Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

Abstract

Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.

The expansion and severity of chronic MS lesions follows a periventricular gradient

“…7,10 Similarly, the acute and chronic white matter lesions contribute independently to disease progression, implying that different mechanisms are likely to be responsible for acute and smouldering inflammation. 1,2,3,26,27 Finally, the gradient of tissue severity damage in NAWM and the presence of chronic active lesions are more prominent in patients with progressive forms of MS. 11,14 Therefore, it is plausible that some of the mechanisms proposed to explain the periventricular predominance of abnormalities in the NAWM, such as a neurotoxic effect of soluble CSF-derived factors, 12,28 hypoxia 29 , reduced remyelinating capacity 30 or increased compartmentalized inflammation 9 in periventricular region and microglial activation 12 are important mediators of the expansion of chronic lesions observed in our study.…”

“…Second, both the rate of lesion expansion and periventricular gradient of tissue damage severity are associated with activation of microglia. Thus, a recent study has shown a periventricular gradient of microglial activation both in NAWM and MS lesions 12 ; and postmortem evidence has suggested the involvement of activated microglia in CSF-related tissue injury. 22 Similarly, microglial activation has been implicated as a principal driver of slowburning inflammation at the rim of chronic active lesions, which represents the pathophysiological equivalent of lesion expansion.…”

“…3 To reduce the disproportionally large impact of small lesions on calculation of CSF-related gradient of lesion expansion, the weight corresponding to number of baseline lesional voxels in each ring was assigned to each lesion, as recently suggested. 12,10 For lesion-based analysis, the "center of mass" for each lesion was calculated using the weighted average of lesional voxels distributed across all the rings. Lesions with a "center of mass" within the first 10 rings were used for analysis.…”

“…5,6 A CSF-related gradient of tissue injury has recently been described in both normalappearing white matter (NAWM) and chronic lesions in patients with MS. 7,8,9,10,11 White matter magnetization transfer ratio (MTR) and Mean Diffusivity (MD) abnormalities were reported around the ventricles, with the most severe abnormalities bordering the ventricular surface. Akin to pathomechanisms thought to be involved in slow lesion expansion, the periventricular injury gradient is linked to innate immune cell activation 12 and seems to be independent of formation of new lesions. 3,7 Therefore, the aim of the current study was to investigate whether slow-burning inflammation at the rim of chronic MS lesions (assessed by the degree of lesion expansion) is associated with proximity to the CSF; and to explore a potential relationship between lesion topography and the degree of progressive tissue injury within the lesional core (as measured by T1 hypointensity and MD).…”

“…A CSF-related gradient of tissue injury has recently been described in both normal-appearing white matter (NAWM) and chronic lesions in patients with MS. 7,8,9,10,11 White matter magnetization transfer ratio (MTR) and Mean Diffusivity (MD) abnormalities were reported around the ventricles, with the most severe abnormalities bordering the ventricular surface. Akin to pathomechanisms thought to be involved in slow lesion expansion, the periventricular injury gradient is linked to innate immune cell activation 12 and seems to be independent of formation of new lesions. 3,7…”