Tau PET Imaging in Neurodegenerative Disorders

The advent of PET ligands that bind tau pathology has enabled the quantification and visualization of tau pathology in aging and in Alzheimer disease (AD). There is strong evidence from neuropathologic studies that the most widely used tau PET tracers (i.e., 18F-flortaucipir, 18F-MK6240, 18F-RO948, and 18F-PI2620) bind tau aggregates formed in AD in the more advanced (i.e., ≥IV) Braak stages. However, tracer binding in most non-AD tauopathies is weaker and overlaps to a large extent with known off-target binding regions, limiting the quantification and visualization of non-AD tau pathology in vivo. Off-target binding is generally present in the substantia nigra, basal ganglia, pituitary, choroid plexus, longitudinal sinuses, meninges, or skull in a tracer-specific manner. Most cross-sectional studies use the inferior aspect of the cerebellar gray matter as a reference region, whereas for longitudinal analyses, an eroded white matter reference region is sometimes selected. No consensus has yet been reached on whether to use partial-volume correction of tau PET data. Although an increased neocortical tau PET signal is rare in cognitively unimpaired individuals, even in amyloid-β-positive cases, such a signal holds important prognostic information because preliminary data suggest that an elevated tau PET signal predicts cognitive decline over time. Also, in symptomatic stages of AD (i.e., mild cognitive impairment or AD dementia), tau PET shows great potential as a prognostic marker because an elevated baseline tau PET retention forecasts future cognitive decline and brain atrophy. For differential diagnostic use, the primary utility of tau PET is to differentiate AD dementia from other neurodegenerative diseases, as is in line with the conditions for the approval of 18F-flortaucipir by the U.S. Food and Drug Administration for clinical use. The differential diagnostic performance drops substantially at the mild-cognitive-impairment stage of AD, and there is no sufficient evidence for detection of sporadic non-AD primary tauopathies at the individual level for any of the currently available tau PET tracers. In conclusion, while the field is currently addressing outstanding methodologic issues, tau PET is gradually moving toward clinical application as a diagnostic and possibly prognostic marker in dementia expert centers and as a tool for selecting participants, assessing target engagement, and monitoring treatment effects in clinical trials.