Multiple sclerosis.

Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes.

The time to include cognition in the multiple sclerosis concept of progression independent from relapse activity is now.

Progression independent of relapse activity (PIRA) has been recently proposed in multiple sclerosis (MS) as a model identifying a continuous silent progression of disability without the manifestation of new clinical and magnetic resonance imaging (MRI) events that contribute to MS worsening. Despite evidence suggesting that clinical MS manifestations often affect cognitive functioning and the importance of neuropsychological monitoring over time, attention to silent cognitive progression is lacking, and the PIRA concept does not include a measure of cognitive function. In this personal viewpoint, we highlight the need to include cognition in the PIRA model to have a more comprehensive understanding of clinical progression in patients with MS.

Cognitive phenotypes predict response to restorative cognitive rehabilitation in multiple sclerosis.

BACKGROUND: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis. OBJECTIVE: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR). METHODS: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation. RESULTS: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory. CONCLUSIONS: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall.

Cognitive progression independent of relapse in multiple sclerosis.

BACKGROUND: Substantial physical-disability worsening in relapsing-remitting multiple sclerosis (RRMS) occurs outside of clinically recorded relapse. This phenomenon, termed progression independent of relapse activity (PIRA), is yet to be established for cognitive decline. METHODS: Retrospective analysis of RRMS patients. Cognitive decline was defined using reliable-change-index cut-offs for each test (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test-II). Decline was classified as PIRA if the following conditions were met: no relapse observed between assessments nor within 9 months of cognitive decline. RESULTS: The study sample (n = 336) was 80.7% female with a mean (standard deviation (SD)) age, disease duration, and observation period of 43.1 (9.5), 10.8 (8.4), and 8.1 (3.1) years, respectively. A total of 169 (50.3%) subjects were cognitively impaired at baseline relative to age-, sex-, and education-matched HCs. Within subjects who experienced cognitive decline (n = 167), 89% experienced cognitive PIRA. A total of 141 (68.1%) cognitive decline events were observed independent of EDSS worsening. Cognitive PIRA was more likely to be observed with increased assessments (p < 0.001) and lower assessment density (p < 0.001), accounting for baseline clinical factors. CONCLUSION: These results establish the concept of cognitive PIRA and further our understanding of progressive cognitive decline in RRMS.

Predicting employment deterioration with the Processing Speed Test (PST) and SDMT in multiple sclerosis.

BACKGROUND: Employment deterioration is common in people with multiple sclerosis (PwMS). Clinicians often learn of job loss after its occurrence, leaving no opportunity for preventive measures. OBJECTIVES: Identify which neuropsychological measures discriminate between healthy volunteers (HVs) and employed/disabled PwMS at baseline and predict work deterioration over 2 years. METHODS: We examined 198 PwMS with computerized tests such as the Processing Speed Test (PST) and conventional tests such as the Symbol-Digit Modalities Test (SDMT), administered at baseline. Employment was assessed via Buffalo Vocational Monitoring Survey. Univariate and regression analyses identified significant predictors of PwMS categorized as work-stable versus work-deteriorated status. RESULTS: PwMS were impaired on all baseline assessments relative to HVs (p's < 0.001). Post hoc analyses showed that employed PwMS and HVs performed similarly and better than work-disabled PwMS. At the univariate level, both PST and SDMT discriminated between work-deteriorated and work-stable PwMS (p's < 0.01). The logistic regression model accounting for all measures retained PST and the computerized Walking Speed Test. PwMS with increased negative work events had lower PST (p < 0.001), SDMT (p < 0.001), and BVMT-R (p < 0.01) scores than stable PwMS. The related regression model retained PST and BVMT-R (p < 0.001). CONCLUSION: Cognition, as measured by the PST and BVMT-R, are predictive of job deterioration in PwMS and may be a useful screening tool to identify those at high risk of unemployment.

Paramagnetic rim lesions are associated with greater incidence of relapse and worse cognitive recovery following relapse.

BACKGROUND: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS). OBJECTIVE: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. METHODS: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-). RESULTS: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL (p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS (n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS (n = 7; p = 0.027). CONCLUSION: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.

