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

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

Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration