Understanding cognitive dysfunction in secondary progressive multiple sclerosis using functional and structural MRI

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

Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial

Magnetic resonance imaging; Neurofilament light; Secondary progressive multiple sclerosisImatge per ressonància magnètica; Llum del neurofilament; Esclerosi múltiple secundària progressivaImagen por resonancia magnética; Luz de neurofilamento; Esclerosis múltiple secundaria progresivaBackground: Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention. Objective: The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI. Methods: Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes. Results: Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score (p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components. Conclusion: Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: No specific funding was received for this research. T.W. is currently funded by the MS-STAT2 trial grant (NCT03387670). This is funded by the NIHR Health Technology Assessment (HTA) Programme, Multiple Sclerosis Society (UK) and the National Multiple Sclerosis Society (US)

Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial.

Background: Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention. Objective: The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI. Methods: Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes. Results: Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score (p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components. Conclusion: Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes

Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials

BACKGROUND: Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease. METHODS: Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015-2016 and 2018-2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment. RESULTS: In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART. CONCLUSIONS: Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design. TRIAL REGISTRATION: MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018

Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments

BACKGROUND: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). PURPOSE: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. STUDY-TYPE: Longitudinal. POPULATION: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. FIELD STRENGTH/SEQUENCE: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. ASSESSMENT: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. STATISTICAL TESTS: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. RESULTS: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = -0.21); in the riluzole arm, GM Glx (β = -0.25) and Glx/tCr (β = -0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. DATA CONCLUSION: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4

Longitudinal metabolite changes in progressive multiple sclerosis:A study of 3 potential neuroprotective treatments

Background: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). Purpose: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. Study-type: Longitudinal. Population: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. Field strength/sequence: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. Assessment: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. Statistical tests: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value&lt;0.05 was considered statistically significant. Results: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = -0.21); in the riluzole arm, GM Glx (β = -0.25) and Glx/tCr (β = -0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. Data conclusion: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. Level of evidence: 1 TECHNICAL EFFICACY: Stage 4

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial

BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening

Regional Efficacy of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis (RRMS)

Natalizumab is an established treatment for highly active Relapsing-Remitting Multiple Sclerosis (RRMS). Two-year efficacy in the AFFIRM trial showed No Evidence of Disease Activity(NEDA) – no relapses, no disability progression, no new MRI lesions – in 37% of patients compared with 7% in the placebo group. NEDA is increasingly used as a treatment goal in RRMS.MethodologyWe performed a retrospective analysis of Natalizumab treatment in RRMS patients in our centre. We assessed the proportion of patients achieving NEDA in a typical clinical setting with at least 1 year treatment duration and analysed for predictors of response.ResultsMean age was 41.44 (13–62), 77% (51) of patients were female. 56 out of 66 patients had been on Natalizumab for &gt;1year and were analysed. 55.36% patients achieved NEDA at 1 year. No statistically significant predictors (age, gender, starting disability and relapse rate) of response were identified.DiscussionThe data confirms in a typical UK clinical setting good treatment response was achieved in highly active RRMS patients using Natalizumab. No additional factors were found which could predict treatment response suggesting within the limitations of power and length of this study that Natalizumab is effective in a broad range of highly active RRMS patients.</jats:sec