Carbon 11–Labeled Pittsburgh Compound B and Carbon 11–Labeled (R)-PK11195 Positron Emission Tomographic Imaging in Alzheimer Disease

A Definitive Diagnosis of Alzheimer disease (AD) relies on the demonstration of β-amyloid (Aβ) plaques and neurofibrillary tangles at autopsy.1 Microglial activation frequently accompanies Aβ deposition, although the time course of their relationship is unclear.2 While the exact time course of Aβ deposition in AD has not been elucidated, evidence gained through a postmortem study of Down syndrome (a condition in which Aβ deposition is always present by age 40 years and dementia is common) and an increasing number of reports using the positron emission tomographic (PET) Aβ imaging agent carbon 11 ([11C])–labeled Pittsburgh Compound B (PiB) suggests that Aβ deposition precedes development of the clinical symptoms of dementia.3–5 Compared with control subjects, patients with AD show marked retention of [11C]PiB in areas of brain association cortex known to contain large amounts of Aβ deposits in AD.6–8 Levels of [11C]PiB retention comparable to those seen in some subjects with AD have been observed in the cognitively normal elderly population.4,5 These and other studies suggest that Aβ deposition precedes significant cognitive decline, although more definitive longitudinal studies in healthy elderly persons are needed to fully characterize the relationship between Aβ deposition and cognitive decline. The colocalization of activated microglia with Aβ-containing neuritic plaques that are characteristic of AD was highlighted by McGeer et al.9 There is much debate surrounding the central question of whether the role of activated microglia in the pathophysiology of AD is one of neuroprotection or neurotoxicity; this issue has been the subject of many recent reviews.2,10 Together, these investigations implicate microglia as at least a participant in the AD process. Several groups have investigated the utility of selective ligands of the peripheral benzodiazepine receptor (PBR) as surrogate markers for activated brain microglia (as reviewed by Venneti et al11). Unlike the central benzodiazepine receptor, the PBR is expressed at low levels in the healthy brain. During neuroinflammation associated with AD and a variety of other central nervous system diseases, binding of the PBR radioligand [11C](R)-PK11195 increases in the brain.11 We have confirmed specific binding of tritium-labeled (R)-PK11195 to simian and human microglia using ex vivo autoradiography in lentiviral encephalitis and AD.12 Additionally, we have demonstrated increased radiotracer retention in the simian brain consistent with postmortem histopathological confirmation of microglial activation.13 The goal of our work was to use PET radiotracers to label cerebral Aβ deposits and activated microglia and assess their potential temporal relationship using a cross-sectional design. The presence of significant elevations of [11C]PiB retention in asymptomatic elderly subjects4,5 suggests that significant Aβ aggregation precedes detectable cognitive dysfunction by many years.14 Therefore, if microglia are involved in the deposition of Aβ, one would expect these cells also to be activated years before cognitive dysfunction is detected clinically. One hypothesis is that the brain’s immune response to fibrillar Aβ deposits in the form of activation of microglia results in the secretion of a plurality of neurotoxic factors that contribute to synaptic loss and cognitive impairments. The correlation of the time course of microglial activation with the time course of Aβ deposition will help to elucidate the role of neuroinflammation in the pathophysiology of AD.