Plasma biomarkers in chronic single moderate-severe traumatic brain injury

Abstract

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

Keywords: MRI; PET; blood biomarkers; chronic outcomes; traumatic brain injury.

Figure 1

Chronic traumatic brain injury is associated with elevated levels of UCH-L1 and phosphorylated tau. TBI participants had elevated levels of ubiquitin C-terminal hydrolase L1 (UCH-L1; A) and phosphorylated tau (P-tau181; B), but not glial fibrillary acidic protein (GFAP; C), neurofilament light (NfL; D) and tau (E). The figure presents violin plots overlayed with a box plot. Individual participant values are included. Large red points indicate the group mean. Statistical information refers to the parameter coefficient for each blood marker, along with the corresponding P-value and 95% confidence intervals. P_Adjust values indicate P-values after FDR adjustment for multiple comparisons. exp = exponent; Ln = natural logarithm.

Figure 2

Blood plasma is associated with white matter microstructure following traumatic brain injury. This figure illustrates the regression results for each blood biomarker on measures of white matter microarchitecture in participants with traumatic brain injury (TBI), with adjustments made for age, sex and brain volume. (A) Both uncorrected P-values and false discovery rate (FDR)-corrected P-values are given. Large dots denote associations surviving FDR correction for multiple comparisons, while small dots represent associations statistically significant only using uncorrected P-values. Furthermore, red dots signify positive associations between white matter and blood measures, whereas blue dots indicate a negative association. Our findings reveal that higher concentrations of plasma glial fibrillary acidic protein (GFAP) exhibited the strongest association with various white matter measures, followed by neurofilament light (NfL), phosphorylated tau (P-tau181) and ubiquitin C-terminal hydrolase L1 (UCH-L1). Notably, blood concentration of tau showed no significant association with any white matter tract after FDR correction. (B) Visual representation of these results on the brain, with tract directionality indicated by colour. Only associations surviving FDR correction are presented in the axial, coronal and sagittal orientations. AF = arcuate fasciculus; ATR = anterior thalamic radiation; CA = commissure anterior; CC_1 = corpus callosum rostrum; CC_2 = corpus callosum genu; CC_3 = corpus callosum rostral body (premotor); CC_4 = corpus callosum anterior midbody (primary motor); CC_5 = corpus callosum posterior midbody (primary somatosensory); CC_6 = corpus callosum isthmus; CC_7 = corpus callosum splenium; CG = cingulum; CST = corticospinal tract; FPT = fronto-pontine tract; IFO = inferior occipital-frontal fascicle; ILF = inferior longitudinal fascicle; MLF = middle longitudinal fascicle; OR = optic radiation; POPT = parieto-occipital pontine; SLF_I = superior longitudinal fascicle I; SLF_II = superior longitudinal fascicle II; SLF_III = superior longitudinal fascicle III; T_OCC = thalamo-occipital; T_PAR = thalamo-parietal; T_POSTC = thalamo-postcentral; T_PREF = thalamo-prefrontal; T_PREM = thalamo-premotor; T_PREC = thalamo-precentral; UC = uncinate fascicle.

Figure 3

Chronic single moderate–severe traumatic brain injury is associated with impaired verbal-episodic memory. A single chronic moderate–severe traumatic brain injury (TBI) was found to be associated with impaired immediate (A), short delay (B) and long delay (C) verbal-episodic memory, in comparison to healthy controls. Group comparisons controlled for age at assessment, sex and premorbid IQ. Large red circles denote the group mean.

Figure 4

Higher concentrations of phosphorylated tau, tau and UCH-L1 are associated with reduced verbal-episodic memory in chronic traumatic brain injury. Following traumatic brain injury (TBI), higher blood concentration of phosphorylated tau (P-tau181) was associated with reduced verbal-episodic short delay (A) and long delay (B) recall. Higher concentrations of tau were associated with poorer immediate memory (C). Higher concentrations of ubiquitin C-terminal hydrolase L1 (UCH-L1) were associated with poorer immediate memory (D). Ln = natural logarithm.