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 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.

Functional alteration due to structural damage is network dependent: insight from multiple sclerosis.

Little is known about how the brain's functional organization changes over time with respect to structural damage. Using multiple sclerosis as a model of structural damage, we assessed how much functional connectivity (FC) changed within and between preselected resting-state networks (RSNs) in 122 subjects (72 with multiple sclerosis and 50 healthy controls). We acquired the structural, diffusion, and functional MRI to compute functional connectomes and structural disconnectivity profiles. Change in FC was calculated by comparing each multiple sclerosis participant's pairwise FC to controls, while structural disruption (SD) was computed from abnormalities in diffusion MRI via the Network Modification tool. We used an ordinary least squares regression to predict the change in FC from SD for 9 common RSNs. We found clear differences in how RSNs functionally respond to structural damage, namely that higher-order networks were more likely to experience changes in FC in response to structural damage (default mode R2 = 0.160-0.207, P < 0.001) than lower-order sensory networks (visual network 1 R2 = 0.001-0.007, P = 0.157-0.387). Our findings suggest that functional adaptability to structural damage depends on how involved the affected network is in higher-order processing.

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.

Thalamic Nuclei Volumes and Their Relationships to Neuroperformance in Multiple Sclerosis: A Cross-Sectional Structural MRI Study.

BACKGROUND: Although reduced thalamic volume is associated with multiple sclerosis (MS)-related clinical impairment, the role of individual thalamic nuclei remains poorly understood. PURPOSE/HYPOTHESIS: To test whether individual thalamic nuclei volumes are more strongly associated with clinical disability than the whole thalamic volume. STUDY TYPE: Retrospective analysis of a prospective dataset. SUBJECTS: A total of 108 MS patients and 48 age- and sex-matched healthy controls (HCs) FIELD STRENGTH: 3T. SEQUENCES: 3D T1 -weighted inversion recovery spoiled gradient echo; 2D T2 -weighted fluid-attenuated inversion recovery spin echo; 2D dual-echo proton density-weighted/T2 -weighted spin echo. ASSESSMENTS: Clinical assessments included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMTR), and the California Verbal Learning Test (CVLT2). FreeSurfer provided anterior, intralaminar, lateral, medial, ventral, posterior, and total volumes. STATISTICAL TESTS: False discovery rate-corrected partial correlations (controlling for age, sex, and education) to assess the relationships between volumes and neuroperformance. RESULTS: Compared to HCs, MS patients presented with lower thalamic nuclei volumes (P < 0.05) except for the intralaminar nucleus (P = 0.279) and scored worse on all neuroperformance scales (P ≤ 0.05) except for CVLT2 (P = 0.151). All nuclei except intralaminar were associated with EDSS (correlation coefficient range: -0.233 to -0.395), SDMT (range: 0.247-0.423), and 9HPT (range: -0.232 to -0.303) (all P < 0.05). BVMTR was associated with anterior (r = 0.319), lateral (r = 0.31), and medial (r = 0.304) volumes (all P < 0.05). T25FW correlated with ventral (r = -0.392) and total (r = -0.309) volumes (both P < 0.05), with the latter being significantly greater (P < 0.05). DATA CONCLUSION: Assessing individual nuclei volume can aid in unraveling the relationship between thalamic pathology and disparate aspects of MS-related disability. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

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.

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.

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.

Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study.

