Neurology and therapy · 2025
Оценка когнитивных результатов в множестве склерозов: Реальное влияние Ozanimod на скорость обработки с использованием BICAMS.
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Zanghì Aurora, Di Filippo Paola Sofia, Avolio Carlo, D'Amico Emanuele
Аннотация
ВВЕДЕНИЕ: Когнитивная дисфункция представляет собой основное бремя множественного склероза (МС). Воздействие озанимодов на когнитивные результаты в реальных условиях еще предстоит выяснить в полной мере. МЕТОДЫ: В ходе исследования, проведенного в одном центре наблюдения, мы провели оценку когнитивных показателей у 67 пациентов, у которых MS (74,6% женщин) получают озанимод (менее продолжительность лечения 17,7 ± 3,0 месяца). Когнитивная оценка проводилась с использованием краткой международной когнитивной оценки аккумулятора с множественным склерозом (BICAMS), включавшего испытание с использованием символического дигитационного метода (SDMT), испытание на боковое обучение в Калифорнии (CVLT-II) и короткую проверку пространственной памяти (BVMT-R), собранную в различные моменты времени.Результаты: Анализ свидетельствует о значительном улучшении показателей SDMT Z (среднее улучшение 0,337, SD 0.638; Cohen's d = 0,42, p = 0,00031). Базовый Z-score SDMT стал единственным значительным предсказателем когнитивных изменений (коэффициент - 0,345, p < 0,001), на который приходится 32,4% разницы. Показатели CVLT-II и BVMT-R оставались стабильными во всех временных точках. ВЫВОДЫ: Это исследование, проведенное в реальных условиях, свидетельствует о том, что лечение озанимодов связано со значительным повышением скорости обработки информации, независимо от традиционных прогнозируемых факторов. Эти выводы дополняют существующие данные клинических испытаний и требуют дальнейшего изучения в рамках более широких, многоцентровых исследований с более длительными сроками последующей деятельности для подтверждения этих когнитивных преимуществ.
Оригинал публикации
Evaluating Cognitive Outcomes in Multiple Sclerosis: Real-World Impact of Ozanimod on Processing Speed Using BICAMS.
INTRODUCTION: Cognitive dysfunction represents a major burden in multiple sclerosis (MS). The impact on cognitive outcomes of ozanimod in real-world settings remains to be fully elucidated.
METHODS: In this single-center observational study, we evaluated cognitive performance in 67 patients with MS (74.6% female) receiving ozanimod (mean treatment duration 17.7 ± 3.0 months). Cognitive assessment was performed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, comprising Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and Brief Visuospatial Memory Test-Revised (BVMT-R) collected at different time points.
RESULTS: Analysis suggested significant improvement in SDMT Z-scores (mean improvement 0.337, SD 0.638; Cohen's d = 0.42, p = 0.00031). Baseline SDMT Z-score emerged as the sole significant predictor of cognitive change (coefficient - 0.345, p < 0.001), accounting for 32.4% of variance. CVLT-II and BVMT-R scores remained stable across time points.
CONCLUSIONS: This real-world study suggests that ozanimod treatment is associated with significant improvement in information processing speed, independent of traditional prognostic factors. These findings complement existing clinical trial data and warrant further investigation through larger, multicenter studies with extended follow-up periods to validate these cognitive benefits.
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Key Summary Points
Why
carry
out
the
study? The study evaluated the real-world impact of ozanimod on cognitive function, particularly processing speed, in patients with relapsing–remitting multiple sclerosis (RRMS). What
was
learned
from
the
study? The primary outcome was the change in cognitive function, specifically processing speed, as measured by the Symbol Digit Modalities Test (SDMT) component of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). The analysis revealed a significant improvement in SDMT Z-scores from baseline to follow-up assessments, suggesting a meaningful cognitive benefit in the majority of treated patients with MS.
