In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging

Abstract

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Keywords: [F-18]FDDNP PET; chronic traumatic encephalopathy; concussions; tau imaging; traumatic brain injury.

Conflict of interest statement

Conflict of interest statement: J.R.B., G.W.S., and S.-C.H. are coinventors of the [F-18]FDDNP PET technology that is covered under University of California, Los Angeles patents and licensed to TauMark, LLC. J.R.B., G.W.S., R.P.F., and B.O. have a financial interest in TauMark, LLC.

Figures

Fig. 1.

(Upper) [F-18]FDDNP distribution volume ratios (DVR) parametric images showing patterns T1 to T4 of increased [F-18]FDDNP signal observed in the mTBI group compared with cognitive control subjects (Left). The T1 pattern shows involvement of two core areas which have consistently increased [F-18]FDDNP signal in all four patterns: amygdala (limbic) and dorsal midbrain (subcortical). Patterns T2 to T4 are marked by increase of [F-18]FDDNP signal in these two core regions and progressively larger number of subcortical, limbic, and cortical areas. Although more complex patterns (e.g., T4) overlap with AD in the cortex, midbrain and amygdala signals are elevated above the levels in AD (Table 2). An AD case is shown in the right column for comparison. (Lower) A is a 2D scatter plot showing [F-18]FDDNP DVR values in two core areas consistently involved in CTE (subcortical structures (dorsal midbrain) and limbic structures (amygdala)), clearly demonstrating separation of mTBI and CTRL groups. B and C demonstrate similar separation effect when dorsal midbrain is compared with cortical areas typically associated with CTE and its mood disorders, namely anterior cingulate gyrus (ACG) (B) and frontal lobe (C). mTBI subjects are represented by green circles, and CTRL subjects are represented by blue circles. See SI Materials and Methods for additional correlations of [F-18]FDDNP PET DVR values in dorsal midbrain and amygdala with several cortical and subcortical areas (Fig. S1).

Fig. 2.

[F-18]FDDNP PET DVR value analysis separates mTBI, CTRL and AD groups. (A) A 3D scatter plot correlation of subcortical regions (dorsal midbrain) with limbic structures (amygdala) and cortical regions (frontal lobe) shows that all three groups (mTBI, green; AD, red; CTRL, blue) can be effectively separated based on the differences in binding patterns in these three areas. The mTBI group is significantly separated from control group in all three areas and from the AD group in the limbic and subcortical areas (Table 2). (B) A 3D scatter plot correlation of cortical structures alone, without comparison with subcortical or limbic structures, demonstrates that the mTBI group overlaps both with AD and CTRL groups. Results of discriminant analysis for the correlation of three areas depicted in each 3D scatter plot are shown underneath each graph.

Fig. 3.

Involvement of amygdala and midbrain areas in concussion-based mTBI is supported by both mechanistic concept of injury (I) and by the results of neuropathological examinations in deceased retired American football players with premortem complaints of functional impairments (II and III). (I) Rotation of the brain in the sagittal plane during a concussion, associated with significant accelerations and deceleration, will have significant negative effect on the brain tissue in the midbrain and thalamus (green shaded area) and on the affected cortical areas (red area). Stretching, compression, and shearing of axons during such sudden brain movements is hypothesized to be the cause of axonal injury (reprinted from ref. ; reproduced with permission from Massachusetts Medical Society.) Online version of ref. also contains an animated version of this figure (www.nejm.org/doi/full/10.1056/NEJMcp064645). Similarly, rotation in the coronal plane has been shown to lead to consistent damage to midbrain region tracts (27). (II) A–D show results of tau immunohistochemistry and demonstrate that in the mTBI group areas of increased [F-18]FDDNP signal in amygdala and dorsal midbrain coincide with presence of dense tau deposits in periaqueductal gray (PAG) in dorsal midbrain (A and B) and in amygdala (C and D; reprinted from ref. ; reproduced with permission from Wolters Kluwer Health). (III) Amygdala and MTL areas are affected in the brains of retired professional American football players who died due to suicide (Left; 45-y-old retired player; reprinted from ref. ; reproduced with permission from Wolters Kluwer Health) or due to natural causes [Right; 80-y-old retired NFL player; © Oxford University Press (brain.oxfordjournals.org/content/136/1/43) (reprinted from ref. 11)]. Amygdala and MTL areas are the first areas with high density of tau deposits in the neocortex and remain one of the most affected cortical regions in the majority of retired professional American football player cases.