Doshi, Anisha H; (2021) Understanding cognitive dysfunction in secondary progressive multiple sclerosis using functional and structural MRI. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis concerns a 2 year follow-up study of people with secondary progressive multiple sclerosis (SPMS). I investigate: (1) cognitive performance of SPMS and changes over time, (2) the classification of cognitive impairment and predictors of this, (3) mechanisms underlying the SPMS phenotype with and without cognitive impairment using functional and structural MRI. The literature has highlighted the input of executive dysfunction in the cognitive profile of SPMS over and above that seen in other multiple sclerosis (MS) phenotypes. I looked at cognitive performance in SPMS, and predictors of this in this pure SPMS cohort study. I found that being employed, having higher IQ, more premorbid leisure interests, and higher qualifications mitigate against negative cognitive outcomes in SPMS. Additionally, anxiety, even when not reaching clinically diagnostic levels, impacts on tests of information processing speed, verbal working memory, and executive function in SPMS. The symbol digit modality test (SDMT) at baseline is predicted by MS lower limb disability outcome measures; the Expanded Disability Status Scale (EDSS) and timed 25 foot walk (T25FW) which emphasises the role of the SDMT as an adjunctive measure of clinical disability prediction in studies. I show that decline on the SDMT at follow-up is purely predicted by cognitive measures of information processing speed and working memory at either timepoint, supporting, and furthering, the evidence for the SDMT as a sentinel assessment of cognitive performance in SPMS. These findings inform future longitudinal cognitive studies in SPMS, particularly with regards to the importance of tests of executive function, and important associations with clinical outcomes in a highly disabled cohort. I also considered the threshold for classifying cognitive impairment, and its implications. There is marked heterogeneity in these thresholds due to the lack of current consensus on a diagnostic criteria. Using a higher threshold for cognitive impairment in my studies strengthened the associations with clinically relevant outcomes. Additionally, unemployment showed the greatest association with cognitive impairment regardless of criteria used. I found that assessments of information processing speed, verbal memory, and executive function had the greatest input to cognitive impairment in SPMS. These findings indicate the importance of these cognitive domains and demographic factors when evaluating cognitive status in SPMS. These results will guide the international consensus on how best to measure cognitive impairment in SPMS, and in MS more broadly. Posterior and deep resting state networks (RSNs) have been shown to be altered in resting state functional MRI (rs-fMRI) studies of progressive MS phenotypes. I confirm this using functional connectivity (FC) and highlight that this is mainly in terms of cognitive RSNs in SPMS versus healthy controls using a global rs-fMRI analysis technique. Additionally, with cognitive impairment in SPMS, I show that there are key attentional RSN FC reductions. I further highlight the importance of more stringent classification criteria of cognitive impairment to allow for more detailed evaluation of dynamic FC changes, that are missed when using a lenient criteria. Over time, the development of cognitive impairment in SPMS from a preserved state appears to relate to reduced FC in working memory, posterior default mode (DMN) and visual RSNs, and increased FC in the executive control, and more anterior DMN hubs at baseline. Therefore, alterations in posterior cognitive and executive RSNs may inform cognitive status in SPMS. These results provide, to my knowledge, the first longitudinal rs-fMRI study of cognitive status in SPMS. Regional grey matter atrophy has been shown to be greater in SPMS then in other MS phenotypes. I found that SPMS cognitive impairment is associated with grey matter volume, cortical grey matter volume, and deep grey matter and regional deep grey matter atrophy. I also highlighted that proportionally, within the cerebellum, there are greater percentage changes in FC versus volume in those with SPMS with cognitive impairment versus in SPMS overall. These findings therefore show the importance of deeper grey matter atrophy in SPMS underlying cognitive impairment, and indicate the need for a longitudinal study of rs-fMRI and regional grey matter MRI metrics to understand the interplay of underlying mechanisms in more detail.

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