Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series

Abstract

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.

Keywords: biomarker; chronic traumatic encephalopathy; concussion; hippocampal sclerosis; limbic-predominant age-related TDP-43 encephalopathy; traumatic encephalopathy syndrome.

FIG. 1.

Common regions of grey matter atrophy in patients with repetitive head impacts (RHI) and traumatic encephalopathy syndrome (TES). W score frequency map showing common voxels with significantly low grey matter volume (W ≤ -2.0) among the nine patients irrespective of underlying neuropathologic diagnosis (left) and the subset of four patients with high chronic traumatic encephalopathy (High CTE) pathology. Warmer colors represent voxels with a higher frequency of patients with low volume (e.g., red voxels show regions where all nine patients had low volume).

FIG. 2.

Common regions of white matter injury in patients with repetitive head impacts (RHI) and traumatic encephalopathy syndrome (TES). W-score frequency map showing common voxels with significantly low fractional anisotropy (FA W score ≤ -2.0) among the six patients with diffusion tensor imaging irrespective of underlying neuropathologic diagnosis. Warmer colors represent voxels with a higher frequency of patients with low FA (e.g., red voxels show regions where all six patients had low FA; best visualized on slices showing the fornix).

FIG. 3.

Common regions of glucose hypometabolism in patients with repetitive head impacts (RHI) and traumatic encephalopathy syndrome (TES). W-score frequency map showing common voxels with significantly low glucose metabolism (glucose uptake W score ≤ -2.0) on FDG-PET among five patients irrespective of underlying neuropathological diagnosis. Warmer colors represent voxels with a higher frequency of patients with low glucose metabolism (e.g., yellow and red voxels show regions where four or five patients had low glucose metabolism, respectively).

FIG. 4.

Plasma biomarker changes in patients with repetitive head impacts (RHI) and traumatic encephalopathy syndrome (TES). Plasma concentrations of (A) glial fibrillary acidic protein (GFAP), (B) neurofilament light chain (NfL), and (C) total tau obtained during life from eight patients with plasma biomarker data. Data shown as W scores representing standardized protein concentrations relative to age-matched controls (N = 108; mean age = 73.2 ± 7.3 years old, range = 52–91 years old). Longitudinal evaluations were performed in five patients for GFAP and NfL and two patients for total tau. Neuropathological features for each patient are listed along with the specific “Patient #,” which corresponds with additional clinical history provided in Table 1. CTE, chronic traumatoc encephalopathy; FTLD, frontotemporal lobar degeneration; ADNC, Alzheimer disease neuropathological change; HS, hippocampal sclerosis; CBD, corticobasal degeneration; TDP43 – transactive response DNA-binding protein of 43 kDa; MND, motor neuron disease; U, unclassifiable.