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Background: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing., Objective: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition., Methods: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO 2 ., Results: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes., Conclusion: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.

Behavioral studies investigating fundamental cognitive abilities provide evidence that processing speed accounts for large proportions of performance variability between individuals. Processing speed decline is a hallmark feature of the cognitive disruption observed in healthy aging and in demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica, and Wilson's disease. Despite the wealth of evidence suggesting a central role for processing speed in cognitive decline, the neural mechanisms of this fundamental ability remain unknown. Intact neurovascular coupling, acute localized blood flow increases following neural activity, is essential for optimal neural function. We hypothesized that efficient coupling forms the neural basis of processing speed. Because MS features neural-glial-vascular system disruption, we used it as a model to test this hypothesis. To assess the integrity of the coupling system, we measured blood-oxygen-level-dependent (BOLD) signal in healthy controls (HCs) and MS patients using a 3T MRI scanner while they viewed radial checkerboards that flickered periodically at 8 ​Hz. To assess processing speed and cognitive function, we administered a battery of neuropsychological tests. While MS patients exhibited reduced ΔBOLD with reductions in processing speed, no such relationships were observed in HCs. To further investigate the mechanisms that underlie ΔBOLD-processing speed relationships, we assessed the physiologic components that constitute ΔBOLD signal (i.e., cerebral blood flow, ΔCBF; cerebral metabolic rate of oxygen, ΔCMRO 2 ; neurovascular coupling ratio) in speed-preserved and -impaired MS patients. While ΔCBF and ΔCMRO 2 showed no group-differences, the neurovascular coupling ratio was significantly reduced in speed-impaired MS patients compared to speed-preserved MS patients. Together, these results suggest that neurovascular uncoupling might underlie cognitive slowing in MS and might be the central pathogenic mechanism governing processing speed decline., Competing Interests: Declaration of competing interest DS, KW, MT, DA, YZ, HL, JS, MZ, BR report no disclosures related to the work presented here. DO received advisory and consulting fees from Celgene, EMD Serono, Genentech, Genzyme, and Novartis and research support from Biogen., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cerebral metabolic rate of oxygen (CMRO 2 ), a measure of global oxygen metabolism, reflects resting cellular activity. The mechanisms underlying fatigue and cognitive dysfunction in multiple sclerosis (MS) remain unknown. If fatigue indeed reflects ongoing autoimmune activity and cortical reorganization, and cognitive decline is the result of gray matter atrophy and white matter degeneration, we postulate that changes in CMRO 2 should reflect disease activity and predict these symptoms., Objective: We sought to utilize T 2 -Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI to measure global CMRO 2 to understand its relationships to white matter microstructure, fatigue and cognitive dysfunction., Methods: We measured venous oxygenation (TRUST) and cerebral blood flow (PC-MRI) in superior sagittal sinus to calculate global CMRO 2 and diffusion tensor imaging (DTI) to evaluate white matter microstructure in healthy controls (HC) and MS patients. Participants underwent neuropsychological examinations including Modified Fatigue Impact Scale (MFIS) and Symbol-Digit-Modalities Test (SDMT)., Results: We observed lower CMRO 2 in MS patients compared to HC. After controlling for demographic and disease characteristics (i.e., age, education, disability, lesion volume), CMRO 2 predicted increased fatigue (MFIS) and reduced cognitive performance (SDMT) in MS patients. Finally, MS patients with higher CMRO 2 have reduced FA in normal-appearing white-matter., Conclusion: Altogether, these results suggest that increased CMRO 2 reflects ongoing demyelination and autoimmune activity which plays an important role in both fatigue and cognitive dysfunction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Learning and memory impairments are common in multiple sclerosis (MS) and may be related to difficulty acquiring (encoding or consolidating) new information. We evaluate the role of retroactive interference and investigate whether minimizing interference immediately following encoding (early during consolidation) will improve MS participants' ability to remember new verbal information. Additionally, we investigate processing speed differences between memory-impaired and unimpaired participants and present an exploratory analysis of how the dual-components of working memory (capacity vs. processing) relate to memory impairment., Method: MS memory-unimpaired (N = 12) and MS memory-impaired participants (N = 12) were compared to healthy controls (N = 15). Interference onset following encoding (early, mid, late, no interference) was manipulated over the retention interval of a verbal learning and memory task. Response times (RT) were recorded during interference trials., Results: MS memory-impaired participants encoded less information and lost proportionally more information over the retention interval (weak consolidation). Lengthening the onset of interference did not benefit memory performance in this sample. Memory performance was unrelated to RT but was related to performance on the Symbol Digit Modalities Test. Primary capacity of working memory did not differ across groups; however, secondary memory processing was reduced for MS memory-impaired participants., Conclusion: Minimizing interference following encoding did not improve memory in this sample. Both initial encoding and early consolidation were reduced for memory-impaired MS participants. Evidence for a relationship between processing speed and memory was mixed and depended on the processing speed assessment used. Memory impairment in MS may be partially due to inefficient processing within working memory.