Potential antecedent marker of Alzheimer disease

Background: Beta-amyloid (A ) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to A plaques in vivo, N-methyl-[C]2-(4=-methylaminophenyl)-6-hydroxybenzothiazole (or [C]PIB for “Pittsburgh Compound-B”), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes. Methods: Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [C]PIB-A binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue. Results: Patients with DAT had elevated BP values vs nondemented subjects (p 0.0001). Four of the 41 nondemented subjects had elevated cortical BP values and their BP values as a group were not significantly different from the DAT subjects’ BP values. Two of these four nondemented subjects had [C]PIB uptake, both visually and quantitatively, that was indistinguishable from the DAT subjects. Conclusions: Elevated [C]PIB binding in nondemented subjects suggests that [C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer disease state. Longitudinal studies will be required to determine the association of elevated [C]PIB binding and risk of developing dementia of the Alzheimer type. NEUROLOGY 2006;67:446–452 Several radiotracers with high affinity to betaamyloid (A ) plaques have been developed for the purposes of in vivo human imaging.1-9 One of these tracers, N-methyl-[C]2-(4=-methylaminophenyl)-6hydroxybenzothiazole (or [C]PIB for “Pittsburgh Compound-B), in preclinical evaluation demonstrated rapid diffusion across the blood–brain barrier, very high affinity to a single binding site on synthetic A (KD 4.7 nM), and very high affinity to a single binding site to homogenates of frontal cortex from brains with Alzheimer disease (AD) (KD 1.4 nM). 8 The first human studies of [C]PIB reported significantly increased uptake in individuals with dementia of the Alzheimer type (DAT) compared to healthy controls10,11 although the sample sizes were relatively modest (16 DAT subjects, 6 old controls, and 3 young controls). PET images of [C]PIB in DAT subjects indicated widespread increased tracer uptake in neocortical regions with relative sparing of the occipital and sensory/motor cortices and with little uptake in the cerebellar cortex. The capability to image A plaque burden in vivo has potential implications for the diagnosis and management of AD. One application may be in the identification of the neuropathologic changes of AD in clinically normal individuals, prior to the development of cognitive changes.12-16 We evaluated the potential for PET [C]PIB imaging to detect this putative preclinical AD state of [C]PIB in vivo in nondemented older subjects. For comparison purposes, and to extend the original findings,11 we also performed PET [C]PIB imaging in a group of DAT subjects. Methods. Human subjects. Ten subjects with DAT and 41 subjects with no evidence for cognitive impairment gave written informed consent and underwent PET imaging. All assessment and imaging procedures were approved by Washington University’s Human Studies Committee. Both the DAT and the nondemented individuals (except for three subjects who were 30 years old) were community dwelling volunteers enrolled in the Washington University AD Research Center (ADRC). The assessment protocol has been described.17,18 In brief, an experienced clinician conducts semi-structured interviews with both the subject and an informant to assess potential impairment in the subject’s cognitive and functional performance. A neurologic examination of the subject Additional material related to this article can be found on the Neurology Web site. Go to www.neurology. org and scroll down the Table of