Amyloid Imaging in Alzheimer’s Disease and Other Dementias

Abstract

With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). (11)C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. (11)C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden in the brain, (11)C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and 50-60% of people with mild cognitive impairment, present with cortical (11)C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition in the course of Alzheimer's disease.

A review of β-amyloid neuroimaging in Alzheimer's disease

“…Many of the molecular probes are derivatives of histological dyes such as Congo Red, thioflavin S and T, Acridine Orange and Chrysamine-G (Coimbra et al, 2006; Fodero-Tavoletti et al, 2009) or other molecules such as styrylbenzene. Two of the most extensively used ligands are [ 11 C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh Compound B or PIB) (Small et al, 2008; Fodero-Tavoletti et al, 2009; Mosconi et al, 2010) and 2-(1-{6-[2-[ 18 F]-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([ 18 F]-FDDNP) (Small et al, 2008; Fodero-Tavoletti et al, 2009; Mosconi et al, 2010). [ 18 F]-FDDNP was the first ligand successfully employed in humans (Rabinovici and Jagust, 2009).…”

“…PIB on the other hand binds with high affinity and specificity to fibrillar Aβ (Coimbra et al, 2006; Fodero-Tavoletti et al, 2009; Mosconi et al, 2010) and its in vivo PET signal correlates strongly with in vitro measures of Aβ burden in post-mortem AD brains (Rabinovici and Jagust, 2009). Studies have demonstrated elevated retention of PIB in the brains of AD patients compared to healthy controls (Coimbra et al, 2006; Small et al, 2008; Mosconi et al, 2010).…”

“…Studies have demonstrated elevated retention of PIB in the brains of AD patients compared to healthy controls (Coimbra et al, 2006; Small et al, 2008; Mosconi et al, 2010). Significant PIB retention is found in 90% of clinically diagnosed AD patients and approximately 60% of individuals with MCI and 25–30% of normal elderly (Fodero-Tavoletti et al, 2009; Mosconi et al, 2010). The regional distribution of high retention in AD brains is in areas known to have high amyloid deposition, most prominently the frontal cortex, parietal cortex, lateral temporal cortex, posterior cingulated cortex/precuneus, thalamus and striatum (Coimbra et al, 2006; Rabinovici and Jagust, 2009; Mosconi et al, 2010).…”

PET imaging in neurology

“…Maximum 11 C-PiB uptake in DLBD patients was seen in the anterior or posterior cingulate cortex, followed by the frontal, parietal, temporal, and occipital cortices [27]. Significant 11 C-PiB retention was reported in ∼ 50-60% of individuals with MCI [20]. A meta-analytic sensitivity and specificity of 11 C-PiB for predicting progression from MIC to AD ranged from 83.3 to 100% and from 41.1 to 100%, respectively, with pooled estimates of 94.7 and 57.2%, respectively [28].…”

“…However, a positive PET can also be seen in normal older individuals as well as in other medical conditions, such as DLBD and cerebral amyloid angiopathy (CAA), and a negative PET can be seen in rare forms of AD with unusual amyloid [20][21][22]. Significant 11 C-PiB retention was reported in ∼ 30% of normal healthy older people, and the mean cortical binding potential for PiB rose in an agedependent manner [20,21]. PiB PET was positive in 18% of persons aged 60-69 years and in 65% of those over 80 years, most strongly in epsilon4 carriers [21].…”