Fig. 1 Flortaucipir BPND z-score maps for each TBI individual are compared voxel-wise to healthy controls. TBI participants are presented in descending order of number of voxels with flortaucipir BPND z > 1.645 (see Fig. 2). Axial images are displayed in radiological convention at MNI coordinate 55. Patchy cortical and subcortical increase in tracer uptake is observed in some TBI participants, most consistently in the lateral occipital cortex (P1 to P8 and P10), whereas others show similar BPND values as controls (P17 to P21). The corresponding clinical characteristics are presented in Table 1. Participant designations correspond to those in Table 1, Fig. 2, and fig. S1.
Fig. 2 The spatial extent of increased flortaucipir binding in TBI is expressed as the number of voxels with flortaucipir BPND z > 1.645 for each patient with TBI compared to the healthy control group. The dashed line represents the number of voxels above threshold in the healthy control participant with the maximum number of voxels above that threshold (compared to the rest of the controls). Participant designations correspond to those in Table 1, Fig. 1, and fig. S1. The inset figure shows the number of voxels above threshold (in logarithmic scale) in TBI and healthy controls.
Fig. 3 Flortaucipir BPND is increased in TBI compared to healthy controls. Voxels with increased flortaucipir uptake in TBI at P < 0.05, not adjusted for multiple comparisons, are shown on axial slices for illustration. Flortaucipir binding was increased in TBI in a small cluster of voxels in the right parietal cortex (inset, P < 0.05, corrected for multiple comparisons).
Fig. 4 Flortaucipir binding is associated with CSF biomarkers in TBI. CSF total tau (T-tau) (A), phosphorylated (P-tau) (B), and UCH-L1 (C) concentrations in the CSF are positively correlated with flortaucipir BPND (normalized against the healthy control group) in the cerebral gray matter (GM; T-tau and UCH-L1) and in the cerebral white matter (WM; P-tau) in TBI participants.
Fig. 5 White matter microstructural changes in TBI are associated with flortaucipir spatial extent. (A) Cerebral white matter fractional anisotropy (FA) and (B) voxel-based morphometry (VBM)–derived white matter tissue density are reduced in TBI when compared to healthy controls (HC). This was not observed with gray matter tissue density (C). Flortaucipir spatial extent (number of voxels above threshold) in TBI is associated with reduced white matter FA (D) and white matter tissue density (E) but not with gray matter tissue density (F). **P < 0.005, *P < 0.05.
Fig. 6 Increased white matter flortaucipir BPND colocalizes with white matter microstructural changes in TBI. Skeletonized FA (A) and white matter density (C), standardized against controls, were compared within participant between areas of increased flortaucipir binding (in red) and areas where binding was not increased (in blue). A representative axial slice for each patient shows the spatial distribution of the white matter areas compared, and images are presented in the order of greatest to smallest effect size (greatest decrease in FA or white matter density z-score in high flortaucipir areas shown top left). Both FA z-scores (B) and white matter density z-scores (D) are lower within areas of increased flortaucipir binding, defined as BPND z > 1.645.
Fig. 7 Increased cortical flortaucipir binding in the right lateral occipital area is associated with microstructural white matter damage in TBI. (A) Increased flortaucipir BPND in the right lateral occipital cortex in TBI participants was associated with reduced diffusion MRI–derived FA in remote white matter tracts (top), partly overlapping with white matter tracts of reduced FA in TBI when compared to controls (bottom). (B) Flortaucipir BPND in the right lateral occipital cortex in TBI participants correlated negatively with average skeletonized FA within the genu and body of the corpus callosum as well as within the cingulum bundle, inferior longitudinal fasciculus (ILF), anterior thalamic radiation (ATR), and uncinate fasciculus in the right hemisphere. Correlation coefficients and P values are presented in table S2. (C) Top: Increased flortaucipir BPND in the right lateral occipital cortex in TBI participants is associated with reduced VBM-derived white matter density in the corpus callosum (cal) and right prefrontal area (PF). This distribution partly overlaps with areas of white matter atrophy in TBI when compared to controls (bottom). Results are presented in radiological convention; color maps represent P < 0.05, adjusted for multiple comparisons.
- Table 1 Clinical characteristics of individual TBI participants.
Participant designations correspond to those in Figs. 1 and 2 and fig. S1. APOE, apolipoprotein E genotype; GOS-E, Glasgow Outcome Scale–Extended; MMSE, Mini-Mental State Examination; NA, not available; RTA, road traffic accident; TBI, traumatic brain injury.
