Subcortical Deep Gray Matter Pathology in Patients with Multiple Sclerosis Is Associated with White Matter Lesion Burden and Atrophy but Not with Cortical Atrophy: A Diffusion Tensor MRI Study

BACKGROUND AND PURPOSE:The association between subcortical deep gray matter, white matter, and cortical pathology is not well understood in MS. The aim of this study was to use DTI to investigate the subcortical deep gray matter alterations and their relationship with lesion burden, white matter, and cortical atrophy in patients with MS and healthy control patients.MATERIALS AND METHODS:A total of 210 patients with relapsing-remitting MS, 75 patients with progressive MS, and 110 healthy control patients were included in the study. DTI metrics in whole brain, normal-appearing white matter, normal-appearing gray matter, and subcortical deep gray matter structures were compared. The association between DTI metrics of the subcortical deep gray matter structures with lesion burden, normalized white matter volume, and normalized cortical volume was investigated.RESULTS:DTI measures were significantly different in whole brain, normal-appearing white matter, and normal-appearing gray matter among the groups (P < .01). Significant differences in DTI diffusivity of total subcortical deep gray matter, caudate, thalamus, and hippocampus (P < .001) were found. DTI diffusivity of total subcortical deep gray matter was significantly associated with normalized white matter volume (P < .001) and normalized cortical volume (P = .033) in healthy control patients. In both relapsing and progressive MS groups, the DTI subcortical deep gray matter measures were associated with the lesion burden and with normalized white matter volume (P < .001), but not with normalized cortical volume.CONCLUSIONS:These findings suggest that subcortical deep gray matter abnormalities are associated with white matter lesion burden and atrophy, whereas cortical atrophy is not associated with microstructural alterations of subcortical deep gray matter structures in patients with MS.

Although in the past MS has been considered an inflammatory demyelinating disease affecting primarily the white matter of the central nervous system, currently, a substantial number of studies have established that gray matter is also involved in different stages of the disease.^1–5 Cortical and subcortical deep gray matter (SDGM) atrophy occurs also in the early stages of MS, and disability progression is significantly influenced by the neuronal loss of the gray matter.^6–8Atrophy of the SDGM structures is associated with disability progression and cognitive dysfunctions and can also predict the conversion to clinically definite MS.^9–12 An increasing body of evidence suggests that the atrophy of cortical and SDGM structures is associated with white matter lesion burden,¹³ but the underlying pathophysiologic processes remain poorly understood. Secondary Wallerian degeneration is certainly implicated in neuronal damage of gray matter structures; however, it seems unlikely to be the sole cause of gray matter pathology.^4,14DTI is an advanced MR imaging technique that has been used in a number of in vivo and ex vivo studies.^15,16 DTI measures are able to identify alterations outside the focal lesions in the so-called normal-appearing white matter and normal-appearing gray matter that remain largely undetected with conventional MR imaging in patients with MS.¹⁷There is a growing interest in studying the DTI alterations of the SDGM in the different stages of the MS disease process. Previous studies suggested that SDGM DTI abnormalities are also present in patients with clinically isolated syndrome^18,19 and are associated with disability progression as well as cognitive dysfunctions in patients with MS.^20–23Although different studies have investigated the associations between white matter lesions, brain atrophy, and DTI alteration in patients with MS,^24–26 the same relationships were not extensively investigated in healthy people whose pathophysiologic alteration of the brain cannot be attributable to the inflammatory process in the central nervous system. Therefore, in the current study, we aimed to investigate volumetric and DTI global, tissue-specific, and regional brain differences in a large cohort of healthy control (HC) patients, patients with relapsing-remitting MS (RRMS), and patients with progressive MS (PMS). We hypothesized that microstructural abnormalities of SDGM structures detected by DTI techniques are associated with lesion burden, and with white matter and gray matter volume alterations in patients with MS. Another aim was to explore the same associations in the HC group.