BACKGROUND: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS). OBJECTIVE: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs). MATERIALS: One hundred twenty-seven PwMS (85 relapsing-remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years. sNfL levels were measured using the single-molecule array (Simoa) assay and quantified in picograms per milliliter. Expanded Disability Status Scale (EDSS), walking, and manual dexterity tests were obtained. At follow-up, Brief International Cognitive Assessment for MS (BICAMS) was utilized. Cognitively impaired (CI) status was derived using HC-based z-scores. Age-, sex-, and education-adjusted analysis of covariance (ANCOVA) and regression models were used. Multiple comparison-adjusted values of q < 0.05 were considered significant. RESULTS: In PwMS, sNfL levels were cross-sectionally associated with walking speed (r = 0.235, q = 0.036), manual dexterity (r = 0.337, q = 0.002), and cognitive processing speed (CPS; r =-0.265, q = 0.012). Baseline sNfL levels predicted 5-year EDSS scores (r = 0.25, q = 0.012), dexterity (r = 0.224, q = 0.033), and CPS (r =-0.205, q = 0.049). CI patients had higher sNfL levels (27.2 vs. 20.6, p = 0.016) and greater absolute longitudinal sNfL increase when compared with non-CI patients (4.8 vs. 0.7, p = 0.04). CONCLUSION: Higher sNfL levels are associated with poorer current and future clinical and cognitive performance.

Trait Conscientiousness predicts rate of brain atrophy in multiple sclerosis.

BACKGROUND: Conscientiousness is a core personality trait with favorable prognosis in neuropsychiatric disease. OBJECTIVE: We aimed to determine whether baseline Conscientiousness predicts future brain atrophy in multiple sclerosis (MS) after accounting for demographic and basic clinical characteristics. METHODS: Trait Conscientiousness, clinical features, and Expanded Disability Status Scale (EDSS) were obtained at baseline. Lateral ventricle volume (LVV) was measured longitudinally. In a retrospective general linear mixed effects model, data from 424 patients were analyzed (mean 6 time-points, up to 15 years). RESULTS/CONCLUSION: We observed significant age and Conscientiousness by time-from-baseline interactions indicating that younger age and higher Conscientiousness are associated with reduced progression of brain atrophy.

Preserved network functional connectivity underlies cognitive reserve in multiple sclerosis.

Cognitive reserve is one's mental resilience or resistance to the effects of structural brain damage. Reserve effects are well established in people with multiple sclerosis (PwMS) and Alzheimer's disease, but the neural basis of this phenomenon is unclear. We aimed to investigate whether preservation of functional connectivity explains cognitive reserve. Seventy-four PwMS and 29 HCs underwent neuropsychological assessment and 3 T MRI. Structural damage measures included gray matter (GM) atrophy and network white matter (WM) tract disruption between pairs of GM regions. Resting-state functional connectivity was also assessed. PwMS exhibited significantly impaired cognitive processing speed (t = 2.14, p = .037) and visual/spatial memory (t = 2.72, p = .008), and had significantly greater variance in functional connectivity relative to HCs within relevant networks (p < .001, p < .001, p = .016). Higher premorbid verbal intelligence, a proxy for cognitive reserve, predicted relative preservation of functional connectivity despite accumulation of GM atrophy (standardized-ß = .301, p = .021). Furthermore, preservation of functional connectivity attenuated the impact of structural network WM tract disruption on cognition (ß = -.513, p = .001, for cognitive processing speed; ß = -.209, p = .066, for visual/spatial memory). The data suggests that preserved functional connectivity explains cognitive reserve in PwMS, helping to maintain cognitive capacity despite structural damage.

White matter tract network disruption explains reduced conscientiousness in multiple sclerosis.

Quantifying white matter (WM) tract disruption in people with multiple sclerosis (PwMS) provides a novel means for investigating the relationship between defective network connectivity and clinical markers. PwMS exhibit perturbations in personality, where decreased Conscientiousness is particularly prominent. This trait deficit influences disease trajectory and functional outcomes such as work capacity. We aimed to identify patterns of WM tract disruption related to decreased Conscientiousness in PwMS. Personality assessment and brain MRI were obtained in 133 PwMS and 49 age- and sex-matched healthy controls (HC). Lesion maps were applied to determine the severity of WM tract disruption between pairs of gray matter regions. Next, the Network-Based-Statistics tool was applied to identify structural networks whose disruption negatively correlates with Conscientiousness. Finally, to determine whether these networks explain unique variance above conventional MRI measures and cognition, regression models were applied controlling for age, sex, brain volume, T2-lesion volume, and cognition. Relative to HCs, PwMS exhibited lower Conscientiousness and slowed cognitive processing speed (p = .025, p = .006). Lower Conscientiousness in PwMS was significantly associated with WM tract disruption between frontal, frontal-parietal, and frontal-cingulate pathways in the left (p = .02) and right (p = .01) hemisphere. The mean disruption of these pathways explained unique additive variance in Conscientiousness, after accounting for conventional MRI markers of pathology and cognition (ΔR2  = .049, p = .029). Damage to WM tracts between frontal, frontal-parietal, and frontal-cingulate cortical regions is significantly correlated with reduced Conscientiousness in PwMS. Tract disruption within these networks explains decreased Conscientiousness observed in PwMS as compared with HCs.

