Aging Effect, Reproducibility, and Test–Retest Reliability of a New Cerebral Amyloid Angiopathy MRI Severity Marker—Cerebrovascular Reactivity to Visual Stimulation

Abstract

Background Decreased cerebrovascular reactivity, measured as changes in blood‐oxygen‐level‐dependent (BOLD) signal, is a potential new cerebral amyloid angiopathy (CAA) severity marker. Before clinical application, the effect of aging on BOLD parameters, and reproducibility and test–retest reliability of these parameters should be assessed. Purpose Assess the effect of healthy aging on cerebrovascular reactivity (BOLD amplitude, time to peak, and time to baseline). And determine reproducibility and test–retest reliability of these parameters. Study Type Prospective‐observational. Population Eighty‐six healthy adults (mean age 56 years, 55% female), 10 presymptomatic D‐CAA mutation carriers (mean age 34 years, 70% female), and 10 symptomatic D‐CAA mutation carriers (mean age 54 years, 70% female). Field Strength/Sequence 3‐T, three‐dimensional (3D) T1‐weighted MRI and gradient echo BOLD fMRI. Assessment To assess test–retest reliability of BOLD parameters, i.e. BOLD amplitude, time to peak, and time to baseline, BOLD fMRI scans were repeated three times immediately after each other, in both controls and mutation carriers. To assess reproducibility, BOLD fMRI scans were repeated with a 3‐week interval for each subject. Statistical Tests Linear regression analyses and two‐way mixed absolute agreement intra‐class correlation approach. Results Healthy aging was associated with decreased BOLD amplitude (β = −0.711) and prolonged time to baseline (β = 0.236) in the visual cortex after visual stimulation Reproducibility of BOLD amplitude was excellent (ICC 0.940) in the subgroup of healthy adults. Test–retest reliability for BOLD amplitude was excellent in healthy adults (ICC 0.856–0.910) and presymptomatic D‐CAA mutation carriers (ICC 0.959–0.981). In symptomatic D‐CAA mutation carriers, test–retest reliability was poor for all parameters (ICCs < 0.5). Data Conclusion Healthy aging is associated with decreased cerebrovascular reactivity, measured by changes in BOLD response to visual stimulation. The BOLD amplitude appears to be a robust measurement in healthy adults and presymptomatic D‐CAA mutation carriers, but not in symptomatic D‐CAA mutation carriers.

Impact of region of interest definition on visual stimulation‐based cerebral vascular reactivity functional MRI with a special focus on applications in cerebral amyloid angiopathy

“…To fully explore all of the aforementioned aspects two distinct datasets were analyzed: one dataset with DNA-proven D-CAA mutation carriers and age-and sex-matched control subjects, in which the influence of pathology was studied; and one with strictly healthy participants who were scanned twice, with $3 weeks between sessions, to allow assessment of reproducibility. 18 The D-CAA patient-control dataset was acquired with the same scan parameters and on the same MR scanner as used for the healthy subjects. This D-CAA dataset has been previously described and was acquired as part of the study Early Detection of Angiopathy Network (EDAN).…”

“…The third proposed method selects an individual ROI based on the participant's z-statistic map. 13,18,19,35 For each individual, the top percentile or predetermined volume of voxels with the highest z-score is selected as the ROI. In this study, we included a region with a volume of 11.5 cm 3 , containing the 503 most active voxels.…”

“…17 Moreover, reactivity decreased over time in (D-)CAA patients, in contrast to healthy controls. 13,18,19 Therefore, vascular reactivity can be considered a promising marker to monitor CAA progression over time, for example, as an outcome measure in clinical trials.…”

“…22 To measure vasoreactivity in the field of CAA, most studies employ a visual stimulus and monitor the hemodynamic response to that stimulus in the visual cortex via BOLD fMRI. [13][14][15][17][18][19]23 This relatively simple approach is chosen because CAA pathology appears to have an occipital preference, the robustness of the visual cortex' hemodynamic response to this stimulus and the noninvasive nature of the administration of such a stimulus. As the small penetrating arteries in the brain are affected in CAA, the changes in BOLD signal change are hypothesized as a surrogate marker for vascular reactivity for subsequent quantification.…”

“…More specifically, in patients with Dutch‐type hereditary CAA (D‐CAA, also known as hereditary cerebral hemorrhage with amyloidosis – Dutch type [or HCHWA‐D]), vascular reactivity has been found to be an early marker (i.e., already showing differences compared with age‐matched controls in mutation carriers without prior ICH) 17 . Moreover, reactivity decreased over time in (D‐)CAA patients, in contrast to healthy controls 13,18,19 . Therefore, vascular reactivity can be considered a promising marker to monitor CAA progression over time, for example, as an outcome measure in clinical trials.…”