Auditory Test of Processing Speed: Preliminary validation of a smartphone-based test of mental speed.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is a gold-standard measure of cognitive efficiency and processing speed for people with multiple sclerosis (PwMS) but relies on vision and oculomotor function. OBJECTIVES: To develop and validate a new processing speed test with minimal memory involvement and no eye function requirements. METHODS: We created an Auditory Test of Processing Speed (ATOPS). A total of 122 PwMS, of whom 33 were severely disabled (median Expanded Disability Status Scale 8.0) and 37 healthy volunteers (HVs), were enrolled. We assessed sensitivity to discriminate MS participants from HVs, convergent validity between ATOPS and SDMT, sensitivity to discriminate between cognitively impaired (CI) and cognitively preserved (CP) MS participants, and correlations with MS pathology (overall brain lesion burden). Acceptability was examined with completion rates and participant ratings of ATOPS. RESULTS: ATOPS discriminated PwMS from HVs (d = 0.739-0.856), correlated with SDMT (|r| = 0.528-0.587), discriminated between CI and CP PwMS (d = 0.623-0.776), and correlated with lesion burden (r = 0.332-0.436). All groups indicated high favorability of ATOPS and severely disabled MS patients could be assessed by ATOPS more frequently than by SDMT (100% vs. 72.4% completion). CONCLUSIONS: ATOPS is a novel, accessible, and acceptable cognitive processing speed test that may be useful in clinical and/or research settings.

Benchmarks of meaningful improvement on neurocognitive tests in multiple sclerosis.

BACKGROUND: Previous studies have established benchmarks of clinically meaningful decline on neuropsychological tests. However, little is known about meaningful testing benchmarks based on gains in function. OBJECTIVE: Investigate neuropsychological changes in multiple sclerosis (MS) patients with work gains and calculate benchmarks of meaningful improvement on neuropsychological tests. METHODS: A total of 323 people with MS were monitored longitudinally with neuropsychological testing and the Buffalo Vocational Monitoring Survey. RESULTS/CONCLUSIONS: Those with work gains showed significant improvement (~3 points) on the Symbol Digit Modalities Test (SDMT) over time, p = 0.01. Benchmarks for clinically meaningful improvement on the SDMT are similar to those previously established for clinically meaningful decline.

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years.

BACKGROUND: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. OBJECTIVE: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. METHODS: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). RESULTS: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. CONCLUSION: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. TRIAL REGISTRATION NUMBER: NCT01665144.

Interpreting change on the Symbol Digit Modalities Test in people with relapsing multiple sclerosis using the reliable change methodology.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is increasingly utilized in clinical trials. A SDMT score change of 4 points is considered clinically important, based on association with employment anchors. Optimal thresholds for statistically reliable SDMT changes, accounting for test reliability and measurement error, are yet to be applied to individual cases. OBJECTIVE: The aim of this study was to derive a statistically reliable marker of individual change on the SDMT. METHODS: This prospective, case-control study enrolled 166 patients with multiple sclerosis (MS). SDMT scores at baseline, relapse, and 3-month follow-up were compared between relapsing and stable patient groups. Using data from the stable group and three previously published studies, candidate thresholds for reliable decline were calculated and validated against other tests and a clinically meaningful anchor-cognitive relapse. RESULTS: Candidate thresholds for reliable decline at the 80% confidence level varied between 6 and 11 points. An SDMT change of 8 or more raw score points was deemed to offer the best balance of discriminatory power and external validity for estimating cognitive decline. CONCLUSION: This study illustrates the feasibility and usefulness of reliable change methodology for identifying statistically meaningful cognitive decline that could be implemented to identify change in individual patients, for both clinical management and clinical trial outcomes.

Staging and stratifying cognitive dysfunction in multiple sclerosis.

