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

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.

There is increasing acceptance of epidemiological and pathophysiological links between traumatic brain injury (TBI) and Alzheimer disease (AD).1- 3 β-Amyloid (Aβ) plaques, a hallmark of AD, are found in up to 30% of patients who die in the acute phase following TBI4- 7; they appear within hours of injury and are present in all age groups. In contrast, in individuals dying of nonneurological causes, Aβ plaques tend to be confined to elderly individuals.5 At autopsy, Aβ plaques in patients with TBI are predominantly found in gray matter but have also been reported in white matter.8 The dominant Aβ species found in TBI-associated plaques and oligomers is Aβ42,7,9,10 which is the aggregation-prone species also found in AD. Autopsy studies conducted at varying intervals after TBI suggest that these deposits are cleared over a period of weeks following injury.11 Recent postmortem evidence suggests that, following TBI, the Aβ deposition associated with “normal” aging may be subsequently accelerated,12 but our inability to quantify amyloid binding in vivo limits a broader understanding of the temporal profile and outcome of amyloid deposition in TBI.

Positron emission tomography (PET) may provide one solution to this problem. Several carbon 11–labeled and fluorine 18–labeled PET ligands for amyloid imaging have been developed and used in AD.13 The most widely studied of these, Pittsburgh compound B (PiB),14 is widely validated as a marker of cerebral amyloid deposition. In individuals with AD, and in the general population, the relative distribution of Aβ as measured by carbon 11–labeled PiB ([11C]PiB) PET correlates well with neuropathology, with a predilection for high frontal, temporoparietal, and striatal binding and relatively low but still significant mesial temporal binding.13

However, documented amyloid deposition may be unassociated with [11C]PiB binding seen on PET scans,15- 17 or it may have distinct patterns of binding across the brain, depending on the genetic abnormality predisposing to amyloid deposition,18 suggesting molecular heterogeneity in amyloid species in relation to [11C]PiB binding. Therefore, before using serial [11C]PiB PET to examine amyloid deposition in patients with TBI, we need to be certain of the correspondence between [11C]PiB PET imaging and pathology. Furthermore, we have no idea of the time points following injury when changes in amyloid deposition might be best detected. Given these considerations, we have undertaken a cross-sectional pilot study of [11C]PiB PET for patients with moderate to severe TBI, imaged at a range of times after TBI. To validate our imaging findings, we also undertook a comparison of in vitro tritium-labeled PiB ([3H]PiB) binding against immunocytochemistry for Aβ in autopsy-acquired brain tissue obtained from a separate cohort of patients.

JAMA Neurology 2013