Patient Age Sex TBI etiology Time since TBI
(years)GOS-E current
(change)MMSE current
(change)APOE P1 56 Female RTA 35 5 (0) 22 (−2) ε3/ε3 P2 39 Female RTA 28 5 (−1) 27 (−2) ε3/ε3 P3 61 Female RTA 35 5 (−1) 28 (−2) ε3/ε3 P4 39 Male RTA 32 4 (0) 28 (−1) ε3/ε4 P5 57 Male RTA 35 8 (0) 30 (0) ε3/ε4 P6 54 Female RTA 36 5 (−3) 27 (2) ε3/ε4 P7 65 Male Fall 31 7 (0) 30 (2) ε3/ε4 P8 29 Female RTA 18 7 (NA) 29 (NA) ε3/ε3 P9 49 Male RTA 27 5 (NA) 28 (NA) ε2/ε3 P10 48 Male RTA 37 6 (−2) 29 (−1) ε3/ε3 P11 46 Female RTA 31 8 (0) 29 (0) ε3/ε3 P12 44 Male RTA 29 6 (−1) 24 (−2) ε3/ε3 P13 54 Male RTA 32 7 (0) 29 (NA) ε3/ε3 P14 57 Male RTA 37 8 (0) 30 (3) ε3/ε3 P15 54 Male RTA 34 5 (−1) 29 (2) ε3/ε4 P16 38 Male RTA 19 8 (NA) 29 (NA) ε3/ε3 P17 72 Male Assault 51 5 (NA) 27 (NA) ε3/ε3 P18 40 Female RTA 31 5 (0) 23 (−6) ε3/ε4 P19 43 Male RTA 35 8 (0) 30 (0) ε3/ε3 P20 55 Male Assault 20 8 (NA) 30 (NA) ε3/ε4 P21 43 Male RTA 20 5 (NA) 26 (NA) ε4/ε4 - Table 2 Demographic and neuropsychological comparisons between TBI and healthy control groups, as well as between disabled TBI and good recovery TBI subgroups.
Independent sample Mann-Whitney-Wilcoxon test W and P values (P < 0.05 in bold) for comparisons between groups and subgroups. BIS, Barratt Impulsivity Scale; BVMT, Brief Visuospatial Memory Test; CRT, choice reaction time; PT, People’s Test; FrSBe, Frontal Systems Behavior; HADS, Hospital Anxiety and Depression Score; HVLT, Hopkins Verbal Learning Test; LARS, Lille Apathy Rating Scale; RDI, Recognition Discrimination Index; RT, reaction time; WASI, Wechsler Abbreviated Scale for Intelligence; WTAR, Wechsler Test of Adult Reading.
Outcome measure TBI versus healthy participants Disabled versus good recovery TBI subgroups TBI Controls W P Disabled TBI
subgroupGood
recovery TBI
subgroupW P means (±SD) means (±SD) means (±SD) means (±SD) Age (years) 49.7 (10.3) 54.2 (12.1) 80 0.16 49.9 (10) 49.3 (11.2) 35 0.29 Time since
injury (years)31.1 (7.6) — — — 32.9 (7.4) 28.7 (7.5) 66.5 0.39 Education
(years)12.5 (3.6) 11.5 (2.8) 124.5 0.73 11.5 (3.2) 13.9 (3.8) 33.5 0.15 Premorbid
intelligenceWTAR (scaled) 101.4 (16.4) 110.3 (10.8) 76.5 0.13 92.6 (16.1) 113.1 (6.8) 9.5 0.002 Cognitive
impairmentMMSE (current) 27.8 (2.3) 29.5 (0.9) 57.5 0.017 26.5 (2.3) 29.6 (0.5) 4 <0.001 MMSE (change) −0.5 (2.3) — — — −1.3 (2.4) 1 (1.4) 7 0.041 MMSE (change per year) −0.026
(0.131)— — — −0.073
(0.134)0.058 (0.081) 7 0.045 Logical
reasoningWASI matrix reasoning 22.7 (8.2) 25.2 (7) 87 0.46 18.1 (7.3) 28.9 (4.4) 8.5 0.001 Processing
speedTrail making test A (s) 39.9 (20.6) 28.9 (14.4) 153 0.079 49.7 (22.9) 27.9 (7.6) 81 0.016 Trail making test B (s) 106.8 (69.8) 57.4 (18.3) 158 0.049 140.8 (75.3) 65.2 (30.6) 81 0.016 Stroop combined baseline (s) 50.8 (10.8) 41.1 (8.5) 175 0.017 52.7 (12.3) 48.2 (8.6) 67 0.38 CRT RT (ms) 579 (121) 512 (103) 160.5 0.077 645 (115) 491 (53) 94 0.003 Executive