Brain MRI disease burden and sex differences in cognitive performance of patients with multiple sclerosis.

BACKGROUND: Although there is evidence that shows worse cognitive functioning in male patients with multiple sclerosis (MS), the role of brain pathology in this context is under-investigated. OBJECTIVE: To investigate sex differences in cognitive performance of MS patients, in the context of brain pathology and disease burden. METHODS: Brain MRI, neurological examination, neuropsychological assessment (Brief International Cognitive Assessment in MS-BICAMS, and Paced Auditory Verbal Learning Test-PASAT), and patient-reported outcome questionnaires were performed/administered in 1052 MS patients. RESULTS: Females had higher raw scores in the Symbol Digit Modalities Test (SDMT) (57.0 vs. 54.0; p < 0.001) and Categorical Verbal Learning Test (CVLT) (63.0 vs. 57.0; p < 0.001), but paradoxically, females evaluated their cognitive performance by MS Neuropsychological Questionnaire as being worse (16.6 vs 14.5, p = 0.004). Females had a trend for a weaker negative correlation between T2 lesion volume and SDMT ([Formula: see text] = - 0.37 in females vs. - 0.46 in men; interaction p = 0.038). On the other hand, women had a trend for a stronger correlation between Brain Parenchymal Fraction (BPF) and a visual memory test (Spearman's [Formula: see text] = 0.31 vs. 0.21; interaction p = 0.016). All these trends were not significant after correction for false discovery rate. CONCLUSIONS: Although, females consider their cognition as worse, males had at a group level slightly worse verbal memory and information processing speed. However, the sex differences in cognitive performance were smaller than the variability of scores within the same sex group. Brain MRI measures did not explain the sex differences in cognitive performance among MS patients.

Identifying and understanding cognitive profiles in multiple sclerosis: a role for visuospatial memory functioning.

BACKGROUND: The heterogeneous nature of cognitive impairment in people with multiple sclerosis (PwMS) hampers understanding of the underlying mechanisms and developing patient-tailored interventions. We aim to identify and classify cognitive profiles in PwMS, comparing these to cognitive status (preserved versus impaired). METHODS: We included 1213 PwMS (72% female, age 45.4 ± 10.7 years, 83% relapsing-remitting MS). Cognitive test scores were converted to Z-scores compared to healthy controls for the functions: attention, inhibition, information processing speed (IPS), verbal fluency and verbal/visuospatial memory. Concerning cognitive status, impaired cognition (CI) was defined as performing at Z ≤ - 1.5 SD on ≥ 2 functions. Cognitive profiles were constructed using latent profile analysis on all cognitive functions. Cognitive profiles or status was classified using gradient boosting decision trees, providing the importance of each feature (demographics, clinical, cognitive and psychological functioning) for the overall classification. RESULTS: Six profiles were identified, showing variations in overall performance and specific deficits (attention, inhibition, IPS, verbal fluency, verbal memory and visuospatial memory). Across the profiles, IPS was the most impaired function (%CI most preserved profile, Profile 1 = 22.4%; %CI most impaired profile, Profile 6 = 76.6%). Cognitive impairment varied from 11.8% in Profile 1 to 95.3% in Profile 6. Of all cognitive functions, visuospatial memory was most important in classifying profiles and IPS the least (area under the curve (AUC) = 0.910). For cognitive status, IPS was the most important classifier (AUC = 0.997). CONCLUSIONS: This study demonstrated that cognitive heterogeneity in MS reflects a continuum of cognitive severity, distinguishable by distinct cognitive profiles, primarily explained by variations in visuospatial memory functioning.

