Longitudinal validity of PET-based staging of regional amyloid deposition

Positron emission tomography (PET)-based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET-based amyloid staging using region-specific amyloid-positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region-specific thresholds of amyloid-positivity based on Florbetapir-PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir-PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2-year follow-up Florbetapir-PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross-sectional model based on individual stage transitions and data-driven longitudinal trajectory modeling. Results show a remarkable congruence between cross-sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory-motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET-based staging of regional amyloid accumulation, which may help improving early detection and in-vivo stratification of pathologic disease progression in AD.