Introduction
Cognitive impairment is a prevalent and debilitating aspect of multiple sclerosis (MS), affecting approximately 40–70% of patients during the course of the disease [ 1 , 2 ]. It encompasses deficits in processing speed, memory, attention, and executive function, significantly impacting patients’ quality of life, employment status, and social interactions [ 3 ]. Additionally, many studies have tried to examine the efficacy of cognitive rehabilitation in MS, although few effective cognitive rehabilitation programs for individuals with MS have been identified [ 2 , 4 ]. Insufficient evidence is currently available to support pharmacological approaches for treating cognitive impairment in patients with MS [ 2 , 4 ].
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has emerged as a validated screening tool for cognitive impairment in patients with MS, comprising three tests: the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R) [ 5 , 6 ].
Among the BICAMS measures, the SDMT has demonstrated significant sensitivity in detecting cognitive dysfunction in patients with MS [ 7 ]. It is considered a comprehensive measure of general cognition, rather than solely a test of information processing speed [ 8 , 9 ]. The SDMT is frequently utilized as an outcome measure in clinical trials due to its minimal ceiling effects, robust test–retest reliability, and the availability of alternate forms that reduce practice effects [ 10 ].
Ozanimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, has revealed efficacy in controlling disease activity in relapsing remitting MS (RRMS) through pivotal clinical trials [ 11 – 13 ]. The drug’s mechanism of action, involving modulation of S1P1 and S1P5 receptors, suggests potential neuroprotective effects beyond its established anti-inflammatory properties [ 14 ]. Despite the promising results from clinical trials, there is a paucity of real-world data on the cognitive outcomes associated with ozanimod treatment, particularly as measured by comprehensive cognitive batteries like BICAMS. Notably, the SDMT was employed as an endpoint in the SUNBEAM trial and its open-label extension study [ 15 , 18 , 19 ]. Participants in the ozanimod group were significantly more likely to achieve an 8-point improvement in SDMT scores at SUNBEAM month 12 (SUN-M12) compared to the interferon group [ 15 ]. Upon switching interferon-treated participants to ozanimod, statistical differences between groups were no longer observed [ 15 ]. After both SUNBEAM and the open-label extension (6–7 years total), the continuous-ozanimod group maintained a numerically higher proportion of participants with an 8-point improvement [ 15 ].
This single-center study aims to evaluate changes in cognitive function in patients with RRMS receiving ozanimod in routine clinical practice, with particular attention to processing speed as measured by the SDMT component of BICAMS. By analyzing real-world data, this investigation aims to establish cognitive outcomes as potential therapeutic targets, providing insights into a treat-to-target approach for optimizing treatment strategies in MS clinical practice.
Methods
Study Setting and Design
A real-world monocentric cohort study conducted at University of Foggia, Italy. Data were extracted from electronic health records and patients were followed up regularly to assess cognitive outcomes. Data were collected prospectively at routine clinic visits, and data were then collected retrospectively by chart review for this study. The data entry portal was iMed© software’s (iMed, Geneva, Switzerland).
Participants
The study included patients with a confirmed diagnosis of RRMS according to revised McDonald criteria [ 16 ], who initiated ozanimod therapy from October 2022 to October 2024. Inclusion criteria were: age > 18 years, who actively attended the center and scheduled visits during the study period.
Exclusion criteria included other neurological or psychiatric disorders that could affect cognitive function.
Outcomes
The primary outcome of the study was the change in cognitive function, specifically processing speed, as measured by the SDMT component of the BICAMS. Secondary outcomes included changes in verbal memory and visuospatial memory, assessed by the California Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test-Revised (BVMT-R), respectively. These outcomes were evaluated at baseline and during regular follow-up visits as part of routine clinical care.
Time 0 was the first BICAMS available within 3 months before therapy start, and Time 1 and Time 2 were evaluations each carried out within a range from 6 to 9 months from the previous one.
Covariate Definition
Covariates considered in the analysis included age, sex, disease duration, baseline Expanded Disability Status Scale (EDSS) score, prior disease-modifying therapy (DMT) use, baseline magnetic resonance imaging (MRI), and baseline cognitive scores and longitudinal cognitive scores. A cerebral MRI acquired within 90 days before the treatment start was considered the baseline MRI.