Clinical risk stratification: Development and validation of the DAAE score, a tool for estimating patient risk of transition to secondary progressive multiple sclerosis.

BACKGROUND: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years. METHODS: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting. RESULTS: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %). CONCLUSION: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation.

Thalamic atrophy and dysconnectivity are associated with cognitive impairment in a multi-center, clinical routine, real-word study of people with relapsing-remitting multiple sclerosis.

BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized ß = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized ß = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

Cortical thickness and cognition in older people with multiple sclerosis.

BACKGROUND: The structural changes associated with cognitive performance in older people with multiple sclerosis (PwMS; age ≥ 50 years old) remain unknown. OBJECTIVE: To determine the relationship between whole-brain (WBV), thalamus as the largest deep gray matter nuclei, and cortex-specific volume measurements with both cognitive impairment and numerical performance in older PwMS. The main hypothesis is that cognitive impairment (CI) in older PwMS is explained by cortical thinning in addition to global and thalamic neurodegenerative changes. METHODS: A total of 101 older PwMS underwent cognitive and neuroimaging assessment. Cognitive assessment included tests established as sensitive in MS samples (Minimal Assessment of Cognitive Function in MS; MACFIMS), as well as those tests often utilized in Alzheimer's dementia studies (Wechsler's Memory Scale, Boston Naming Test, Visual Motor Integration and language). Cognitive impairment (CI) was based on -1.5 standard deviations in at least 2 cognitive domains (executive function, learning and memory, spatial processing, processing speed and working memory and language) when compared to healthy controls. WBV and thalamic volume were calculated using SIENAX/FIRST and cortical thickness using FreeSurfer. Differences in cortical thickness between CI and cognitively preserved (CP) were determined using age, sex, education, depression and WBV-adjusted analysis of covariance (ANCOVA). The relationship between domain-specific cognitive performance and cortical thickness was analyzed by linear regression models adjusted for age, sex, education, depression, WBV and thalamic volume. Benjamini-Hochberg-adjusted p-values lower than 0.05 were considered significant. RESULTS: The average age of the study population was 62.6 (5.9) years old. After adjustment, CI PwMS had significantly thinner left fusiform (p = 0.0003), left inferior (p = 0.0032), left transverse (p = 0.0013), and bilateral superior temporal gyri (p = 0.002 and p = 0.0011) when compared to CP PwMS. After adjusting for age, sex, education, depression WBV, and thalamic volume, CI status was additionally predicted by the thickness of the left fusiform (p = 0.001) and left cuneus gyri (p = 0.004). After the adjustment, SDMT scores were additionally associated with left fusiform gyrus (p < 0.001) whereas letter-based verbal fluency performance with left pars opercularis gyrus (p < 0.001). CONCLUSION: In addition to global and thalamic neurodegenerative changes, the presence of CI in older PwMS is additionally explained by the thickness of multiple cortical regions.

MRI-based thalamic volumetry in multiple sclerosis using FSL-FIRST: Systematic assessment of common error modes.