BACKGROUND: The sequence in which cognitive domains become impaired in multiple sclerosis (MS) is yet to be formally demonstrated. It is unclear whether processing speed dysfunction temporally precedes other cognitive impairments, such as memory and executive function. OBJECTIVE: Determine the order in which different cognitive domains become impaired in MS and validate these findings using clinical and vocational outcomes. METHODS: In a longitudinal sample of 1073 MS patients and 306 healthy controls, we measured performance on multiple, consensus-standard, neurocognitive tests. We used an event-based staging approach to model the sequence in which cognitive domains become impaired. Linear and logistic mixed-effects models were used to explore associations between stages of impairment, neurological disability, and employment status. RESULTS: Our model suggested that the order of impairments was as follows: processing speed, visual learning, verbal learning, working memory/attention, and executive function. Stage of cognitive impairment predicted greater neurological disability, ß = 0.16, SE = 0.02, p < 0.001, and probability of unemployment, ß = 1.14, SE = 0.001, p < 0.001. CONCLUSION: This is the first study to introduce a cognitive staging and stratification system for MS. Findings underscore the importance of using the Symbol Digit Modalities Test in routine screening for cognitive impairment and memory testing to assess patients later in disease evolution.

Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial.

BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Do subcortical gray matter volumes and aerobic capacity account for cognitive-motor coupling in multiple sclerosis?

BACKGROUND: There is evidence of cognitive-motor coupling in multiple sclerosis (MS) such that the slowing of cognitive processing speed correlates with the worsening of walking speed and endurance. OBJECTIVE: The current study first established the presence of cognitive-motor coupling and second examined the possibility that volumes of subcortical gray matter (SGM) structures and aerobic capacity might explain the coupling of cognitive and motor functions in persons with MS. METHODS: We included data from 62 persons with clinically definite MS who underwent assessments of cognitive processing speed, walking performance, and aerobic capacity, and completed magnetic resonance imaging (MRI) within 7 days of the aforementioned assessments. RESULTS: The strong correlations between cognitive processing speed and walking performance were attenuated in magnitude and not statistically significant when controlling for aerobic capacity alone and aerobic capacity and SGM volumes together. The associations between cognitive processing speed and walking performance remained statistically significant when controlling for SGM volumes alone. CONCLUSION: Aerobic capacity may be an important target for neurorehabilitation-based approaches for managing co-occurring cognitive and motor dysfunction in MS.

Conscientiousness and deterioration in employment status in multiple sclerosis over 3 years.

BACKGROUND: Physical and cognitive symptoms of multiple sclerosis (MS) correlate with unemployment cross-sectionally. Prospective studies, rarely published, have not accounted for personality traits such as Conscientiousness. METHODS: In a 3-year study of 70 people with MS (PwMS) and 25 healthy controls (HCs), we evaluated employment status using online interviews capturing hours worked, negative work events, employee relations, and accommodations. Deteriorating employment status (DES) was defined as reduced employment (full-time to part-time or negative work events). In PwMS, we explored workplace accommodations, disclosure of disease status, and physical/psychological predictors of DES (e.g. Conscientiousness). RESULTS: At follow-up, DES was 0% in HCs and 25.7% in MS, and 62.7% of work-stable PwMS used at least one work accommodation, most frequently, flexible hours. At baseline, DES-PwMS had lower education (p = 0.009), lower Conscientiousness (p < 0.001), more fatigue (p = 0.033), and performed worse on Symbol Digit Modalities Test (p = 0.013), Brief Visuospatial Memory Test-Revised (p = 0.041), and Nine-Hole Peg Test (p = 0.046) relative to work-stable. The model predicting DES was significant (χ2(7) = 30.936, p < 0.001) and baseline Conscientiousness accounted for more variance in DES (p = 0.004) than other factors. Higher Conscientiousness PwMS were more likely to disclose their condition at work (p = 0.038). CONCLUSION: Accommodations for low Conscientiousness, flexible hours, and physical/cognitive rehabilitation may prevent DES.

A validation study for remote testing of cognitive function in multiple sclerosis.