These covariates were selected based on their potential influence on cognitive outcomes in multiple sclerosis and were extracted from electronic health records at baseline.
A trained neuropsychologist conducted the BICAMS assessments. EDSS was performed by neurologist (A.Z., E.D. with neurostatus certification https://www.neurostatus.net ).
Statistical Analysis
Descriptive statistics were used to summarize baseline characteristics of the study population. Changes in cognitive outcomes from baseline to follow-up were analyzed using paired t tests for normally distributed data or Wilcoxon signed-rank tests for non-normally distributed data. Post hoc comparison was done with Bonferroni test. Cohen’s d was employed to assess the effect sizes of these differences across various time points. Cohen’s d is a statistical measure used to quantify the effect size, or the standardized difference between two means. The strength of agreement was interpreted according to Landis and Koch benchmarks [ 17 ], where κ values are categorized as follows: poor ( κ < 0.00), slight ( κ 0.00–0.20), fair ( κ 0.21–0.40), moderate ( κ 0.41–0.60), substantial ( κ 0.61–0.80), and almost perfect ( κ 0.81–1.00).
A multiple linear regression model was employed to assess the impact of various clinical and demographic factors on changes in SDMT z -scores from baseline to follow-up. The dependent variable was the change in SDMT Z -score, while independent variables included age (continuous variable), sex (as categorical, 0 = male, 1 = female), disease duration: continuous variable (years), previous DMTs (continuous variable, number), EDSS at baseline (ordinal), relapses in previous 12 months (continuous variable, number), baseline MRI activity (categorical variable, 0 = no, 1 = yes), baseline SDMT Z-score.
The model’s goodness-of-fit was evaluated using the R -squared and adjusted R -squared values.
Statistical significance was set at a p value of < 0.05. The statistical analysis was conducted using Python 3.8 with the pandas and statsmodels libraries.
Ethical approval
The study protocol was approved by the local ethics committee (Comitato Etico Bari). All patients signed a written informed consent to participate in the study. The current report does not contain any individual or identifying information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
Results
A total cohort of 67 patients, 50 (74.6%) female, was enrolled. Mean time on ozanimod was 17.7 ± 3.0 months. Baseline characteristics are shown in Table 1 .
Table 1 Baseline demographics and clinical characteristics Demographics All cohort ( n = 67) Sex, female, n (%) 50 (74.6%) Age, years, mean ± SD 47.8 ± 11.1 Patients with comorbidities, n (%) 29 (43.3%) Disease characteristics Lag time, years, median (IQR) 1.0 (0.3–3.1) Disease duration, years, median (IQR) 13.5 (7.1–21.8) Baseline EDSS , median (IQR) 2.5 (2.0–4.0) Patients naive to DMTs 7 (10.4%) No. of previous DMTs, mean ± SD 1.9 ± 1.2 Patients with relapses in previous 24 months before ozanimod prescription, n (%) 35 (52.2%) Patients with Gadolinium enhancing lesions within 12 months before ozanimod prescription, n (%) 11 (16.4%) Time on treatment, months, mean ± SD 17.7 ± 9.0 DMTs disease modifying therapies, EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, IQR interquartile range, n number, SD standard deviation
Baseline demographics and clinical characteristics
DMTs disease modifying therapies, EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, IQR interquartile range, n number, SD standard deviation
Table 2 shows BICAMS scores for investigated timings (0, 1, 2) in our cohort.
