Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease

Abstract

Background: Alzheimer disease (AD) is defined neuropathologically by the presence of neurofibrillary tangles and plaques associated with tau and beta-amyloid protein deposition. The colocalization of microglia and beta-amyloid plaques has been widely reported in pathological examination of AD and suggests that neuroinflammation may play a role in pathogenesis and/or progression. Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood.

Objective: To image microglial activation and beta-amyloid deposition in the brains of subjects with and without AD.

Design, setting, and participants: Using two carbon 11 ([11C])-labeled positron emission tomographic imaging agents, Pittsburgh Compound B (PiB) and (R)-PK11195, we examined the relationship between amyloid deposition and microglial activation in different stages of AD using 5 control subjects, 6 subjects diagnosed with mild cognitive impairment, and 6 patients with mild to moderate AD.

Results: Consistent with prior reports, subjects with a clinical diagnosis of probable AD showed significantly greater levels of [11C]PiB retention than control subjects, whereas patients with mild cognitive impairment spanned a range from control-like to AD-like levels of [11C]PiB retention. Additionally, 2 asymptomatic control subjects also exhibited evidence of elevated PiB retention in regions associated with the early emergence of plaques in AD and may represent prodromal cases of AD. We observed no differences in brain [11C](R)-PK11195 retention when subjects were grouped by clinical diagnosis or the presence or absence of beta-amyloid pathological findings as indicated by analyses of [11C]PiB retention.

Conclusions: These findings suggest that either microglial activation is limited to later stages of severe AD or [11C](R)-PK11195 is too insensitive to detect the level of microglial activation associated with mild to moderate AD.

Figure 1

Time activity curves of radioactivity in the posterior cingulate gyrus and precuneus region following the injection of carbon 11–labeled ([¹¹C]) (R)-PK11195 (A and B) or [¹¹C] Pittsburgh Compound B (PiB) (C and D). Data are grouped by the subject’s [¹¹C]PiB retention (PiB positive or PiB negative) (A and C) or clinical diagnosis (control, mild cognitive impairment [MCI], or Alzheimer disease [AD]) (B and D). Error bars indicate 1 SD about the mean radioactivity concentration for each time point; ID, injected dose.

Figure 2

Carbon 11–labeled ([¹¹C]) Pittsburgh Compound B (PiB) standardized uptake value ratio over 90 minutes (SUVR90) outcome measures corrected for cerebral atrophy for the mesial temporal cortex (MTC), sensorimotor cortex (SMC), frontal cortex (FRT), parietal cortex (PAR), and posterior cingulate or precuneus region (PRC). Data are classified by clinical diagnosis (control, mild cognitive impairment [MCI], or Alzheimer disease [AD]) (A) and [¹¹C]PiB retention (B). Indices of [¹¹C]PiB retention in patients with AD show significantly higher values relative to control subjects in cortical regions (P<.05). Also, when classified on the basis of amyloid pathological findings (PiB positive or PiB negative), PiB-positive subjects showed indices of retention that were approximately 2-fold higher than in PiB-negative subjects (P<.01) in regions where β-amyloid pathological findings are expected.

Figure 3

Carbon 11–labeled ([¹¹C]) (R)-PK11195 region of interest to subcortical white matter ratio (ROI/SWM) outcome measures corrected for cerebral atrophy for the cerebellum (CER), mesial temporal cortex (MTC), sensorimotor cortex (SMC), frontal cortex (FRT), parietal cortex (PAR), and posterior cingulate or precuneus region (PRC). Data are classified by clinical diagnosis (control, mild cognitive impairment [MCI], or Alzheimer disease [AD]) (A) and [¹¹C] Pittsburgh Compound B (PiB) retention (B). No statistically significant differences were noted between diagnostic groups or [¹¹C]PiB retention groups (PiB positive or PiB negative).

Figure 4

Carbon 11–labeled ([¹¹C]) (R)-PK11195 outcome measures (region of interest to subcortical white matter ratio [ROI/SWM]) demonstrating the effects of a magnetic resonance–based correction for cerebral atrophy. Measures are shown as atrophy corrected classified by clinical diagnosis (control, mild cognitive impairment [MCI], or Alzheimer disease [AD]) (A), atrophy corrected classified by [¹¹C] Pittsburgh Compound B (PiB) retention (B), uncorrected classified by clinical diagnosis (C), and uncorrected classified by [¹¹C]PiB retention (D). Uncorrected measures of [¹¹C](R)-PK11195 retention exhibit a trend toward lower levels of [¹¹C](R)-PK11195 retention in subjects with AD and PiB-positive subjects, particularly in the mesial temporal cortex (MTC) where atrophy is the greatest in AD (P=.14). Indices of [¹¹C](R)-PK11195 retention show no significant differences between subject groups (P=.46) or β-amyloid status (P=.46) when data are corrected for the dilutional effects of atrophy. CER indicates cerebellum; SMC, sensorimotor cortex; FRT, frontal cortex; PAR, parietal cortex; PRC, posterior cingulate or precuneus region; and error bars, SD.

Figure 5

Transaxial and sagittal parametric images of the carbon 11–labeled ([¹¹C]) Pittsburgh Compound B (PiB) standardized uptake value ratio (SUVR) and the [¹¹C](R)-PK11195 region of interest to subcortical white matter ratio (ROI/SWM) in a PiB-negative control subject (subject C-1) and the patient with the most advanced Alzheimer disease (AD) in our study (patient A-5). Areas of significantly elevated [¹¹C]PiB retention are evident in the patient with AD in a manner consistent with the known pattern of amyloid deposition in AD. No similar pattern is noted in the [¹¹C](R)-PK11195 binding potential images.