the prognosis using easily accessible samples.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

“…In agreement with our findings, chronically elevated T-tau has been found in soldiers with a history of reported or medically documented concussion up to 18 months postdeployment (47), and elevated levels have also been observed at one month post-severe TBI (44). Regarding the former, there are a number of similarities between SRC and military concussion; both populations are typically young, athletic, have the same physical and mental requirements for success in their fields, and are at risk for repetitive trauma.…”

Traumatic brain injuries

“…Plasma T-tau concentrations correlate poorly with CSF concentrations 180 , but in acute hypoxic brain injury the rise in plasma T-tau is predictive of outcome 178 . During the acute phase of severe TBI, increases in serum T-tau and P-tau have also been described, with levels decreasing, but not down to control levels, during the period up to six months following the acute phase 150 . In sports-related concussion, plasma T-tau has been found to predict return-to-play time with high accuracy 181 .…”

“…Studies using ELISA show that T-tau concentrations in ventricular CSF correlate with lesion size and outcome in severe TBI, so that high levels indicate worse injury. 148,149 A recent pilot study using the enhanced immunoassay using multiarrayed fiberoptics (EIMAF) technique found increases in ventricular CSF in both T-tau and P-tau during the acute phase in a small series of severe TBI cases 150 . Studies on mild TBI show elevated CSF concentrations of both T-tau and NF-L but the magnitude of the rise is larger for NF-L than for T-tau suggesting that blows to the head impact long, myelinated axons in the white matter more than short, non-myelinated axons in the cortex, which is in agreement with experimental, as well as neuroimaging and neuropathological studies 145,151 .…”

Current status of fluid biomarkers in mild traumatic brain injury

“…Some studies suggest it is elevated in mTBI and correlates with post-injury symptoms, while others find it cannot predict CT positive lesions or outcome. Increased sensitivity of tau assays (Rubenstein et al, 2014; Shahim et al, 2014) could clarify utility of tau as a biomarker for mTBI.…”