Deep grey matter volume loss drives disability worsening in multiple sclerosis

Abstract

Objective: Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. MethodsResults: SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p<0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%)[p<0.01]. The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%).Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%) (all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta=0.04, p<0.001).. CC-BY-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/182006 doi: bioRxiv preprint first posted online Aug. 29, 2017; 3 Interpretation: This large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.

Application of mechanistic methods to clinical trials in multiple sclerosis: the simvastatin case

“…Another novelty of our study, is that the spatiotemporal pattern of ongoing atrophy in patients with secondary progressive multiple sclerosis with very long disease duration (21 years), to the best of our knowledge, has never been investigated before. Our regional analysis showed that localised atrophy in the temporal lobe, frontal lobe, limbic cortex, and the basal ganglia continues relentlessly, but the pattern of ongoing atrophy was generalised as opposed to a regional loss (e.g., thalamus) (Eshaghi et al, 2018). Regional susceptibility of neuroanatomical areas to neurodegeneration manifests by faster percentage of atrophy rates than that of the entire brain.…”

“…For example, annual percentage volume loss can be up to 4% in the hippocampus in Alzheimer's disease (Henneman et al, 2009;Josephs et al, 2017), while it is up to 1% for the entire brain. In MS, the deep grey matter atrophy rates can be up to 1.5% (Eshaghi et al, 2018), while the whole brain atrophy is 0.6%. In this study, we found that the highest rate of loss was in the lateral ventricle-a non-specific generalised measure of atrophy.…”

Clinical relevance of cortical network dynamics in early primary progressive MS

“…In primary progressive multiple sclerosis (PPMS), grey matter (GM) damage occurs from the earliest stages of the condition [1][2][3][4] and is associated with greater risk of disability accumulation. [1][2][3] Whole brain GM volume loss is commonly used as marker of GM damage in PPMS. 5 However, the strength of the correlation between GM damage and clinical deterioration in PPMS is only moderate.…”

Brain atrophy in multiple sclerosis: How deep must we go?

“…[6][7][8][9] The thalamus may be particularly susceptible to neurodegeneration due to the effects of demyelinating lesions within the thalamus as well as changes in thalamic input and outflow tracts resulting from cortical and white matter demyelination. 12 In this issue, Eshaghi et al 13 Eshaghi et al's large, multicenter, longitudinal study used a registration-based method to measure the volume of different brain regions and found that the rate of volume decline is fastest in the deep gray matter. 12 In this issue, Eshaghi et al 13 Eshaghi et al's large, multicenter, longitudinal study used a registration-based method to measure the volume of different brain regions and found that the rate of volume decline is fastest in the deep gray matter.…”

“…10,11 Recently, improvements in image-processing methodologies that allow for improved automatic segmentation of different brain regions have made measurement of atrophy in specific brain regions more feasible on a large scale. 12 In this issue, Eshaghi et al 13 and Azevedo et al 14 measure volume loss in specific gray matter regions longitudinally in people with MS with the aim of further characterizing gray matter atrophy and establishing it as a feasible outcome measure for future studies.…”