OBJECTIVES: Determine the validity and reliability of a remote, technician-guided cognitive assessment for multiple sclerosis (MS), incorporating the Symbol Digit Modalities Test (SDMT) and the California Verbal Learning Test, Second Edition (CVLT-II). METHODS: In 100 patients, we compared conventional in-person testing to remote, web-assisted assessments, and in 36 patients, we assessed test-retest reliability using two equivalent, alternative forms. RESULTS: In-person and remote-administered SDMT (r = 0.85) and CVLT-II (r = 0.71) results were very similar. Reliability was adequate and alternative forms of SDMT (r = 0.92) and CVLT-II (r = 0.81) produced similar results. CONCLUSIONS: Findings indicate remote assessment can provide valid, reliable measures of cognitive function in MS.

Quantifying cognition and fatigue to enhance the sensitivity of the EDSS during relapses.

BACKGROUND: Cognition is affected by relapses in persons with multiple sclerosis (PwMS), yet the Expanded Disability Status Scale (EDSS) does not readily detect cognitive changes. OBJECTIVE: The objective of this study is to improve the detection of cognitive decline during relapses, by incorporating the Symbol Digit Modalities Test (SDMT) into the cerebral Functional System Score (CFSS) of the EDSS. METHODS: This prospective study recruited PwMS from three dedicated MS centers. All subjects had EDSS, SDMT, and Fatigue Severity Scale (FSS) administered. Subjects experiencing a relapse were assigned to the relapse group (RG). Matched controls from the larger cohort were assigned to the stable group (SG). RG and SG subjects underwent the same evaluation at relapse and 3 months later. Our main outcomes were a modified CFSS (m-CFSS) and modified EDSS (m-EDSS), incorporating SDMT and FSS, accounting for cognitive performance and fatigue rating, during relapse. RESULTS: The full cohort included 592 subjects; 80 qualified for RG and 72 were matched to the SG. The m-CFSS was significantly higher than CFSS at baseline (median = 2 vs. median = 0, p < 0.001) and relapse (median = 2 vs. median = 1, p < 0.001). The m-EDSS was higher than EDSS (median 3.0 vs. 2.5, p = 0.02) at relapse, where 35 RG subjects (43.8%) had higher m-EDSS than EDSS at relapse. CONCLUSION: This study demonstrates that incorporating the SDMT and FSS improves the accuracy of the EDSS, by accounting for cognitive changes, during relapse activity.

Recovery of cognitive function after relapse in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) but its manifestation as acute disease activity is underappreciated. OBJECTIVE: The aim of this study is to examine recovery after MS relapse on multiple tests of cognitive and motor function and explore correlates of change with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI), and cognitive reserve. METHODS: Fifty relapsing group (RG) and matched stable participants were examined at baseline, during relapse, and at 3-month follow-up. Tests of cognitive processing speed (Symbol Digit Modalities Test (SDMT)) and consensus opinion measures of memory, ambulation, and manual dexterity were administered. All RG patients were treated with a 5-day course of Acthar Gel (5 mL/80 IU). RESULTS: In RG patients, SDMT declined from 55.2 to 44.6 at relapse and recovered to 51.7, a slope differing from stable controls (p = 0.001). A statistical trend (p = 0.07) for the same effect was observed for verbal memory and was significant for ambulation (p = 0.03). The Cerebral Function Score from the EDSS also changed in the RG and recovered incompletely relative to controls (p = 0.006). CONCLUSION: These results replicate earlier reports of cognitive worsening during relapse in MS. Clinically meaningful improvements followed relapse on SDMT and ambulation. Cognitive decline during relapse can be appreciated on neurological exam but not patient-reported outcomes.

Lower total cerebral arterial flow contributes to cognitive performance in multiple sclerosis patients.

