Bloodborne Tau: Foggy Window into the Brain for TBI, Dementia

Alzforum | September 21, 2017

In this month’s JAMA Neurology, two papers examine whether tau circulating in plasma could offer a blood-based biomarker for brain disorders. One, by Kevin Wang, University of Florida, Gainesville, and others, measures total and phosphorylated tau and their ratio to try to detect cases of acute or chronic traumatic brain injury (TBI). It found tau to be up in all forms of TBI, with p-tau better separating patients from controls, and mild from severe cases. The other, led by Jeffrey Dage, Eli Lilly and Company, Indianapolis, and Michelle Mielke, Mayo Clinic, Rochester, Minnesota, examines whether plasma total tau predicts progression to mild cognitive impairment (MCI) or dementia, or risk for cognitive decline in aging. Those researchers find but a tenuous relationship between plasma tau and cognitive decline.

In the TBI field, researchers are searching for blood biomarkers that indicate whether a bang to the head has damaged the brain. Right now, physicians depend on clinical measures and brain scans to assess damage. A biomarker is especially important for mild cases, which often present with subtle symptoms that mask deeper problems. Scientists previously found elevated t-tau and p-tau in the blood of severely concussed patients, but it was unclear whether that is true in mild or chronic cases of TBI, as well (Rubenstein et al., 2015). 

To find out, Wang and co-corresponding authors Geoffrey Manley, University of California, San Francisco, and Richard Rubenstein, State University of New York Downstate Medical Center, Brooklyn, used blood samples from 217 people they enrolled in the TRACK-TBI study, short for Transforming Research and Clinical Knowledge in Traumatic Brain Injury. Of them, 196 acute patients were admitted at one of three trauma centers within 24 hours of an injury. The remaining 21 checked in at a rehab center for chronic symptoms present on average six months after a TBI. All gave a blood sample and underwent a CT scan to assess brain swelling and bleeding at baseline. Plasma tau was measured with a technique called multi-arrayed fiber optics conjugated with rolling circle amplification, aka a-EIMAF. It combines an ELISA with PCR amplification of the antigen to detect femtograms of a protein in fluid. They measured both phosphorylated tau (p-tau) and total tau (t-tau) in the blood, calculated the ratio, and compared that to existing results from 20 age-matched commercial controls.

While t-tau was elevated over controls in all cases, p-tau better differentiated groups. P-tau measured 0.21 fg/mL in healthy controls, but 2.00, 3.07, and 2.95 fg/mL in mild, moderate, and severe TBI, respectively. The ratio of p-tau to t-tau similarly differentiated controls from patients. Patients whose scans showed damage had more p-tau than those whose scans did not. High levels of p-tau predicted poor outcome at six months. For the 21 chronic TBI patients, p-tau and t-tau were both elevated, but p-tau and the ratio again better separated the groups.

“Rubenstein and colleagues shine much-needed light on a common neurologic conundrum, namely how to determine who is hurt, who is healing, and who is healthy after head injury,” wrote Lee Goldstein and Ann McKee of Boston University in an accompanying editorial. “They demonstrate the clinical utility of blood-based biomarkers of the tau protein and its pathogenic phosphorylated forms.” They proposed next examining how these biomarkers map to different types of injury, as well as which tau epitopes best reflect brain injury.

Henrik Zetterberg., University of Gothenburg, Sweden, wondered about the mechanism of the immediate p-tau changes in acute TBI, as phosphorylation is usually thought to occur over longer periods. “We need to understand the mechanisms of this rapid increase,” Zetterberg said. He proposed, and Wang agreed, that a breach of the blood-brain barrier likely releases p-tau already lingering in the central nervous system. Wang believes rapid phosphorylation might also be taking place.

Zetterberg advised that the results be replicated, especially since the control samples came from a commercial source and could have been obtained and processed by different methods. The authors, too, note this limitation. Future TRACK-TBI studies will use controls recruited from the families and friends of study participants, Wang said

Zetterberg’s group has found neurofilament light chain to be a candidate biomarker of TBI in the blood, while other groups have focused on GFAP and UCH-L1 (Shahim et al., 2017Papa et al., 2016). 

Other researchers are examining whether plasma tau can forecast a person’s progression to MCI or dementia, or their general cognitive decline. When Zetterberg and colleagues recently probed this question in data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden, they found that total tau in blood only weakly correlated with worse cognition, CSF markers, and AD dementia (Mattson et al,. 2016). 

Mielke and colleagues examined the relationship in 458 participants from the Mayo Clinic Study on Aging (MCSA) between the ages of 56 and 95. They were either cognitively normal or mildly impaired at baseline, and were followed every 15 months for up to 45 months. All gave blood, took cognitive tests, and underwent a positron emission tomography scan with Pittsburgh compound B (PiB-PET) to detect brain amyloid at baseline. The researchers used the bead-based Simoa assay to measure t-tau in the plasma.

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