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Original Investigation |

Amyloid Imaging With Carbon 11–Labeled Pittsburgh Compound B for Traumatic Brain Injury

Young T. Hong, PhD1,5; Tonny Veenith, FRCA2; Deborah Dewar, PhD3; Joanne G. Outtrim, MSc2; Vaithianadan Mani, FRCA2; Claire Williams, FRCA2; Sally Pimlott, PhD4; Peter J. A. Hutchinson, FRCS, PhD5; Adriana Tavares, PhD3; Roberto Canales, PhD1,5; Chester A. Mathis, PhD6; William E. Klunk, MD, PhD7; Franklin I. Aigbirhio, DPhil1,5; Jonathan P. Coles, FRCA, PhD2; Jean-Claude Baron, ScD, FMedSci1,5,8; John D. Pickard, FMedSci1,5; Tim D. Fryer, PhD1,5; William Stewart, FRCPath, PhD4; David K. Menon, PhD, FMedSci1,2
[+] Author Affiliations
1Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, England
2Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England
3Institute of Neuroscience and Psychology, University of Glasgow, Scotland
4University of Glasgow and Southern General Hospital, Glasgow, Scotland
5Department of Clinical Neurosciences, University of Cambridge, Cambridge, England
6Departments of Radiology and Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
7Departments of Psychiatry and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
8INSERM U894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
JAMA Neurol. 2014;71(1):23-31. doi:10.1001/jamaneurol.2013.4847.
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Objectives  To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue.

Design, Setting, and Participants  In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24-60] years) and in 15 patients (median [range] age, 33 [21-50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21-70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29-71] years) who died of other causes.

Main Outcomes and Measures  We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue.

Results  Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels.

Conclusions and Relevance  [11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.

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Figures

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Figure 1.
Carbon 11–Labeled Pittsburgh Compound B ([11C]PiB) Distribution Volume Ratio (DVR) Maps From a Control and 3 Patients With Traumatic Brain Injury (TBI)

Transverse, coronal, and sagittal sections of DVR maps from a healthy control and 3 patients at varying time intervals after TBI, overlaid on coregistered T1-weighted magnetic resonance imaging scans. All maps have the same intensity range (DVRs between 1.00 and 1.30) to aid comparability. The interval between TBI and imaging is shown on the right.

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Figure 2.
Box and Whisker Plots of Regional Carbon 11–Labeled Pittsburgh Compound B Distribution Volume Ratios (DVRs) for Controls and Patients With Traumatic Brain Injury (TBI)

Plots of DVRs in cortical gray matter, white matter, striatal, and thalamic regions of interest from controls and patients with TBI patients are shown. The horizontal line inside each box represents the 50th percentile; the top and bottom borders of each box represent the 75th and 25th percentiles, respectively; the whiskers above and below each box represent the 90th and 10th percentiles, respectively; and the circles beyond the whiskers represent outliers. Significant differences between the 2 groups were found for cortical gray matter (P = .009 [P = .04 when corrected for multiple comparisons]) and the striatum (P = .01 [P = .048 when corrected for multiple comparisons]).

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Figure 3.
Images of β-Amyloid (Aβ) in Cerebellar Tissue From Tritium-Labeled Pittsburgh Compound B ([3H]PiB) Autoradiography and Immunocytochemistry

[3H]PiB autoradiography and immunocytochemistry were performed for 2 patients who died 30 hours (A-C) and 12 hours (D-F) after a traumatic brain injury (TBI). The 2 red boxes shown in the low magnification regions (B and E, respectively) were selected for higher magnification (C and F, respectively). [3H]PiB binding is shown for the patient who died 12 hours after a TBI; this binding corresponds to vascular amyloid in meningeal vessels (D [arrowheads]), which are revealed by immunocytochemistry (E [original magnification ×3] and F [original magnification ×50]) and best seen at high magnification (F [arrowheads]). The neocortical tissue of the patient who died 30 hours after a TBI (A-C) is also shown in Figure 4A-C, where the neocortical tissue shows clear amyloid plaque and [3H]PiB binding, whereas the cerebellar tissue does not.

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Figure 4.
Images of β-Amyloid (Aβ) in Adjacent Tissue Sections From the Parasagittal Cortex From Tritium-Labeled Pittsburgh Compound B ([3H]PiB) Autoradiography and Immunocytochemistry

[3H]PiB autoradiography and immunocytochemistry were performed for 2 patients who died 30 hours (A-C) and 5 days (D-F) after a traumatic brain injury (TBI). Note the regional correspondence in fibrillary Aβ plaque detection with the 2 techniques. However, the predominantly diffuse plaque in the patient who died 30 hours after a TBI is more evident in the stained sections (B and C). The higher magnification fields (C and F [scale bars, 100 μm]) correspond to the boxes (B and E, respectively [scale bars, 1 mm]) in the low magnification regions.

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