Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Abstract

BACKGROUND AND PURPOSE: Deep gray matter involvement is a consistent feature in multiple sclerosis. The aim of this study was to evaluate the relationship between different deep gray matter alterations and the development of subcortical atrophy, as well as to investigate the possible different substrates of volume loss between phenotypes. MATERIALS AND METHODS: Seventy-seven patients with MS (52 with relapsing-remitting and 25 with progressive MS) and 41 healthy controls were enrolled in this cross-sectional study. MR imaging investigation included volumetric, DTI, PWI and Quantitative Susceptibility Mapping analyses. Deep gray matter structures were automatically segmented to obtain volumes and mean values for each MR imaging metric in the thalamus, caudate, putamen, and globus pallidus. Between-group differences were probed by ANCOVA analyses, while the contribution of different MR imaging metrics to deep gray matter atrophy was investigated via hierarchic multiple linear regression models. RESULTS: Patients with MS showed a multifaceted involvement of the thalamus and basal ganglia, with significant atrophy of all deep gray matter structures (P Ͻ .001). In the relapsing-remitting MS group, WM lesion burden proved to be the main contributor to volume loss for all deep gray matter structures (P Յ .006), with a minor role of local microstructural damage, which, in turn, was the main determinant of deep gray matter atrophy in patients with progressive MS (P Յ .01), coupled with thalamic susceptibility changes (P ϭ .05). CONCLUSIONS: Our study confirms the diffuse involvement of deep gray matter in MS, demonstrating a different behavior between MS phenotypes, with subcortical GM atrophy mainly determined by global WM lesion burden in patients with relapsing-remitting MS, while local microstructural damage and susceptibility changes mainly accounted for the development of deep gray matter volume loss in patients with progressive MS. ABBREVIATIONS: DD ϭ disease duration; DGM ϭ deep gray matter; DMT ϭ disease-modifying treatment; EDSS ϭ Expanded Disability Status Scale; FA ϭ fractional anisotropy; HC ϭ healthy controls; LL ϭ lesion load; MD ϭ mean diffusivity; PMS ϭ progressive MS; QSM ϭ Quantitative Susceptibility Mapping; rCBV ϭ relative CBV; RRMS ϭ relapsing-remitting MS

Gray Matter Matters: A Longitudinal Magnetic Resonance Voxel-Based Morphometry Study of Primary Progressive Multiple Sclerosis

“…Thalamic involvement is associated with a wide variety of other clinical manifestations including motor deficits, chronic pain syndromes, and abnormalities in control of eye movements (74-80). Thalamic atrophy can be one of the earliest and most evident signs of MS pathology (79,81) and the rate of atrophy remains high throughout the course of the disease in PPMS (81). Some studies demonstrated worsening disability proportional to the extent of thalamic damage (74-80).…”

“…Mean per-cent change in Brain volumes and ventricular size over 1 year (with SD).to examine regional distribution of GM atrophy in 31 patients with PPMS and identified increased thalamic atrophy compared with healthy controls (74). Pontillo et al showed that PPMS patients had more significant reductions in thalamus when compared to RMS largely due to local microstructural damage and was the most accurate predictor of cognitive impairment(81). Thalamic and cortical gray atrophy have been implicated in objective cognitive impairment as determined by NeuroQuant R analysis in a study byKletenik et al (75) They found that among 158 patients who completed Quality of Life in Neurologic Disorders Measures (Neuro-QoL), those with cognitive concerns were associated with reduced thalamic and cortical GM volumes.…”

What Causes Deep Gray Matter Atrophy in Multiple Sclerosis?

“…It remains unclear, however, whether microglial activation is a cause of neurodegeneration or a consequence of it, or both. Susceptibilityweighted imaging as used in the present study by Pontillo et al 9 has also been indicated to reflect both microglial activation (ie, through changes in iron levels) and myelin content, further complicating matters. 20 As Pontillo et al 9 note, future longitudinal multimodal studies are now required to disentangle the causal chain of events for these different local and network-based pathologic processes.…”

“…What drives this typical neurodegenerative pattern in MS, however, remains unclear, probably including a combination of network disconnection, 7 Wallerian degeneration, and local damage. 8 The study by Pontillo et al, 9 published in the current issue of the American Journal of Neuroradiology, represents a comprehensive way to investigate the possible correlates of deep gray matter atrophy. The authors apply several MR imaging measures of diffusion, perfusion, and susceptibility in the DGM in relapsingremitting MS (RRMS, n ϭ 52) and progressive MS (n ϭ 25), which were compared with those in healthy controls (n ϭ 44).…”

Damage in the Thalamocortical Tracts is Associated With Subsequent Thalamus Atrophy in Early Multiple Sclerosis

“…In addition, subjects with early MS showed a correlation between reduced thalamic volume and reduced FA in the WM adjacent to the thalamus (14) or damage in the connected WM tracts, as seen by decreased FA and increased MD as well as increased WM lesion volume in the thalamocortical projections (13). Although some studies show a relationship between global WM damage and deep GM atrophy (15)(16)(17), no longitudinal studies have focused on damage of the WM specifically connected to these deep GM structures. Moreover, investigation of the directionality of the relationship between GM atrophy and WM damage remains scarce and inconclusive (13,(18)(19)(20).…”