We present an operator-independent software technique for segmentation, realignment and analysis of brain perfusion images, with both voxel-wise and regional quantitation methods. Inter-subject registration with normalized mutual information was tested with simulated defects. Brain perfusion images (HMPAO-SPECT) from 56 subjects (21 AD; 35 controls) were retrospectively analyzed. Templates were created from the 3-D registration of the controls. Automatic segmentation was developed to remove extraneous activity that disrupts registration. Two new registration methods, robust least squares (RLS) and normalized mutual information (NMI) were implemented and compared with sum of absolute differences (CD). The automatic segmentation method caused a registration displacement of 0.4 +/- 0.3 pixels compared with manual segmentation. NMI registration proved to be less adversely effected by simulated defects than RLS or CD. The error in quantitating the patient-template parietal ratio due to mis- registration was 2.0% and 0.5% for 70% and 85% hypoperfusion defects, respectively. The registration processing time was 1.6 min (233 MHz Pentium). The most accurate discriminant utilized a logistic equation parameterized by mean counts of the parietal and temporal regions of the map, (91 +/- 8% Se, 97 +/- 5% Sp). BRASS is a fast, objective software package for single-step analysis of brain SPECT, suitable to aid diagnosis of AD.© (2000) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.