functionTrail making test B-A (s) 66.9 (56) 28.5 (8.7) 145 0.15 91.1 (63) 37.3 (26.3) 79 0.028 Stroop inhibition-switch(s) 93 (48.7) 65.3 (20.4) 164 0.056 116.4 (52.7) 61.9 (14.2) 100 <0.001 Stroop inhibition-switch
versus baseline (s)71.4 (50.7) 51.8 (18.9) 145 0.25 94.6 (54.5) 40.42 (21.2) 96 0.002 FrSBe scale–executive;
current42.2 (8.2) 26.3 (5.7) 181.5 <0.001 46 (8.2) 37.1 (4.9) 89.5 0.012 Apathy LARS −21.5 (10.1) −27.2 (6.3) 134 0.14 −17.2 (10.7) −27.9 (4.5) 82 0.009 FrSBe scale–apathy; current 31.9 (9.6) 21 (5.1) 157.5 0.005 34.3 (10.5) 28.8 (7.8) 71 0.24 Impulsivity/
disinhibitionBIS 66.6 (15.8) 58.1 (6.9) 118.5 0.29 72.9 (15) 57.9 (13.2) 75 0.039 FrSBe scale–disinhibition;
current33.5 (10.3) 24.3 (5.3) 143.5 0.028 36.1 (11.5) 30.1 (7.7) 70.5 0.25 Verbal memory PT immediate recall 18.3 (8.7) 19.8 (8.2) 102 0.61 16.4 (9.2) 20.4 (7.8) 39.5 0.32 PT delayed recall 6.4 (3.8) 7.3 (3.6) 100.5 0.56 5.6 (3.9) 7.6 (3.5) 38.5 0.28 HVLT immediate recall 21.2 (5.3) 25.5 (4.7) 63 0.038 19.4 (4.9) 23.7 (5) 25.5 0.046 HVLT delayed recall 6.3 (3.6) 8.8 (2.5) 65.5 0.048 5.3 (3.9) 7.7 (2.7) 34 0.16 HVLT RDI 9.2 (2.4) 9.9 (2) 97 0.47 8.7 (2.8) 10 (1.5) 40 0.33 Visual memory Paired associates learning
(z-score)−1.47 (0.81) −0.73 (0.92) 66 0.043 −1.79 (0.77) −1.03 (0.69) 25.5 0.036 BVMT immediate recall 16.2 (8.3) 21.7 (5.5) 63 0.039 10.9 (3.7) 23.3 (7.5) 7 <0.001 BVMT delayed recall 6.8 (3.7) 9.5 (1.4) 64.5 0.044 4.7 (3.1) 9.6 (2.4) 12 0.003 BVMT RDI 4.9 (1.3) 5.9 (0.3) 67.5 0.026 4.3 (1.4) 5.9 (0.3) 16 0.004 Visuospatial
abilityFeature match test (z-score) −1.46 (0.74) −1.19 (0.92) 94.5 0.42 −1.88 (0.69) −0.89 (0.31) 6 <0.001 Mood
disturbanceHADS-anxiety 8 (6) 3.9 (3.8) 161.5 0.069 9.9 (5.6) 5.3 (5.7) 80.5 0.063 HADS-depression 4.5 (4.7) 1.9 (2.5) 156 0.11 6.4 (5.1) 1.8 (2.4) 86.5 0.022
Supplementary Materials
stm.sciencemag.org/cgi/content/full/11/508/eaaw1993/DC1
Materials and Methods
Fig. S1. Focal lesions in TBI participants.
Fig. S2. Individual data points as well as means and SDs for demographic and neuropsychological results in the healthy control group, disabled TBI subgroup, and good recovery TBI subgroup.
Fig. S3. Flortaucipir binding and focal lesions.
Fig. S4. Voxel-wise comparisons between subgroups in flortaucipir binding.
Fig. S5. Flortaucipir medial temporal lobe BPND in the healthy control, disabled TBI, and good recovery TBI groups.
Fig. S6. Relationships of CSF T-tau and P-tau and plasma T-tau concentrations with flortaucipir gray matter BPND, white matter BPND, and spatial extent in TBI and healthy controls.
