Structural MRI profiles and tau correlates of atrophy in autopsy-confirmed CTE

Abstract

Background: Chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, cannot currently be diagnosed during life. Atrophy patterns on magnetic resonance imaging could be an effective in vivo biomarker of CTE, but have not been characterized. Mechanisms of neurodegeneration in CTE are unknown. Here, we characterized macrostructural magnetic resonance imaging features of brain donors with autopsy-confirmed CTE. The association between hyperphosphorylated tau (p-tau) and atrophy on magnetic resonance imaging was examined.

Methods: Magnetic resonance imaging scans were obtained by medical record requests for 55 deceased symptomatic men with autopsy-confirmed CTE and 31 men (n = 11 deceased) with normal cognition at the time of the scan, all >60 years Three neuroradiologists visually rated regional atrophy and microvascular disease (0 [none]-4 [severe]), microbleeds, and cavum septum pellucidum presence. Neuropathologists rated tau severity and atrophy at autopsy using semi-quantitative scales.

Results: Compared to unimpaired males, donors with CTE (45/55=stage III/IV) had greater atrophy of the orbital-frontal (mean diff.=1.29), dorsolateral frontal (mean diff.=1.31), superior frontal (mean diff.=1.05), anterior temporal (mean diff.=1.57), and medial temporal lobes (mean diff.=1.60), and larger lateral (mean diff.=1.72) and third (mean diff.=0.80) ventricles, controlling for age at scan (ps<0.05). There were no effects for posterior atrophy or microvascular disease. Donors with CTE had increased odds of a cavum septum pellucidum (OR = 6.7, p < 0.05). Among donors with CTE, greater tau severity across 14 regions corresponded to greater atrophy on magnetic resonance imaging (beta = 0.68, p < 0.01).

Conclusions: These findings support frontal-temporal atrophy as a magnetic resonance imaging finding of CTE and show p-tau accumulation is associated with atrophy in CTE.

Keywords: Atrophy; Chronic traumatic encephalopathy; Magnetic resonance imaging; Neurodegeneration; Tau.

Fig. 1

Sample derivation of brain donors with autopsy-confirmed CTE

Fig. 2

Visually rated MRI patterns of atrophy in CTE compared to participants with normal cognition. The regions (y-axis) were rated on a 5-point scale with 0 = none and 4 = severe and the left and right hemispheres were rated separately and combined into a summary composite for analyses (possible range: 0–8). The “Effect” represents the mean difference (black dot) between the brain donors with CTE compared to participants with normal cognition after accounting for age at the time of MRI. Higher x-axis scores represent higher scores (i.e., greater atrophy) in brain donors with CTE. The whiskers represent 95% confidence intervals. Statistically significant differences (i.e., false discovery rate-adjusted p-value less than 0.05) were found for the medial temporal lobe, anterior temporal lobe, dorsolateral frontal cortex, orbital-frontal cortex, and superior frontal cortex. There was no significant effect for the posterior-occipital lobes (p = 0.375).

Fig. 3

Antemortem MRI scans for brain donors with autopsy-confirmed CTE compared to participants with normal cognition. Three neuroradiologists used established visual rating scales to rate patterns of frontal, anterior temporal, parietal-occipital lobe atrophy on axial T1 sequences, as well as medial temporal lobe atrophy on coronal sequences in brain donors with CTE and participants with normal cognition. The regions were rated on a 5-point scale with 0 = none and 4 = severe. A Axial T1 of a male former professional American football player in his early 60’s with CTE stage IV that was rated to have mild orbital-frontal and anterior temporal lobe atrophy (not shown), moderate dorsolateral and superior frontal lobe atrophy, severe parietal-occipital lobe atrophy, and presence of an anterior and posterior cavum septum pellucidum. B Axial T1 of a participant with normal cognition in his late 60’s rated to have no orbital-frontal, dorsolateral frontal, or anterior temporal lobe (not shown) cortical atrophy; minimal superior frontal atrophy; mild parietal-occipital lobe atrophy; and absence of a cavum septum pellucidum. C and D are coronal sequences that show moderate hippocampal atrophy in a former professional American football player in his early 80’s with CTE stage IV (C) compared to no hippocampal atrophy in a participant with normal cognition in his early to mid-70s (D)

Fig. 4

MRI and autopsy patterns of atrophy and P-tau deposition in a brain donor with CTE. The figure shows an antemortem axial (A) and coronal (D) T1 MRI sequence and corresponding gross atrophy at autopsy (B, C, E) of a male former professional American football player with CTE stage IV. The antemortem MRI scan was done when he was in his early 60’s and he died in his mid-70s and donated his brain. The antemortem MRI and neuropathological examination both showed frontal and temporal cortical atrophy (A–E) along with atrophy of medial temporal lobe structures (C, E) including the hippocampus and amygdala