Using dual-calibrated functional MRI to map brain oxygen supply and consumption in multiple sclerosis

Abstract

Evidence suggests that cerebrovascular function and oxygen consumption are altered in multiple sclerosis (MS). Here, we quantified the vascular and oxygen metabolic MRI burden in patients with MS (PwMS) and assessed the relationship between these MRI measures of and metrics of damage and disability. In PwMS and in matched healthy volunteers, we applied a newly developed dual-calibrated fMRI method of acquisition and analysis to map grey matter (GM) cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen consumption (CMRO2) and effective oxygen diffusivity of the capillary network (DC). We also quantified physical and cognitive function in PwMS and controls. There was no significant difference in GM volume between 22 PwMS and 20 healthy controls (p=0.302). Significant differences in CBF (PwMS vs. controls: 44.91 ± 6.10 vs. 48.90 ± 5.87 ml/100g/min, p=0.010), CMRO2 (117.69 ± 17.31 vs. 136.49 ± 14.48 μmol/100g/min p<0.001) and DC (2.70 ± 0.51 vs. 3.18 ± 0.41 μmol/100g/mmHg/min, p=0.002) were observed in the PwMS. No significant between-group differences were observed for OEF (PwMS vs. controls: 0.38 ± 0.09 vs. 0.39 ± 0.02, p=0.358). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS compared to healthy volunteers. There was a significant correlation between physiological measures and T2 lesion volume, but no association with current clinical disability. Our findings demonstrate concurrent reductions in oxygen supply and consumption in the absence of an alteration in oxygen extraction that may be indicative of a reduced demand for oxygen (O2), an impaired transfer of O2 from capillaries to mitochondria, and/or a reduced ability to utilise O2 that is available at the mitochondria. With no between-group differences in GM volume, our results suggest that changes in brain physiology may precede MRI-detectable GM loss and thus may be one of the pathological drivers of neurodegeneration and disease progression.

Oxygen treatment reduces neurological deficits and demyelination in two animal models of multiple sclerosis

“…Certainly, hypoperfusion in MS has been recognised for over 70 years [ 12 ], and as methods to measure perfusion have become more sophisticated, the overwhelming finding is of very significant hypoperfusion in both relapsing–remitting (RRMS) and primary and secondary progressive MS (PPMS and SPMS) [ 7 , 8 , 9 ] that significantly correlates with disability [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Some studies have considered whether the reduction in cerebral blood flow is likely to be just a secondary consequence of reduced demand and cerebral atrophy, or whether it is a primary cause of damage, and the clear conclusion is that the reduction is a primary event probably causing pathology and thereby disability [ 7 , 8 , 14 , 19 , 20 , 21 , 22 , 23 , 24 ]. Hypoperfusion is likely to result in tissue hypoxia, and there is substantial evidence that the MS brain is actually hypoxic, including the expression of hypoxia‐related antigens [ 25 , 26 ], the upregulation of genes induced by ischaemic preconditioning [ 25 , 26 , 27 , 28 ] and the presence of lesions characterised by hypoxia‐like demyelination [ 27 , 28 , 29 ].…”

Imaging effective oxygen diffusivity in the human brain with multiparametric magnetic resonance imaging

“…3,8–11 In any case, EOD may serve as a valuable clinical biomarker that is sensitive to underlying capillary, pericyte or mitochondrial dysfunction, e.g., in patients with neurovascular and degenerative diseases ranging from carotid artery stenosis and stroke to Alzheimer’s disease. 8,12 Importantly, recent studies in patients with, e.g., unilateral stenosis and occlusion 13 or multiple sclerosis 14 indicated that EOD could provide complementary information – regarding hemodynamic compromise and the association of such impairments with other variables such as age or white matter lesion volume – that is distinct from CBF, OEF or CMRO 2 .…”