BACKGROUND: The cognitive performance in multiple sclerosis (MS) patients declines with aging, longer disease duration, and possibly cardiovascular comorbidities. OBJECTIVES: We investigated whether lower total cerebral arterial blood flow (CABF) measured at the level of the carotid and vertebral arteries may contribute to worse cognitive performance in 132 MS patients and 47 healthy controls. METHODS: Total CABF was evaluated with extracranial Doppler, whereas structural T2-lesion volume (LV) and gray matter volume (GMV) were measured on 3T MRI. The cognitive performance was assessed by Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and California Verbal Learning Test-Second Edition (CVLT-II). Analysis of covariance, partial correlation, and regression models were used to test the differences between study groups and cognition/CABF correlations. False discovery rate (FDR)-corrected (Benjamini-Hochberg) p-values (i.e. q-values) less than 0.05 were considered significant. RESULTS: Association between lower total CABF and the lower cognitive performance was observed only in MS patients (r = 0.318, q < 0.001 and r = 0.244, q = 0.012 for SDMT and BVMT-R, respectively). Lower GMV, higher T2-LV, and CABF were significantly associated with poorer performance on the processing speed measure of SDMT (adjusted R2 = 0.295, t-statistics = 2.538, standardized ß = 0.203, and q = 0.020), but not with memory tests. Cognitively impaired MS patients had lower total CABF compared to cognitively preserved (884.5 vs 1020.2 mL/min, q = 0.008). CONCLUSION: Cognitively impaired MS patients presented with lower total CABF. Altered CABF may be a result of reduced metabolic rate and might contribute to abnormal cognitive aging in MS.

Dalfampridine benefits ambulation but not cognition in multiple sclerosis.

BACKGROUND: Impaired cognition and ambulation are common in multiple sclerosis (MS). Dalfampridine is the first Food and Drug Administration (FDA)-approved medication to treat impaired ambulation in MS. Dalfampridine may benefit patients with cognitive impairment, given its effects on saltatory conduction and the association between cognitive and motor function. OBJECTIVE: To examine the effects of dalfampridine on cognition in MS. To determine if the anticipated improved cognition is grounded in dalfampridine's effects on ambulation. METHODS: Adults with MS were randomized to dalfampridine (n = 45) or placebo (n = 16) for 12 weeks. Cognition and motor function were assessed at baseline and end-point. RESULTS: T25FW and 6-minute walk (6MW) performance improved at end-point in the treatment group but not in the placebo group (p < 0.05). Our primary outcome, performance on the Symbol Digit Modalities Test, did not improve. About 30% (n = 12) of the dalfampridine group demonstrated ⩾20% improved ambulation and were categorized "responders." Among "responders", Symbol Digit Modalities test performance did not improve. However, performance on the Paced Auditory Serial Addition Test improved among "responders" (p < 0.05). CONCLUSION: Dalfampridine benefits timed ambulation but not cognition. Some improvement among ambulation "responders" is consistent with prior reports of cognition-motor coupling in MS ( ClinicalTrials.gov #: NCT02006160).

Trait Conscientiousness predicts rate of longitudinal SDMT decline in multiple sclerosis.

BACKGROUND: Many people with multiple sclerosis (MS) exhibit cognitive decline over several years. Baseline differences may put people at greater risk for such decline. OBJECTIVE: To characterize rates of longitudinal cognitive decline and investigate baseline clinical predictors. METHODS: We report a retrospective analysis of 531 MS patients whose data were gleaned from a multi-study database, aggregated over 16 years. Linear mixed effects modeling was applied to estimate the average rate of decline on Symbol Digit Modalities Test (SDMT) performance and to predict rates of decline using baseline clinical variables. RESULTS: Participants exhibited an average estimated decline of 0.22 SDMT raw-score points/year (95% confidence interval (CI) (-0.32, -0.12)). We observed a significant main effect of time from baseline (t = -2.78, p = 0.006), test form (t = 2.13, p = 0.034), disease course (t = 2.91, p = 0.004), age (t = -2.76, p = 0.006), sex (t = -2.71, p = 0.007), subjective cognitive impairment (t = -2.00, p = 0.046), premorbid verbal intelligence (t = 5.14, p < 0.001), and trait Conscientiousness (t = 2.69, p = 0.008). A significant interaction emerged for Conscientiousness and time from baseline (t = 2.57, p = 0.011). CONCLUSION: Higher baseline trait Conscientiousness predicts slower rates of longitudinal cognitive decline in MS. This relationship, the average rate of decline, and practice effects can inform future research and clinical treatment decisions.