Fig. S7. Relationships of CSF and plasma UCH-L1, NFL, GFAP, S100, and CSF Aβ42 with cerebral gray matter and white matter flortaucipir BPND in TBI and healthy controls.
Fig. S8. Gray matter density within areas of increased flortaucipir BPND in TBI.
Fig. S9. Flortaucipir right parietal cluster (TBI > control) BPND (z-score compared to healthy controls) and FA in white matter tracts in TBI.
Fig. S10. No difference in flortaucipir BPND (z-score compared to healthy controls) or spatial extent (number of voxels above threshold) in TBI when comparing individuals with at least one APOE ε4 allele and those not carrying an ε4 allele.
Fig. S11. Interactions between APOE genotype and each of time since injury, age, CSF T-tau, P-tau, Aβ42, NFL, GFAP, S100 concentrations, white matter and gray matter densities, and MMSE scores (longitudinal change and current) on flortaucipir BPND [z-score compared to controls and spatial extent (N voxels above threshold)] in TBI.
Fig. S12. Off-target flortaucipir binding in the striatum and choroid plexus compared to other cerebral areas in healthy controls and TBI.
Fig. S13. Flortaucipir reference region (cerebellar gray matter) time activity curves.
Table S1. Correlations between neuropsychological measures and average white matter tract FA in TBI.
Table S2. Correlations between flortaucipir right parietal cluster (TBI > control) BPND (z-score compared to healthy controls) and FA in white matter tracts in TBI participants.
Table S3. Correlations between clinical measures and each of flortaucipir right parietal cluster (TBI > control) BPND, whole cerebral cortex BPND (z-score compared to the healthy control group), white matter BPND (z-score compared to the healthy control group), and spatial extent (N of voxels with BPND z-score > 1.645 of healthy controls) in TBI participants.
References (69–82)
Additional Files
This PDF file includes:
- Materials and Methods
- Fig. S1. Focal lesions in TBI participants.
- Fig. S2. Individual data points as well as means and SDs for demographic and neuropsychological results in the healthy control group, disabled TBI subgroup, and good recovery TBI subgroup.
- Fig. S3. Flortaucipir binding and focal lesions.
- Fig. S4. Voxel-wise comparisons between subgroups in flortaucipir binding.
- Fig. S5. Flortaucipir medial temporal lobe BPND in the healthy control, disabled TBI, and good recovery TBI groups.
- Fig. S6. Relationships of CSF T-tau and P-tau and plasma T-tau concentrations with flortaucipir gray matter BPND, white matter BPND, and spatial extent in TBI and healthy controls.
- Fig. S7. Relationships of CSF and plasma UCH-L1, NFL, GFAP, S100, and CSF Aβ42 with cerebral gray matter and white matter flortaucipir BPND in TBI and healthy controls.
- Fig. S8. Gray matter density within areas of increased flortaucipir BPND in TBI.
- Fig. S9. Flortaucipir right parietal cluster (TBI > control) BPND (z-score compared to healthy controls) and FA in white matter tracts in TBI.
- Fig. S10. No difference in flortaucipir BPND (z-score compared to healthy controls) or spatial extent (number of voxels above threshold) in TBI when comparing individuals with at least one APOE ε4 allele and those not carrying an ε4 allele.
- Fig. S11. Interactions between APOE genotype and each of time since injury, age, CSF T-tau, P-tau, Aβ42, NFL, GFAP, S100 concentrations, white matter and gray matter densities, and MMSE scores (longitudinal change and current) on flortaucipir BPND [z-score compared to controls and spatial extent (N voxels above threshold)] in TBI.
- Fig. S12. Off-target flortaucipir binding in the striatum and choroid plexus compared to other cerebral areas in healthy controls and TBI.
- Fig. S13. Flortaucipir reference region (cerebellar gray matter) time activity curves.
- Table S1. Correlations between neuropsychological measures and average white matter tract FA in TBI.
- Table S2. Correlations between flortaucipir right parietal cluster (TBI > control) BPND (z-score compared to healthy controls) and FA in white matter tracts in TBI participants.
- Table S3. Correlations between clinical measures and each of flortaucipir right parietal cluster (TBI > control) BPND, whole cerebral cortex BPND (z-score compared to the healthy control group), white matter BPND (z-score compared to the healthy control group), and spatial extent (N of voxels with BPND z-score > 1.645 of healthy controls) in TBI participants.
- References (69–82)
