Data Pre-processing

MRI markers including WMH volume, lacune and MTLA were measured. The WMH was defined as hyperintensity as reflected on FLAIR image, according to the STRIVE standard²³ and automatically segmented with manual correction where appropriate. WMH segmentation was performed based on a validated pipeline - coarse-to-fine detection of WMH using co-registered T1W and FLAIR²⁴. Lacunae were defined according to the STRIVE standard and segmented in T1W images²³. The number was counted as isolated regions automatically. MTLA was visually rated on T1W images using the Schelten’s scale²⁵. fMRI imaging data were pre-processed using Statistical Parametric Mapping software version 12 (http://www.fil.ion.ucl.ac.uk/spm/). The first 10 volumes of each participant were discarded to allow for T1W equilibration effects. Then the functional images were slice-time corrected for timing offsets between different slices and realigned to the first image to correct for head motion between scans. The high-resolution T1W image was then co-registered to the mean of the corrected functional images. In order to improve the brain tissues segmentation in aging, a multi-channel segmentation approach in SPM 12 was used. The FLAIR image was coregistered to the T1W image, and the coregistered T1W and FLAIR images were combined underwent multi-channel segmentation to extract different tissues including gray matter, white matter and cerebrospinal fluid. A study-specific template was created using the DARTEL toolbox²⁶. The functional images were then spatially normalized to the standard MNI space by using the nonlinear normalization parameters estimated by the DARTEL toolbox, resampled to 3 × 3 × 3 mm³ and spatially smoothed with a 6 mm full-width half-maximum Gaussian kernel. Finally, additional preprocessing steps were implemented to the normalized function images to eliminate the effect of low-frequency drifts and physiological noise, which included removing linear trends, temporally band-pass filtering (0.01–0.1 Hz) and regressing out several nuisance signals (six head-motion profiles, the averaged signals from white matter, cerebrospinal fluid, and the whole brain and the first derivatives thereof)²⁷.