Clinical and Pathological Validation of CT-Based Regional Harmonization Methods of Amyloid PET

Purpose: The CT-based regional direct comparison Centiloid (dcCL) method was developed to harmonize and quantify regional beta-amyloid (A beta) burden. In the present study, we aimed to investigate correlations between the CT-based regional dcCL scales and A beta pathological burdens and to validate the clinical utility using thresholds derived from pathological assessment. Patients and Methods: We included a pathological cohort of 63 cases and a clinical cohort of 4062 participants, and obtained modified Consortium to Establish a Registry for Alzheimer's Disease criteria (mCERAD) scores by assessment of neuritic plaque burdens in multiple areas of each cortical region. PET and CT images were processed using the CT-based regional dcCL method to calculate scales in 6 distinct regions. Results: The CT-based regional dcCL scales were correlated with neuritic plaque burdens represented by mCERAD scores, globally and regionally (r = 0.56 similar to 0.76). In addition, striatum dcCL scales reflected A beta involvement in the striatum (P < 0.001). The regional dcCL scales could predict significant A beta deposition in specific brain regions with high accuracy: area under the receiver operating characteristic curve of 0.81-0.97 with an mCERAD cutoff of 1.5 and area under the receiver operating characteristic curve of 0.88-0.93 with an mCERAD cutoff of 0.5. When applying the dcCL thresholds of 1.5 mCERAD scores, the G(-)R(+) group showed lower performances in memory and global cognitive functions and had less hippocampal volume compared with the G(-)R(-) group (P < 0.001). However, when applying the dcCL thresholds of 0.5 mCERAD scores, there were no differences in the global cognitive functions between the 2 groups. Conclusions: The thresholds of regional dcCL scales derived from pathological assessments might provide clinicians with a better understanding of biomarker-guided diagnosis and distinguishable clinical phenotypes, which are particularly useful when harmonizing different PET ligands with only PET/CT.