0210

Associations between cerebral microvascular hemodynamics and white matter lesion burden in typically aging older adults

Meher R Juttukonda^1,2, Kimberly A Stephens¹, Yi-Fen Yen^1,2, Casey M Howard¹, Jonathan R Polimeni^1,2, Bruce R Rosen^1,2, and David H Salat^1,2
¹Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States, ²Radiology, Harvard Medical School, Boston, MA, United States

Synopsis

Hypoperfusion is frequently considered a cause of age-related white matter lesions (WML). However, reductions in oxygen availability to brain tissue may also be caused by impaired oxygen extraction fraction (OEF). Here, we tested the hypothesis that venous hyperintense signal (VHS) in arterial spin labeling (ASL) MRI is indicative of impaired OEF in typically aging older adults. In participants aged 60–80 years (n=40), we measured VHS with ASL and maximum OEF (OEF_max) with dynamic susceptibility contrast MRI. Lower OEF_max was uniquely associated with higher WML volume in participants with VHS, indicating a potentially distinct cerebrovascular aging pattern in these individuals.

Introduction

The presence of cerebral white matter lesions (WML) has been linked to declining cognitive function in typical aging as well as in patients with Alzheimer’s disease.^1-7 While the etiology of these lesions is presumed to be vascular in nature,^8,9 microvascular hemodynamic mechanisms underlying these lesions remain incompletely understood. Tissue hypoperfusion is frequently considered a cause of WML, but reductions in oxygen availability to the brain could also be caused by impairment in oxygen exchange efficiency. Recently, venous hyperintense signal (VHS) in arterial spin labeling (ASL) MRI has been characterized as a marker of capillary shunting and reduced OEF in young adults.^10,11 VHS in perfusion-weighted ASL is thought to arise from reduced capillary transit times that allow labeled arterial blood to traverse the microvasculature without properly exchanging with tissue. Here, we tested the hypothesis that VHS in ASL MRI may also represent a general marker of impaired oxygen extraction in typically aging older adults.

Methods

Participants. Older adult volunteers (60–80 years of age) were recruited as part of an IRB-approved study. Exclusion criteria included major neurological or psychiatric disorders, including vascular dementia or clinical stroke, as well other substantial systemic illnesses likely to confound the study.

Data acquisition. Participants underwent two imaging sessions: non-contrast MRI at 3T (Siemens Biograph mMR) and contrast-enhanced MRI at 7T (Siemens Magnetom). T₁-weighted MRI was acquired at 3T using a multi-echo MPRAGE sequence (TR=2530 ms; TI=1100 ms; TE=1.69 ms, 3.55 ms, 5.41 ms, and 7.27 ms; flip angle=7°; and spatial resolution=1.0×1.0×1.0 mm³). ASL MRI was acquired at 3T with pseudo-continuous labeling (total labeling duration=1500 ms and post-labeling delay=1200 ms) and without background or vascular suppression using a 2D EPI readout (slice thickness=5.0 mm; TR=4000 ms; TE=12 ms; matrix size=64×64; slices=22; field of view = 220×220 mm²; control/label pairs=40). Dynamic susceptibility contrast (DSC) MRI was acquired at 7T with gadolinium contrast and a 2D single-shot EPI readout (TR=1500 ms, TE=22 ms, flip angle=75°, slices=58, spatial resolution=1.5×1.5×1.5 mm³, nominal echo spacing=0.69 ms, GRAPPA=3, multiband=2, frames=100).

Data processing. T₁-weighted images were processed to reconstruct cortical surfaces and to segment volume regions-of-interest, including gray matter and WML volume, using the Freesurfer ‘recon-all’ procedure. ASL images from each participant were pre-processed and quantified into CBF using a two-compartment kinetic model.¹² CBF images from each participant were also qualitatively assessed for the presence (VHS+) or absence (VHS−) of labeled blood inside of large draining veins, including the superior sagittal sinus, inferior sagittal sinus, and straight sinus, according to a previously established procedure (Figure 1).¹⁰ DSC-MRI data were processed using the Penguin/pgui software to convert the T2* signal time curves of each voxel to contrast concentration time curves¹³ and used in a vascular model developed by Ostergaard et al^13-15to derive images of maximum oxygen extraction fraction (OEF_max). Average CBF and OEF_max values in global gray matter were extracted for each participant using FreeSurfer segmentations.

