## 4 Quantitative Methods for the Detection of AD
### Stereotactic Surface Projection
A distinct advantage of this method is its intrinsic motivation, based on well-known findings from FDG-PET studies on AD patients: hypometabolism in the parietotemporal cortex, bilateral symmetry of metabolic reduction, frequently reduced metabolic activity in the frontal cortex, and preservation of the primary sensorimotor cortex and thalamus [95; 96; 97; 98]. A great advantage of this design choice is that it easily allows for the incorporation of new information on the nature or etiology of AD. Another is that the method automatically prepares and presents data-driven hypotheses in the form of a \(\Delta Z\)-score in a visually interpretable manner (color-scale on a brain template), thus complementing the role of the specialist physician in the diagnosis of AD. This is, however, a potential disadvantage, as it is notably distinct from the proper diagnostic tools as the method only presents quantitative information instead of performing a classification alongside the presentation of the information. This is particularly notable when using the method for differential diagnosis of DSDs because the result remains entirely dependent on the specialist physician's subjective impression of the spatial distribution of altered metabolism. Most notably used as a portion of the Neurostat(r) (Department of Internal Medicine, University of Michigan, Michigan, Ann Arbor, MI, USA) software package, 3D-SSP has been demonstrated to increase clinician confidence and accuracy in the diagnosis of DSDs and also serve as the inspiration behind further methods of analysis on the cortical surface [99; 100; 101; 102; 103]. Most of the literature making use of 3D-SSP has been focused on the features derived from FDG-PET imaging; however, there is an increasing penetrance of amyloid and tau data into the domain of 3D-SSP. A novel use of 3D-SSP was reported by [PERSON] et al., using rifampicin, a drug used to treat mycobacterium infection that has also been shown to prevent amyloid oligomerization and tau hyper-phosphorylation in mouse models [104]. Forty subjects with AD-like hypometabolism undergoing treatment for mycobacterium infection were given 12 months of treatment with 450 mg of rifampicin and showed increased or stabilized FDG uptake within the posterior cingulate cortex. Results were compared pre- and post-treatment using z-score maps derived from 3D-SSP, showing a milder decline or no further decline with follow-up FDG-PET imaging. Dual-biomarker imaging is an area of PET-based AD investigation that investigates the use of non-FDG tracers to obtain FDG-like diagnostic data. The rationale for using the first phase of the tracer update as a surrogate for FDG-PET is based on the neurovascular coupling hypothesis, which describes how glucose metabolism and oxygen demand are highly correlated in time. [PERSON] et al., compared the performance of FDG and the amyloid tracer florbetaben in gathering perfusion-metabolic information very early post-injection [105]. It was shown that very early florbetaben frames are very similar to data acquired in FDG-PET throughout _a priori_ selected ROIs. Early perfusion amyloid frames (first 5 min post-injection) and FDG values were significantly corrected when normalized to the global metabolic mean in amyloid-positive (r = 0.90) and amyloid-negative (r = 0.79) patients. These data were later presented in the form of 3D-SSP z-score maps to multiple neuroradiological readers who showed high inter-reader agreement (kappa > 0.79) between AD, FID, and HC patients. [PERSON] et al., published a similar report for the correspondence of FDG and the tau tracer THK5351. They discovered an extremely strong correlation between FDG and THK5351 uptake in the first minutes post-injection (dice similarity coefficient = 95%) up to 15 min post-injection (coefficient = 89%) [106]. These similarities were visually confirmed by a neuroradiological reader presented with z-score SSP maps generated from FDG and THK5351 data. [PERSON] et al. 's study was performed on a single patient as a pilot project.