Table 2 Cognitive test scores over time Test Metric T0 Mean ± SD T1 Mean ± SD T2 Mean ± SD Effect size (Cohen’s d ) p value a p value b Overall p SDMT Raw score 44.8 ± 12.7 49.2 ± 12.2 49.2 ± 12.1 0.35 Z -score − 0.6 ± 1.1 − 0.1 ± 1.1 − 0.1 ± 1 0.42 0.0143* 0.0125* 0.0003* BVMT-R Raw score 21.5 ± 7.6 23.5 ± 7.3 23.5 ± 7.3 0.26 Z -score − 0.3 ± 0.9 − 0.1 ± 0.9 − 0.1 ± 0.9 0.17 0.6155 0.6014 0.1926 CVLT-II Raw score 45.2 ± 10.1 47.4 ± 8.5 45.2 ± 10 0.00 Z -score − 0.3 ± 1.1 − 0.1 ± 0.9 − 0.3 ± 1 0.01 1.00 1.00 0.9490 Effect sizes calculated using Cohen’s d between T0 and T2 SDMT Symbol Digit Modalities Test, BVMT-R Brief Visuospatial Memory Test-Revised, CVLT-II California Verbal Learning Test-II, SD standard deviation a p values for pairwise comparisons: T1 with T0, Bonferroni corrected b p values for pairwise comparisons: T2 with T0, Bonferroni corrected *Statistically significant
Cognitive test scores over time
Effect sizes calculated using Cohen’s d between T0 and T2
SDMT Symbol Digit Modalities Test, BVMT-R Brief Visuospatial Memory Test-Revised, CVLT-II California Verbal Learning Test-II, SD standard deviation
a p values for pairwise comparisons: T1 with T0, Bonferroni corrected
b p values for pairwise comparisons: T2 with T0, Bonferroni corrected
*Statistically significant
The analysis indicates a significant improvement in SDMT Z -scores from Time 0 to Time 1, with a moderate effect size (Cohen’s d = 0.42) and a statistically significant t test result ( p overall= 0.0003) (Fig. 1 ).
Violin plots representing BICAMS Z-scores at different time points. BVMT-R brief visuospatial memory test-revised, CVLT-II California Verbal Learning Test-II, SDMT symbol digit modalities, T0 Time 0, T1 Time 1, T2 Time 2
The mean improvement in SDMT z -scores was 0.34 (SD 0.64), with improvements ranging from − 1.04 to 1.89, suggesting a meaningful cognitive benefit in the majority of treated patients.
The CVLT-II and BVMT-R tests showed minimal changes across time points.
The multiple linear regression analysis revealed that the baseline SDMT Z- score was a significant predictor of changes in SDMT Z -scores, with a coefficient of − 0.345 ( p < 0.001) (see Table 3 ). The model explained 32.4% of the variance in SDMT change ( R -squared = 0.324, adjusted R -squared = 0.287). None of the other variables (age, sex, disease duration, number of previous DMTs, baseline EDSS, relapses within 12 months from ozanimod prescription , and presence of Gadolinium enhancing lesions within 12 months from ozanimod prescription) were statistically significant predictors of SDMT change (Table 3 ).
Table 3 Multiple linear regression analysis results Variable Coefficient 95% CI Standard error p value Age − 0.015 (− 0.039, 0.009) 0.012 0.215 Sex (female) 0.234 (− 0.154, 0.622) 0.198 0.238 Disease duration − 0.021 (− 0.056, 0.014) 0.018 0.245 Previous DMTs ( n ) − 0.112 (− 0.283, 0.059) 0.087 0.198 Baseline EDSS − 0.089 (− 0.238, 0.060) 0.076 0.243 Relapses within 12 months from ozanimod prescription − 0.156 (− 0.419, 0.107) 0.134 0.245 MRI activity within 12 months from ozanimod prescription 0.078 (− 0.249, 0.405) 0.167 0.641 Baseline SDMT Z-score − 0.345 (− 0.519, − 0.171) 0.089 < 0.001* Dependent variable: change in SDMT Z -score from baseline to follow-up R -squared: 0.324, adjusted R -squared: 0.287 * F -statistic: 8.45 ( p < 0.001)
Multiple linear regression analysis results
Dependent variable: change in SDMT Z -score from baseline to follow-up
R -squared: 0.324, adjusted R -squared: 0.287
* F -statistic: 8.45 ( p < 0.001)
Discussion
Our analysis suggested that treatment with ozanimod is associated with significant improvement in cognitive performance as measured by SDMT, with 69.7% of patients showing improvement in SDMT scores. The mean improvement in SDMT z -scores was 0.34 (SD 0.64), with improvements ranging from − 1.04 to 1.89, suggesting a meaningful cognitive benefit in the majority of treated patients.
