Short-Range Structural Connections Are More Severely Damaged in Early-Stage MS

Abstract

BACKGROUND AND PURPOSE: Long-range connections are more severely damaged and relevant for cognition in long-standing MS. However, the evolution of such coordinated network damage in patients with MS is unclear. We investigated whether short-and long-range structural connections sustained equal damage in early-stage MS. MATERIALS AND METHODS:Sixteen patients with early-stage MS and 17 healthy controls were scanned by high-resolution, multishell diffusion imaging on 7T MR imaging and assessed cognitively. We investigated macrostructural properties in short-and longrange fibers and of microstructural metrics derived from 2 quantitative diffusion MR imaging models: DTI and neurite orientation dispersion and density imaging.RESULTS: Patients had significant WM integrity damage-that is, higher radial diffusivity and a lower intracellular volume fraction in the focal WM lesions. Compared with the healthy controls, the patients had noticeable microstructure changes in both short-and long-range fibers, including increased radial diffusivity, mean diffusivity, and axial diffusivity. Z scores further indicated greater damage in the short-range fibers than in the long-range fibers. CONCLUSIONS:Our findings demonstrate that more severe demyelination preceding axonal degeneration occurs in short-range connections but not in long-range connections in early-stage MS, suggesting the possibility that there are cortical lesions that are undetectable by current MR imaging.ABBREVIATIONS: AD ¼ axial diffusivity; EDSS ¼ Expanded Disability Status Scale; FA ¼ fractional anisotropy; f icvf ¼ intracellular volume fraction; HC ¼ healthy control; MD ¼ mean diffusivity; NODDI ¼ neurite orientation dispersion and density imaging; ODI ¼ Orientation Dispersion Index; RD ¼ radial diffusivity M S has been histologically characterized by the aggregation of inflammation, demyelination, gliosis, and axonal transection that ultimately leads to neurologic disability in young adults. MS can present with highly variable symptoms such as loss of vision, limb weakness, sensory loss, ataxia, and cognitive impairment. 1,2 Neuroimaging studies have helped to define the pathologic substrates and microstructure (eg, demyelination) alternations of this disorder in focal lesions and diffusely abnormal tissue. 3,4 While the specific WM fiber changes remain elusive, these local abnormalities in tissue microstructure are not enough to explain the clinically observed functional impairment. 5,6 Nevertheless, there is growing evidence that neurologic impairment in MS is determined more by specific large-scale functional network alterations than by local tissue microstructural alterations. 7,8 The subtle balance between short-and long-range connections contributes to the integration and segregation of the brain connectome. Connections of different lengths are found in different locations across the brain; short-range fibers are more abundant than their long-range counterparts, and the short-range fibers connect adjacent anatomic gyri that integrate multimodal informati...

Neurite Orientation Dispersion and Density Imaging in Multiple Sclerosis: A Systematic Review

“…Four studies highlighted reduced ODI in WM lesions compared to NWM from HC, 16,28,31,33 while opposite findings were reported in two independent studies 25,40 . One study even indicated comparable ODI values in MS WM lesions and NWM of controls 43 . Similar incongruent results were observed when investigating ODI in WM lesions compared to NAWM 16,18,30 .…”

“…Decreased NDI was the most consistent NODDI feature in WM lesions. Specifically, NDI showed systematic reduction within WM lesions compared to NAWM 16,18,30,38,39 and normal WM (NWM, that is WM from healthy individuals) 16,25,28,31–33,38–40,43 . Studies also reported reduced NDI values in MS NAWM compared to WM in HC.…”

“…Participants were age‐matched in four studies, 24,28,37,39 sex‐matched in one study 36 . Meanwhile, 15 studies controlled for both age and gender 16,18,23,26,27,29–31,33–35,40–43 …”

The different damage patterns of short-, middle- and long-range connections between patients with relapse-remitting multiple sclerosis and neuromyelitis optica spectrum disorder

“…It may be helpful to explain that long-range connections are more likely to undergo damage in MS (24,25). At the same time, a previous study also reported that early MS is more likely to have short-range connection damage (16). Thus, pathological changes, such as specific white matter demyelination, axonal damage and degenerative degeneration, may cause the presence of extensive white matter damage and microstructural damage of different lengths of connections in MS patients.…”

“…The different lengths of connections may have other effects on brain networks, implying that damage to either type of connection may have relatively specific effects. Even though there were numerous studies have proved the impairment of brain connection based on graph analysis (12-14), only a few studies have reported that MS patients have varying degrees of impairment in both short-and long-range connections (15,16). However, it is unclear whether similar or different alteration patterns exist in NMOSD patients as in MS. Additionally, it is unknown whether the damage of different fibers may influence the structural and functional networks in two diseases.…”