BACKGROUND AND PURPOSE: FSL's FMRIB's Integrated Registration and Segmentation Tool (FSL-FIRST) is a widely used and well-validated tool. Automated thalamic segmentation is a common application and an important longitudinal measure for multiple sclerosis (MS). However, FSL-FIRST's algorithm is based on shape models derived from non-MS groups. As such, the present study sought to systematically assess common thalamic segmentation errors made by FSL-FIRST on MRIs from people with multiple sclerosis (PwMS). METHODS: FSL-FIRST was applied to generate thalamic segmentation masks for 890 MR images in PwMS. Images and masks were reviewed systematically to classify and quantify errors, as well as associated anatomical variations and MRI abnormalities. For cases with overt errors (n = 362), thalamic masks were corrected and quantitative volumetric differences were calculated. RESULTS: In the entire quantitative volumetric group, the mean volumetric error of FSL-FIRST was 2.74% (0.360 ml): among only corrected cases, the mean volumetric error was 6.79% (0.894 ml). The average percent volumetric error associated with seven error types, two anatomical variants, and motions artifacts are reported. Additional analyses showed that the presence of motion artifacts or anatomical variations significantly increased the probability of error (χ2  = 18.14, p < .01 and χ2  = 64.89, p < .001, respectively). Finally, thalamus volume error was negatively associated with degree of atrophy, such that smaller thalami were systematically overestimated (r = -.28, p < .001). CONCLUSIONS: In PwMS, FSL-FIRST thalamic segmentation miscalculates thalamic volumetry in a predictable fashion, and may be biased to overestimate highly atrophic thalami. As such, it is recommended that segmentations be reviewed and corrected manually when appropriate for specific studies.

Repeated forms, testing intervals, and SDMT performance in a large multiple sclerosis dataset.

BACKGROUND: The Symbol Digit Modalities Test (SDMT), the most reliable and sensitive measure of cognition in people with multiple sclerosis (PwMS), is increasingly used in clinical trials and care. OBJECTIVES: We aimed to establish how SDMT performance is influenced by repeating forms and frequency of use in PwMS. METHODS: A retrospective analysis was completed on a large database of PwMS (n = 740) with multiple SDMT administrations. Change in SDMT performance was analyzed, accounting for frequency of tests and utilization of alternate- versus same-form conditions. RESULTS: SDMT administrations ranged from 2 to 14 per subject over a mean (SD) of 5.9 (4.5) years. Accounting for demographics, the mixed effects model revealed a significant main effect of SDMT exposures (1.8 point improvement per repetition, p = 0.001) and an interaction between time since previous SDMT and whether the same test form was administered in the previous administration (estimate=-1.1, p = 0.037). As well, SDMT decline is observed when testing intervals exceed two years (F = 9.69, p<0.001). CONCLUSION: Improvements in SDMT performance with repeated exposure, likely reflecting practice effects, were greatest when repeating the same SDMT form over briefer intervals. We recommend the use of alternate forms or analogous versions of timed symbol-digit coding particularly where samples are saturated with many administrations.

Preliminary Support of a Behavioral Intervention for Trait Conscientiousness in Multiple Sclerosis.

Background: Conscientiousness, or the proclivity for deliberation, achievement, and order, declines in many individuals with multiple sclerosis (MS). Decreased conscientiousness predicts future cognitive deterioration, brain atrophy, and employment loss in individuals with MS. As a psychological trait, it may be an actionable antecedent to these important outcomes. We pilot tested an application (app)-facilitated behavioral intervention to help adaptation to low conscientiousness and, in turn, improve employment. Methods: Eleven individuals with MS (5 treatment, 6 control) with low conscientiousness were recruited for a 12-week randomized controlled trial. The treatment group received a newly developed behavioral treatment and smartphone app designed to help people behave more conscientiously, 2 teleconference booster sessions, and weekly telephone calls to monitor progress. Employment changes were recorded at baseline and follow-up. Patients provided detailed posttreatment interviews. Results: Participant groups were matched on baseline age, sex, education, disease duration, hours worked, and conscientiousness. All participants in the treatment arm reported benefits, found the app easy to use, and would recommend it to others. The treatment group reported significantly more positive work outcomes relative to controls at follow-up (P = .028). Other positive life changes were described by treatment participants during post-treatment interviews. Conclusions: These results support the hypothesis that behaviors typically associated with low conscientiousness may be addressed by behavioral therapy in the MS population. In addition to the positive employment changes in the treatment group, several other quality of life changes were described by study participants. Additional research is needed.