Results

Demographics. Overall, VHS was present in 42.5% of participants (17/40). Participants with VHS (median age=70 years) were older than those without VHS (median age=64 years; p<0.01), and there were no sex differences in the groups with VHS (47% male) and without VHS (57% male; p=0.55).

Cerebrovascular physiology. Older age was correlated with decreasing gray matter CBF (ρ=−0.32; p=0.05), and there was no interaction between age and VHS presence when examining the association with CBF (Figure 2A; p=0.81). There was no relationship between OEF_max and age in all participants (ρ=0.25; p=0.18), but there was a significant interaction between age and VHS presence (p<0.01). More specifically, older age is associated with higher OEF_max in participants without VHS, while older age is associated with lower OEF_max in participants with VHS (Figure 2B).

White matter lesions. WML volume was inversely correlated with CBF (ρ=−0.39; p=0.01), but there was no interaction between CBF and VHS presence for the association with WML volume (p=0.15; Figure 3A). There was no relationship between OEF_max and WML volume (ρ=−0.001; p=0.99) overall, but there was a significant interaction between OEF_max and VHS status (p=0.02). More specifically, lower OEF_max was associated with higher WML volume in participants with VHS, while higher OEF_max was associated with higher WML volume in participants without VHS (Figure 3B).

Discussion

We characterized a novel imaging marker of oxygen extraction inefficiency and its relationship with age, cerebral hemodynamic physiology, and white matter lesion burden in a cohort of older adults between 60–80 years of age. We observed that venous ASL signal indicative of capillary shunting was prevalent in 42% of older adults, and participants with VHS were older (median age=70 years) compared to participants without VHS (median age=64 years). While associated with lower CBF in both groups, the relationship between age and OEFmax was dependent on VHS presence, with lower OEF_max corresponding to older age when VHS was present. Finally, individuals with VHS exhibited greater WML burden, and higher WML volumes were correlated with both lower CBF and lower OEF_max in participants with VHS but not in those without VHS. These results indicate that the presence of VHS on perfusion-weighted ASL data could serve as a marker of a distinct cerebrovascular aging pattern that involves physiological mechanisms including oxygen extraction inefficiency in addition to hypoperfusion.

Acknowledgements

This work was supported by the National Institutes of Health (R01NR010827) and the American Heart Association (19CDA34790002).

References

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Figures

Figure 1: CBF-weighted images derived with ASL were assessed for venous hyperintense signal (VHS). Representative CBF images are shown here for individuals with VHS present (A; VHS+; 79 y.o. female) and VHS absent (B; VHS−; 64 y.o. female). Participants were classified as VHS+ if bright signals were contiguously observed where large draining veins, including the superior sagittal sinus or straight sinus, are expected to be present (green arrows). Images where no signal enhancement was observed relative to surroundings in such regions (green circle) were classified as VHS−.

Figure 2: There was no significant interaction between age and venous hyperintense signal (VHS) presence (VHS+) or absence (VHS−) on the association between cerebral blood flow (CBF) and age (A). There was a significant interaction between age and VHS on maximum oxygen extraction fraction (OEF_max), with older age associated with higher OEF_max in VHS− participants and lower OEF_max in VHS+ participants (B).

Figure 3: There was no significant interaction between cerebral blood flow (CBF) and venous hyperintense signal (VHS) presence (VHS+) or absence (VHS−) on white matter lesion (WML) volume (A). There was a significant interaction between maximum oxygen extraction fraction (OEF_max) and VHS on WML volume, with lower OEF_max associated with higher WML volume in VHS+ participants and lower WML volume in VHS− participants (B).

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

0210

DOI: https://doi.org/10.58530/2022/0210