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.
- Plasma tau rises in mild, severe, and chronic TBI.
- Phosphorylated beats total tau at separating patients from controls, and mild from severe.
- People whose cognition will decline have more total tau in blood, but the effect is too small for diagnosis.
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
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.
During follow-up, 67 of 335 cognitively normal people developed MCI. Those in the highest and middle tertiles of plasma t-tau were likelier to progress than those in the lowest. Over that same period, 28 of 123 people with MCI progressed to dementia, however, t-tau did not predict who would.
Tau correlated with cognitive decline in the sense that higher plasma levels in both the cognitively normal and MCI groups predicted steeper drops in global cognition, memory, attention, and visuospatial ability over three years. If Mielke and colleagues restricted their analysis to 15 months, similar to the length of a clinical trial, plasma t-tau predicted worsening global cognition and visuospatial ability in people with MCI. Thus, over a shorter period, t-tau may be able to predict whose MCI will progress fastest, the authors wrote.
Surprisingly, any influence of t-tau on progression or cognitive decline remained independent of Aβ levels measured by PiB-PET. Dage said he would have expected those with a combination of high amyloid and t-tau to decline fastest.
“These findings suggest that non-AD causes of MCI are mediating the association between plasma total tau and MCI,” said Suzanne Schindler, Washington University School of Medicine in St. Louis, who was not involved in the study. “It looks like plasma total tau is not a good biomarker of AD brain pathology.” She pointed out that only 58 percent of MCI patients in this study tested positive for amyloid, implying that the other 42 percent had a disease other than AD.
Rahul Desikan, University of California, San Francisco, cautioned that it is difficult to draw conclusions from this study because the Mayo cohort is population-based and has a slow rate of conversion, therefore the study may have too little power to detect effects, especially in 15 months. He also wondered what the authors would have seen if they had measured p-tau in the blood.
The large overlap in blood t-tau levels between all three groups means t-tau won’t be useful as a diagnostic biomarker, wrote the authors, agreeing with the conclusion reached in the Mattsson study. However, in clinical trials, blood t-tau may help select people who are likely to decline cognitively, Dage believes.
“I think this study points toward the feasibility of finding a tau signal in blood, and that these changes could be quite early and predictive,” said Zetterberg. He agreed that the differences were too small and tau too unstable in the blood for diagnosis; instead, he advised looking in plasma for tau fragments that are potentially more stable and better correlate with tau in cerebrospinal fluid. Dage agreed. "Plasma tau is the foundation to show it’s possible to correlate tau with cognitive decline and progression, and now we will try to find something better.”—Gwyneth Dickey Zakaib
- Rubenstein R, Chang B, Davies P, Wagner AK, Robertson CS, Wang KK. A novel, ultrasensitive assay for tau: potential for assessing traumatic brain injury in tissues and biofluids. J Neurotrauma. 2015 Mar 1;32(5):342-52. Epub 2014 Dec 23 PubMed.
- Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017 May 9;88(19):1788-1794. Epub 2017 Apr 12 PubMed.
- Papa L, Brophy GM, Welch RD, Lewis LM, Braga CF, Tan CN, Ameli NJ, Lopez MA, Haeussler CA, Mendez Giordano DI, Silvestri S, Giordano P, Weber KD, Hill-Pryor C, Hack DC. Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury. JAMA Neurol. 2016 May 1;73(5):551-60. PubMed.
- Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, Palmqvist S, Baker D, Tan Hehir CA, Jeromin A, Hanlon D, Song L, Shaw LM, Trojanowski JQ, Weiner MW, Hansson O, Blennow K, ADNI Investigators. Plasma tau in Alzheimer disease. Neurology. 2016 Oct 25;87(17):1827-1835. Epub 2016 Sep 30 PubMed.
- Bogoslovsky T, Wilson D, Chen Y, Hanlon D, Gill J, Jeromin A, Song L, Moore C, Gong Y, Kenney K, Diaz-Arrastia R. Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury. J Neurotrauma. 2016 Jul 8; PubMed.
- Blennow K, Brody DL, Kochanek PM, Levin H, McKee A, Ribbers GM, Yaffe K, Zetterberg H. Traumatic brain injuries. Nat Rev Dis Primers. 2016 Nov 17;2:16084. PubMed.
- Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D. Blood biomarkers for brain injury: What are we measuring?. Neurosci Biobehav Rev. 2016 Sep;68:460-73. Epub 2016 May 12 PubMed.
- Kovacs GG, Andreasson U, Liman V, Regelsberger G, Lutz MI, Danics K, Keller E, Zetterberg H, Blennow K. Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort. Eur J Neurol. 2017 Nov;24(11):1326-e77. Epub 2017 Aug 16 PubMed.
- Rubenstein R, Chang B, Yue JK, Chiu A, Winkler EA, Puccio AM, Diaz-Arrastia R, Yuh EL, Mukherjee P, Valadka AB, Gordon WA, Okonkwo DO, Davies P, Agarwal S, Lin F, Sarkis G, Yadikar H, Yang Z, Manley GT, Wang KK, and the TRACK-TBI Investigators, Cooper SR, Dams-O'Connor K, Borrasso AJ, Inoue T, Maas AI, Menon DK, Schnyer DM, Vassar MJ. Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers. JAMA Neurol. 2017 Sep 1;74(9):1063-1072. PubMed.
- Mielke MM, Hagen CE, Wennberg AM, Airey DC, Savica R, Knopman DS, Machulda MM, Roberts RO, Jack CR Jr, Petersen RC, Dage JL. Association of Plasma Total Tau Level With Cognitive Decline and Risk of Mild Cognitive Impairment or Dementia in the Mayo Clinic Study on Aging. JAMA Neurol. 2017 Sep 1;74(9):1073-1080. PubMed.
- Goldstein LE, McKee AC. Shining (Laser) Light on Traumatic Brain Injury Blood Biomarkers. JAMA Neurol. 2017 Sep 1;74(9):1045-1047. PubMed.