Elsevier

Neurobiology of Disease

Volume 72, Part A, December 2014, Pages 117-122
Neurobiology of Disease

Review
Early detection of Alzheimer's disease using PiB and FDG PET

https://doi.org/10.1016/j.nbd.2014.05.001Get rights and content

Highlights

  • PiB and FDG are able to detect early AD pathological processes and subsequent neurodegeneration.

  • Imaging with PiB and FDG has potential clinical benefits, including preclinical detection of AD.

  • PiB and FDG allow the study of relationships of Aβ to changes in cognition and neurodegeneration.

  • The present review focuses on use of PiB and FDG-PET and their relationship to one another.

Abstract

Use of biomarkers in the detection of early and preclinical Alzheimer's disease (AD) has become of central importance following publication of the NIA-Alzheimer's Association revised criteria for the diagnosis of AD, mild cognitive impairment (MCI) and preclinical AD. The use of in vivo amyloid imaging agents, such a Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) is able to detect early AD pathological processes and subsequent neurodegeneration. Imaging with PiB and FDG thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other etiologies in patients presenting with mild or atypical symptoms or confounding comorbidities in which the diagnostic distinction is difficult to make clinically. From a research perspective, this allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to MCI to AD. The present review focuses on use of PiB and FDG-PET and their relationship to one another.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a worldwide prevalence estimated to quadruple over the next 50 years. AD is pathologically characterized by the presence of amyloid plaques, containing amyloid-beta (Aβ), and neurofibrillary tangles, containing hyperphosphorylated tau, as well as significant loss of neurons and deficits in neurotransmitter systems. A growing consensus points to deposition of Aβ plaques as a central event in the pathogenesis of AD. This “amyloid cascade hypothesis” (Hardy and Allsop, 1991, Hardy and Higgins, 1992) states that overproduction of Aβ, or failure to clear this peptide, leads to AD primarily through amyloid deposition, which triggers the production of NFT, cell death and, ultimately, the clinical symptoms such as memory loss and cognitive impairment (Hardy et al., 1998).

Definitive diagnosis of AD relies on the demonstration of sufficient amounts of Aβ plaques and NFT in autopsy brains (Mirra et al., 1991). Recently, the development of the PET tracer Pittsburgh Compound-B has made the in-vivo imaging of amyloid possible, with striking differences in PiB retention observed between control and AD subjects in brain areas known to contain significant amyloid deposits in AD (e.g., frontal cortex and parietal cortex) (Fig. 1) (Klunk et al., 2004). Fluoro-2-deoxy-D-glucose (FDG) PET shows decreases in cerebral glucose metabolism, with a characteristic regional pattern of posterior temporoparietal > frontal hypometabolism in AD (Foster et al., 2007, Friedland et al., 1983, Herholz et al., 2007, Jagust et al., 2007) (Fig. 1).

Imaging AD pathology, using amyloid PET imaging agents such as PiB, and imaging AD neurodegenerative processes, using FDG PET (as well other markers such as structural MRI and CSF tau), have several potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from non-AD dementia in patients with mild or atypical symptoms or confounding comorbidities (in which the distinction is difficult to make clinically). From a research perspective, these imaging techniques allow us to study relationships between amyloid, cognition and neurodegenerative processes across the continuum from normal aging to AD; and to monitor the biological effects of anti-Aβ drugs and relate them to effects on neurodegeneration and cognition. In particular, understanding biomarkers such as PiB and FDG in relation to normal aging has become critical given that we have entered the era of “prevention” trials in AD with two studies targeting autosomal dominant AD (DIAN and API), one study targeting homozygous APOE*4 carriers (API) and one study targeting typical late-onset disease (A4). All of these studies rely heavily on biomarkers in general and on Aβ biomarkers in particular. A key concept underlying these trials is the recently developed NIA-Alzheimer's Association research criteria for preclinical AD, suggesting that Aβ deposition in cognitively normal individuals is in fact a preclinical stage of AD (Sperling et al., 2011). These criteria were recently operationalized by Jack et al. (Jack et al., 2012) and suggest that amyloid biomarkers, including PiB-PET, become abnormal first and are followed by biomarkers of neuronal injury and degeneration, including FDG-PET, closer to the time when cognitive symptoms appear (Fig. 2) (Jack et al., 2012). The present review focuses on use of PiB and FDG-PET and their relationship to one another.

Section snippets

Amyloid imaging using PiB PET

The earliest studies with PiB in AD patients showed that markedly increased PiB retention was observed in brain areas known to contain high levels of amyloid plaques when compared to HC subjects. In brain regions such as parietal and frontal cortices, the pattern of PiB retention was markedly different in AD patients compared to the HC subjects (Klunk et al., 2004). PiB retention in AD patients was generally most prominent in cortical areas and lower in white matter areas, in a manner most

Cerebral glucose metabolism imaging using FDG PET

Reductions of cerebral metabolism are well established in AD (Lopresti et al., 2005, Minoshima, 2003, Mosconi et al., 2007, Silverman and Alavi, 2005). Similar changes have been reported in cognitively normal individuals at high risk for AD due to expression of the ApoE4 alelle (Reiman et al., 1996, Small et al., 2000). Further, hypometabolism has been reported in cognitively normal individuals with a parent with AD (Mosconi et al., 2008a, Mosconi et al., 2009, Mosconi et al., 2013, Mosconi et

Relationship between amyloid deposition and glucose metabolism

Comparisons of PiB and FDG PET data for detection of AD found PiB was more accurate than FDG both on visual reading (accuracy, 90% vs. 70%) and ROC analysis (95% vs. 83%). The authors concluded that the visual analysis of PiB images appears more accurate than visual reading of FDG for identification of AD (Ng et al., 2007). Similar results were found by Rabinovici et al.(Rabinovici et al., 2011) with inter-rater agreement significantly higher for PiB (kappa = 0.96) than FDG (kappa = 0.72), as was

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