The sequence of regional structural disconnectivity due to multiple sclerosis lesions

Abstract

Objective: Prediction of disease progression is challenging in multiple sclerosis (MS) as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in MS. Methods: In a full cohort of 482 patients, the Expanded Disability Status Scale was used to classify patients into (i) no or mild vs (ii) moderate or severe disability groups. In 363 out of 482 patients, Quantitative Susceptibility Mapping was used to identify paramagnetic rim lesions (PRL), which are maintained by a rim of iron-laden innate immune cells. In 171 out of 482 patients, Brief International Cognitive Assessment was used to identify subjects with cognitive impairment. Network Modification Tool was used to estimate the regional structural disconnectivity due to MS lesions. Discriminative event-based modeling was applied to investigate the sequence of regional structural disconnectivity due to all representative lesions across the spectrum of disability and cognitive impairment. Results: Structural disconnection in the ventral attention and subcortical networks was an early biomarker of moderate or severe disability. The earliest biomarkers of disability progression were structural disconnections due to PRL in the motor-related regions. Subcortical structural disconnection was an early biomarker of cognitive impairment. Interpretation: MS lesion-related structural disconnections in the subcortex is an early biomarker for both disability and cognitive impairment in MS. PRL-related structural disconnection in the motor cortex may identify the patients at risk for moderate or severe disability in MS.

Thalamic network controllability changes and cognitive impairment in multiple sclerosis

“…That is, in MS, the highest subcortical average controllability further increased, while the lowest subcortical modal controllability further decreased. The subcortical regions have proven to be the first and most vulnerable parts to disease attacks across the whole brain in MS. [18][19][20] Therefore, one possible mechanism underlying the imbalanced subcortical controllability in MS might be due to an early compensation strategy against the disease, which prioritizes the preservation of transitions towards fundamental brain states (such as the easy-to-reach resting state) while relinquishing transitions towards high-order states (such as the difficult-to-reach cognitive task state). This might further relate to the subsequent development of high-order cognitive dysfunction in patients with this disease.…”

“…8 The subcortical regions, which are strongly connected to the rest of the brain, have gained wide attention in MS, with many studies reporting associations between cognitive impairment and functional connectivity changes in the subcortical network [8][9][10] as well as in specific regions within the subcortex, such as the thalamus, [11][12][13][14] hippocampus, [15][16][17] and caudate. 10 Central to these findings is the idea that the subcortical regions (like the thalamus) are particularly affected early in the course of MS. [18][19][20] This early involvement may drive the subsequent changes of the rest of the brain, leading the brain switch towards unexpected states and causing reduced efficiency in high-order cognitive functions. However, current studies have not directly examined the effects that the subcortical regions have on driving network changes of the other parts of the brain, and cannot address the factors that make these subcortical regions exhibit changes early in MS, and especially in CIMS.…”

Reduced Oxygen Extraction Fraction in Deep Cerebral Veins Associated with Cognitive Impairment in Multiple Sclerosis

“…[6][7][8][9] Cognitive impairment in MS can arise from decreased oxygen metabolism manifesting either as direct damage to brain tissue or as a decline in neuronal/axonal activity. [10][11][12] Specifically, cognitive dysfunction is linked to damage in deep gray matter nuclei 11,13,14 , with the thalamus being identified as the primary contributor. 15,16 Therefore, measurements of OEF in deep cerebral regions could serve as a specific imaging biomarker of cognitive decline in MS.…”