Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

Abstract

White matter hyperintensities of presumed vascular origin are frequently observed on MRI in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply-demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion-, and diffusion-weighted MRI in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity – the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared to normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply-demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals

“…This finding thus lends credence to the idea of a two‐hit hypothesis of AD, such that vascular disease combines with preexisting AD pathology to cause a significant decline in OEF, 66 rather than either process alone. Also of note, whole white matter OEF decreased with increasing WMH burden, which is compatible with a prior study reporting decreased tissue oxygenation in WMH 67 …”

“…Also of note, whole white matter OEF decreased with increasing WMH burden, which is compatible with a prior study reporting decreased tissue oxygenation in WMH. 67 The third major finding was that both age and WMH burden showed mild regional associations with χ n in the cognitively impaired but not in the cognitively intact group. Although a prior study reported an association between increasing age and iron levels, particularly in motor and premotor areas, 68 we did not find this association in our cognitively intact group.…”

Modelling the Anatomical Distribution of Neurological Events in COVID-19 Patients: A Systematic Review

“…84-88 While the pathogenesis of white matter hyperintensities remains under debate, roles for hypoxia, immune activation, endothelial cell dysfunction and altered metabolism have been posited; not dissimilar from the neuropathological suggestions within COVID-19. 13-89…”

Blood flow, capillary transit times, and tissue oxygenation: the centennial of capillary recruitment

“…To address this question further, new diagnostic methods and biomarkers must be developed to allow easy assessment of capillary function and tissue oxygenation across organs (72). Thus far, findings support the hypothesis that capillary transit time effects play a role in vascular disease pathology (4,6,11,14,41), as well as in conditions less associated with vascular disease pathology (35), including AD (15,18,42,43) and cancer (10,59).…”