Is MS starving the brain?

Impaired Cerebrovascular Reactivity in Multiple Sclerosis

Olga Marshall, MS; Hanzhang Lu, PhD; Jean-Christophe Brisset, PhD; Feng Xu, PhD; Peiying Liu, PhD; Joseph Herbert, MD; Robert I. Grossman, MD; Yulin Ge, MD

JAMA Neurol. 2014;71(10):1275-1281. doi:10.1001/jamaneurol.2014.1668


Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS).


To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS.


A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF.


Cerebrovascular reactivity was calculated as the percent increase of  normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS.


A significant decrease of mean (SD) global gray matter CVR was found in patients with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a significant negative correlation between gray matter CVR and lesion volume (R = 0.6, P = .004) and a significant positive correlation between global gray matter CVR and gray matter atrophy index (R = 0.5, P = .03).


Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.

This piece of research is a game-changer in my books; I don't think I quite appreciated how complex this disease is until I came across this article last night! Not only have we to contend with a frankly a confused immune system, but we now also have to think about strategies to combat brain hypoxia (the lack of oxygen) and ischaemic injury (lack of oxygen leading to areas of stroke) caused by the presence of vascular abnormalities observed in MS (see figure below). 

The authors may be onto something here, and large scale brain hypoxia may be the penultimate factor/missing link in the spiraling trajectory towards brain  atrophy in MS.

Figure: The mean gray matter cerebrovascular reactivity (CVR) maps of the control group (top) and multiple sclerosis group (bottom) show the diffuse decrease of CVR in the patients with multiple sclerosis. The color bar shows the range of CVR values (white=good CVR, black=poor CVR).

They postulate that abnormalities in CVR observed in MS may be the result of vascular (i.e. the vessel wall) habituation to nitric oxide (which results in vessel wall dilatation) produced during the chronic inflammatory process, ultimately leading to narrowing of blood vessels. But, I don't think this is the cause in entirety. This theory ignores the fact that the vessel wall (aka endothelium) also locally produces factors that regulate blood vessel tone, and the role of blood pressure, which is the largest regulator of perfusion to vital organs. 

It is clear more work is needed in this area. And no CCSVI has no role here.

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