Editors' Note: Blood Biomarkers of Traumatic Brain Injury and Cognitive Impairment in Older Veterans

Abstract

Dr. Peltz et al. examined whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment in a cross-sectional study of 155 veterans from 2 veterans' retirement homes. They found that increased levels of blood-based, CNS-enriched exosomal biomarkers—particularly phosphorylated tau (p-tau), neurofilament light (NfL), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α)—were associated with cognitive impairment and TBI. In response, Drs. Wisniewski and Fossati question the clinical utility of these biomarkers, suggesting that the differences in these biomarkers may be driven more by the presence of cognitive impairment rather than the history of TBI. They argue that there is no proven causal relationship between the remote TBI and the observed cognitive impairment in this group and point to the absence of differences in any of the biomarkers in the control group and the TBI group without cognitive impairment to support their position. They also note a previous article from the group in which amyloid beta 42 (Aβ42) was reported to be elevated for decades after TBI, not replicated in this article. Responding to these comments, the authors agree that their findings are most likely explained by cognitive impairment but argue that the biomarkers could differentiate non–TBI-related cognitive impairment from TBI-associated cognitive impairment. They acknowledge the differences in results between their 2 biomarker articles but note that different assays were used, analyzed in different laboratories, and that the samples were overlapping but different. Nevertheless, they hypothesize that biomarkers for TBI-associated cognitive impairment are likely to differ from classic biomarkers for Alzheimer disease. This exchange highlights the challenges of disentangling the cognitive effects of remote TBI from other causes of cognitive impairment and the potential variability in the results of biomarker studies depending on the assays and laboratories used. Dr. Peltz et al. examined whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment in a cross-sectional study of 155 veterans from 2 veterans' retirement homes. They found that increased levels of blood-based, CNS-enriched exosomal biomarkers—particularly phosphorylated tau (p-tau), neurofilament light (NfL), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α)—were associated with cognitive impairment and TBI. In response, Drs. Wisniewski and Fossati question the clinical utility of these biomarkers, suggesting that the differences in these biomarkers may be driven more by the presence of cognitive impairment rather than the history of TBI. They argue that there is no proven causal relationship between the remote TBI and the observed cognitive impairment in this group and point to the absence of differences in any of the biomarkers in the control group and the TBI group without cognitive impairment to support their position. They also note a previous article from the group in which amyloid beta 42 (Aβ42) was reported to be elevated for decades after TBI, not replicated in this article. Responding to these comments, the authors agree that their findings are most likely explained by cognitive impairment but argue that the biomarkers could differentiate non–TBI-related cognitive impairment from TBI-associated cognitive impairment. They acknowledge the differences in results between their 2 biomarker articles but note that different assays were used, analyzed in different laboratories, and that the samples were overlapping but different. Nevertheless, they hypothesize that biomarkers for TBI-associated cognitive impairment are likely to differ from classic biomarkers for Alzheimer disease. This exchange highlights the challenges of disentangling the cognitive effects of remote TBI from other causes of cognitive impairment and the potential variability in the results of biomarker studies depending on the assays and laboratories used.