β-amyloid imaging
Where? When? Why? so What?
Aβ deposition if a key feature of AD and is now visible in vivo thanks to the development of specific radiotracers for PET imaging (Klunk et al., 2004). This new technique has been a major step forward in the field as it has huge implications, both in terms of clinical diagnosis and research on AD mechanisms.
Aβ deposition and other biomarkers in patients
In an article published in The Journal of Neuroscience (La Joie et al., 2012), we studied the topography of Aβ deposition, assessed with Florbetapir-PET, and its relationship with biomarkers of neurodegeneration (atrophy with MRI, and hypometabolism with FDG-PET) in patients with AD dementia.
Contrary to previous studies that showed similarities similarities between these alterations (Buckner et la., 2005), we focused on the differences between the patterns of Aβ deposition, hypometabolism and atrophy.
Using a method that was specifically designed to integrate data from different imaging modalities (W-score maps, an extension from the Z-score technique developed in Chételat et al., Brain 2008), we showed that the hierarchy between the three biomarkers was variable across brain regions.
Specifically, we highlighted a dissociation between Aβ and neurodegeneration. In medial temporal regions, neurodegeneration was important while Aβ was minimal, while frontal regions showed the reverse contrast: extreme Aβ with very little atrophy/neurodegeneration (see Figure below). Moreover, levels of Aβ were not related to levels of neurodegeneration across patients: these individuals with massive Aβ did not have more atrophied/hypometabolic brains.
MULTIMODAL IMAGING OF AD AT THE DEMENTIA STAGE. Left panel provides individual images from an healthy control (HC) and AD patients, as well as voxelwise analyses showing brain alterations identified using MRI, FDG-PET and Florbetapir-PET (20 patients with AD versus 36 HC). Right panel shows a clustering analysis that enable grouping regions with comparable degrees of atrophy, hypometabolism and amyloid deposition. (derived from La Joie et al., The Journal of Neuroscience 2012).
Overall, Aβ and neurodegeneration appeared to be uncoupled at the dementia stage, suggesting that Aβ does not have a local effect on brain structure and function. This might be due to our measure of Aβ (PET identifies fibrillar Aβ, not the soluble form that is more likely to be toxic) or to differences in the timing of these different alterations.
Papers I (co)authored: La Joie et al., 2012; Camus et al., 2012; La Joie et al., 2013
Further reading: Buckner et al., 2005; Jack et al., 2008; Li et al., 2008; Chételat et al., 2008
Factors associated with the presence of Aβ in healthy elders
Using PET (or CSF measures), it has been possible to show that a certain proportion of cognitively normal individuals harbor Aβ in their brain. In a review (Chételat et al., Neuroimage Clinical 2013), we summarized the factors predicting a higher prevalence of Aβ: increasing age, presence of the APOE4 allele, subjective memory complaint and environmental factors. We also reviewed the existing literature on cognitive and neuroimaging differences associated with the presence of Aβ in cognitively normal elders and discussed ethical issues related to Aβ imaging in normal individuals.
ILLUSTRATION OF FACTORS ASSOCIATED WITH THE PRESENCE OF BETA-AMYLOID DEPOSITION IN HEALTHY ELDERS. The bar graph on the left illustrates data from multiple papers assessing the prevalence of Aβ in healthy elders, either E4 carriers or non carriers (reviewed in Chételat & Fouquet, 2013) . In spite of major differences in the overall prevalence of Aβ (likely due to variations in demographics and imaging techniques), all studies show a clear increase of Aβ in E4 carriers. The lower panel shows PiB-PET scans from 5 healthy elders with increasing radiotracer binding from the left to the right (data from the Jagust lab, UC Berkeley).
In another review dealing with neuroimaging characterization of healthy individuals carrying the APOE4 allele (Fouquet et al., 2014), we suggested that increased Aβ deposition is the most consistent and undoubted feature of E4 carriers, while hypometabolism and atrophy appear more subtle, with several studies failing to show significant differences.
Recently, Miranka Wirth conducted a study in the BACS cohort (UC Berkeley), and showed that lifetime cognitive activity was associated a decrease of Aβ deposition, especially in E4 carriers (Wirth et al., The Journal Of Neuroscience 2014). This example of gene-environment interaction has important implications for prevention of AD in genetically-susceptible individuals.
GENE-ENVIRONMENT INTERACTION. Lifelong cognitive activity seems to partly mitigate the increased Aβ deposition (PiB-PET imaging) associated with the presence of the APOE4 allele (derived from Wirth et al., The Journal of Neuroscience 2014).
Papers I (co)authored: Chételat et al., 2013; Wirth et al., 2014; Fouquet et al., 2014.
Further reading: Chételat & Fouquet 2013.
Renaud La Joie 