Original Article
Hypoperfusion of the thalamus is associated with disability in relapsing remitting multiple sclerosis

https://doi.org/10.1016/j.neurad.2016.10.001Get rights and content

Summary

Background

While gray matter (GM) perfusion abnormalities have been evidenced in multiple sclerosis (MS) patients, the relationships with disability still remain unclear. Considering that atrophy is known to impact on perfusion, we aimed to assess perfusion abnormalities in GM of MS patients, outside atrophic regions and investigate relationships with disability.

Methods

Brain perfusion of 23 relapsing remitting MS patients and 16 matched healthy subjects were assessed at 3T using the pseudo-continuous arterial spin labeling magnetic resonance imaging technique. In order to locate potential GM perfusion abnormalities in regions spared by atrophy, we combined voxelwise comparisons of GM cerebral blood flow (CBF) maps (cortex and deep GM) (P < 0.005, FWE-corrected) and voxel-based-morphometry analysis (P < 0.005, FDR-corrected) to exclude atrophic regions. Disability was assessed using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC).

Results

In patients, significant GM hypoperfusion outside atrophic regions was depicted only in bilateral thalami. No other cluster was found to be hypoperfused compared to controls. Perfusion of thalami was correlated to MSFC (P = 0.011, rho = 0.523). A trend of correlation was found between perfusion of thalami and EDSS (P = 0.061, rho = –0.396).

Conclusion

In relapsing remitting MS, perfusion abnormalities in thalamic regions contribute to disability. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.

Introduction

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system and is the most frequent cause of non-traumatic neurological disability in young adults. Beyond white matter (WM) involvement, recent studies have highlighted the existence of structural and functional gray matter (GM) injuries, related to demyelination [1], cortical lesions [2], atrophy [1], [3], [4] and hypoperfusion [5]. These findings also suggest that GM involvement could better reflect clinical disability [6] and cognitive dysfunction [7], [8] than WM lesion load.

In the GM, abnormal hypoperfusion, hypothesized to be caused by neuronal metabolic dysfunction or local neuronal loss, was reported in MS patients [5], [9], [10], [11] from the early stage of the disease [12]. Comparing patients at different stages of MS, GM hypoperfusion was shown to increase during the course of the disease, especially in the deep GM [12]. Concurrently, GM atrophy, that is present from disease onset [3], [13], is also known to increase with disease progression [14]. Although perfusion could be modified by tissue damage mainly reflected by atrophy, recent studies that have reported relationships between GM hypoperfusion and clinical deficits [15], [16], [17] have not taken into account the impact of atrophy.

In the present study, we aimed to assess perfusion abnormalities in GM of MS patients, using pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI), outside atrophic regions and investigate the potential relationships with disability.

Section snippets

Subjects

Relapsing Remitting MS (RRMS) patients according to the revised 2010 McDonald criteria [18] and healthy subjects were enrolled prospectively. The exclusion criteria were alcohol or other drug abuse, history of psychiatric diseases and any central nervous diseases other than MS, progressive forms of MS, relapse or treatment with steroids in the preceding 3 months. At the time of MRI examination, each patient underwent a comprehensive neurological examination by a certified neurologist to collect

Demographic and clinical data

Twenty-three patients fulfilled the whole protocol (19 women, mean age: 34.2 years [SD ± 9.3]). The mean disease duration was 4.5 years (SD ± 4.6). The mean EDSS was 1.5 (SD ± 1.2) and the mean MSFC z-score was –0.70 (SD ± 1.04). Ten out of the twenty-three patients (43%) received disease-modifying therapy: natalizumab (n = 4), fingolimod (n = 3), glatiramer acetate (n = 2) and interferon beta1a (n = 1). Treated patients showed a higher EDSS (mean 2.3 [SD ± 1.3]) than non-treated patients (mean 0.8 [SD ± 0.5]) (P = 

Discussion

The present study showed that early RRMS patients exhibit substantial hypoperfusion of the bilateral thalami, in regions not affected by atrophy, with extent of hypoperfusion associated with physical disability.

Several recent neuroimaging studies showed involvement of thalamic injury in MS, confirming previous histopathological studies evidencing demyelinating lesions and neuronal loss in the thalamus of MS patients [25], [26]. Using magnetization transfer ratio combined with voxel-based

Conclusion

The present study demonstrates for the first time that, perfusion abnormalities in non-atrophic thalamic regions contribute to disability in RRMS. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.

Disclosure of interest

The authors declare that they have no competing interest.

Acknowledgments

E.D. received a grant from les Journées de neurologie de langue française – Société française de neurologie. This work was supported by ARSEP Foundation. J.P. received an unconditional grant from Merck Serono France.

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