Staging β-Amyloid Pathology With Amyloid Positron Emission Tomography

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Abstract
Alzheimer disease (AD) is characterized by accumulation of β-amyloid (Aβ), which likely starts before cognitive impairment, precedes neurodegeneration, and continues in the symptomatic stage.1,2 The accumulation may affect different regions of the brain at different time points,3,4 making it possible to characterize Aβ deposition in a staging system in vivo, as has been done with postmortem neuropathologic studies of the brain (eg, Thal phases).3,4 Neuropathologic studies cannot directly be applied to in vivo assessments using Aβ position-emission tomography (PET), because Aβ binding may differ between neuropathology staining and PET uptake, where the Aβ PET tracer predominantly binds to the fibrillary conformation of Aβ.5,6 A modern Aβ staging system can also leverage that cerebrospinal fluid (CSF) measurements of the Aβ42 peptide may identify Aβ accumulation earlier than Aβ PET.7-9 Combinations of PET and CSF studies may be used to identify regions where accumulation of Aβ fibrils begin (by studying individuals who are Aβ42 positive in CSF studies but still Aβ PET negative) and regions that are affected later in the disease.10 We used this method to construct a staging system, which we validated by examining the prevalence of unambiguously classified participants, differences in cognition by stage, biomarkers, and imaging, regional gene expression, and longitudinal transition because it is crucial to demonstrate that individuals are at risk for transitions from lower to higher stages.

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