## 3 Positron Emission Tomography & Tracers for the Detection of AD
### Amyloid-Binding Tracers  
The development of the amyloid cascade hypothesis highlights the role of a range of dynamic and heterogeneous soluble amyloid species as the primary instigator of neurotoxicity and cellular dysfunction [40]. Both synthetic and proto-fibrillar amyloid species have been demonstrated to directly induce oxidative stress, neuroinflammation, and synaptic hyperactivity, leading to neurodegeneration and the development of several amyloid-binding tracers and clinical trials of amyloid-targeting pharmaceuticals [41, 42, 43]. AD patients also display higher cortical retention of amyloid than elderly healthy controls in the orbitofrontal, inferior parietal/posterior cingulate cortices, and the precunei [44]. Cortical retention of amyloids also appears to stop increasing upon reaching a plateau early on in disease progression; however, there is some evidence to suggest this may not be a universal feature of amyloid accumulation [45].  
The first amyloid tracer was N-methyl-[\({}^{11}\)C]-2-(4-methylaminophenyl)-6-hydroxybenzothiazzo, which is commonly known as Pittsburgh compound B or PIB and is a derivative of the amyloid staining compound thiooflavin-T [46,47]. It has been  
Figure 1: Brain regions that typically show hypometabolism from FDG-PET imaging. Images visualized with BrainNet Viewer [39]. In the top row, we see these areas on the left, top, and right of the outer surface of the brain. In the middle row, we see the left and right medial brain surfaces and the underside of the brain in the center. In the bottom row, we see the anterior and posterior views of the brain. Each color represents a distinct anatomical region of interest.  
shown that the distribution and retention of PIB in vivo correlate very well with amyloid found post-mortem at autopsy and shows that PIB is sensitive to soluble and insoluble forms of amyloid protein [48]. Amyloid imaging with PIB is also sensitive in differentiating AD patients from elderly healthy controls; however, imaging studies in MCI patients have revealed a bimodal distribution of amyloid positivity. However, those with a greater amyloid burden are more likely to develop AD [49; 50; 51]. The retention of PIB also correlates with glucose hypometabolism in the parietotemporal regions in AD patients but not in those with MCI [47; 52]. As with FDG-based imaging, carriers of the _APOE-e4_ allele show a greater degree of amyloid plaque deposition revealed by PIB imaging [46].  
The greatest challenge to the clinical adoption of PIB has been the short half-life of the \({}^{11}\)C atom at approximately 20 min, which has greatly limited its use to locales with an on-site cyclotron. This has driven the development of \({}^{18}\)F-based tracers for amyloid imaging since the half-life is much longer at nearly two hours. This not only greatly increases ease-of-access but also yields less noisy images, which allows for more precise quantitation. Three of these fluorine-based tracers have received approval for clinical use (tradenames: florbetapir, florbetapen, and flutemetamol), and these have been demonstrated to correlate well with the results of PIB studies and post-mortem autopsies [53; 54]. Differences in target sensitivity and non-specific binding between these have been reported; however, efforts are underway to standardize amyloid staging, such as the cetiloid project [55].  
Amyloid-based imaging is not without its drawbacks. Amyloid is extremely useful for the differential diagnosis of DSDs that do not have an amyloid pathology, such as frontotemporal dementia disorder (FTD); however, the presence of accumulated extracellular amyloid plaques is relatively common in the general population of older adults [55; 56]. As such, it is a nonspecific indicator on its own, so its diagnostic value is as a predictor of possible future effects, or else it must be considered in conjunction with other more specific biomarkers.