These findings complement, in a real-world setting, the cognitive outcomes reported in ozanimod’s pivotal trials [ 15 , 18 , 19 ]. In the phase 3 SUNBEAM, ozanimod-treated patients showed greater SDMT improvement than those receiving IFN β-1a: at 12 months, the least squares mean difference in SDMT Z-scores was 0.102 (95% CI, 0.031–0.174; p = 0.0051), with a higher proportion of ozanimod-treated patients achieving clinically meaningful improvement (35.6% vs 27.9%) [ 18 ]. Extension data from DAYBREAK further supported these findings, showing sustained cognitive stability in ozanimod-treated patients over 24 months [ 19 ].
Furthermore, the ENLIGHTEN phase 3 trial of ozanimod, designed to assess cognitive processing speed over three years, has reported preliminary data suggesting cognitive stability or improvement in treated patients, with nearly half of patients showing clinically meaningful improvement in SDMT performance at one year [ 20 ]. Similar findings have been observed with other S1P receptor modulators, such as fingolimod, where real-world studies have demonstrated cognitive benefits, particularly in information processing speed measured by SDMT, and siponimod [ 21 – 24 ].
Our analysis found no significant predictive factors for cognitive improvement, including age, disease duration, or baseline EDSS. This suggests that cognitive benefits might occur independently of these traditional prognostic factors, a finding that could have important implications for treatment selection in clinical practice.
Our study has several limitations that warrant consideration. The relatively small sample size and the monocentric nature limits statistical power for detecting subtle associations or subgroup effects. The single-center nature of our study may affect generalizability, and the absence of a control group makes it challenging to definitively attribute cognitive changes to ozanimod treatment versus natural variation or practice effects.
Additionally, the cognitive profile may have been influenced by concurrent conditions, such undiagnosed psychiatric comorbidities (e.g., mood disorders), well documented in the MS population, which could have negatively impacted cognitive performance [ 25 , 26 ]. Moreover, disease heterogeneity and concurrent treatments were not explored in depth [ 27 , 28 ]. Additionally, longer follow-up periods would be valuable to assess the durability of cognitive improvements.
These limitations notwithstanding, our findings contribute to real-world evidence supporting potential cognitive benefits with ozanimod treatment in MS. The alignment of our results with both clinical trial data and emerging real-world evidence strengthens their validity and clinical relevance.
Conclusions
Future research should focus on larger, multicenter studies with longer follow-up periods to further characterize the cognitive benefits of ozanimod and identify any patient subgroups who might derive particular benefit from this treatment approach.
Acknowledgements
Contributors: Martina Iorio collaborate for data acquisition.
Author Contributions
Aurora Zanghì: conceptualization, data curation, formal analysis, writing-draft. Paola Sofia Di Filippo: conceptualization, data curation; Carlo Avolio: conceptualization, data curation. Emanuele D’Amico conceptualization, data curation, visualization, supervision, writing, original draft.
Funding
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors. The researchers were independent from funders and sponsors. All researchers could access all the data.
Data Availability
Anonymised data will be shared upon request from any qualified investigator for the sole purpose of replicating procedures and results presented in the report provided that data transfer is in agreement with EU legislation on the general data protection regulation.
Declarations
Conflict of interest
Aurora Zanghì has nothing to disclose related to the submitted manuscript. Paola Sofia Di Filippo has nothing to disclose related to the submitted manuscript. Carlo Avolio has nothing to disclose related to the submitted manuscript. Emanuele D’Amico has nothing to disclose related to the submitted manuscript.
Ethical Approval
The study protocol was approved by the local ethics committee (Comitato Etico Bari). All patients signed a written informed consent to participate in the study. The current report does not contain any individual or identifying information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
References
Associated Data
Data Availability Statement
Anonymised data will be shared upon request from any qualified investigator for the sole purpose of replicating procedures and results presented in the report provided that data transfer is in agreement with EU legislation on the general data protection regulation.
Why
carry
out
the
study? The study evaluated the real-world impact of ozanimod on cognitive function, particularly processing speed, in patients with relapsing–remitting multiple sclerosis (RRMS). What
was
learned
from
the
study? The primary outcome was the change in cognitive function, specifically processing speed, as measured by the Symbol Digit Modalities Test (SDMT) component of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). The analysis revealed a significant improvement in SDMT Z-scores from baseline to follow-up assessments, suggesting a meaningful cognitive benefit in the majority of treated patients with MS.
Introduction
Cognitive impairment is a prevalent and debilitating aspect of multiple sclerosis (MS), affecting approximately 40–70% of patients during the course of the disease [ 1 , 2 ]. It encompasses deficits in processing speed, memory, attention, and executive function, significantly impacting patients’ quality of life, employment status, and social interactions [ 3 ]. Additionally, many studies have tried to examine the efficacy of cognitive rehabilitation in MS, although few effective cognitive rehabilitation programs for individuals with MS have been identified [ 2 , 4 ]. Insufficient evidence is currently available to support pharmacological approaches for treating cognitive impairment in patients with MS [ 2 , 4 ].
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has emerged as a validated screening tool for cognitive impairment in patients with MS, comprising three tests: the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R) [ 5 , 6 ].
Among the BICAMS measures, the SDMT has demonstrated significant sensitivity in detecting cognitive dysfunction in patients with MS [ 7 ]. It is considered a comprehensive measure of general cognition, rather than solely a test of information processing speed [ 8 , 9 ]. The SDMT is frequently utilized as an outcome measure in clinical trials due to its minimal ceiling effects, robust test–retest reliability, and the availability of alternate forms that reduce practice effects [ 10 ].
Ozanimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, has revealed efficacy in controlling disease activity in relapsing remitting MS (RRMS) through pivotal clinical trials [ 11 – 13 ]. The drug’s mechanism of action, involving modulation of S1P1 and S1P5 receptors, suggests potential neuroprotective effects beyond its established anti-inflammatory properties [ 14 ]. Despite the promising results from clinical trials, there is a paucity of real-world data on the cognitive outcomes associated with ozanimod treatment, particularly as measured by comprehensive cognitive batteries like BICAMS. Notably, the SDMT was employed as an endpoint in the SUNBEAM trial and its open-label extension study [ 15 , 18 , 19 ]. Participants in the ozanimod group were significantly more likely to achieve an 8-point improvement in SDMT scores at SUNBEAM month 12 (SUN-M12) compared to the interferon group [ 15 ]. Upon switching interferon-treated participants to ozanimod, statistical differences between groups were no longer observed [ 15 ]. After both SUNBEAM and the open-label extension (6–7 years total), the continuous-ozanimod group maintained a numerically higher proportion of participants with an 8-point improvement [ 15 ].
This single-center study aims to evaluate changes in cognitive function in patients with RRMS receiving ozanimod in routine clinical practice, with particular attention to processing speed as measured by the SDMT component of BICAMS. By analyzing real-world data, this investigation aims to establish cognitive outcomes as potential therapeutic targets, providing insights into a treat-to-target approach for optimizing treatment strategies in MS clinical practice.
Methods
Study Setting and Design
A real-world monocentric cohort study conducted at University of Foggia, Italy. Data were extracted from electronic health records and patients were followed up regularly to assess cognitive outcomes. Data were collected prospectively at routine clinic visits, and data were then collected retrospectively by chart review for this study. The data entry portal was iMed© software’s (iMed, Geneva, Switzerland).
Participants
The study included patients with a confirmed diagnosis of RRMS according to revised McDonald criteria [ 16 ], who initiated ozanimod therapy from October 2022 to October 2024. Inclusion criteria were: age > 18 years, who actively attended the center and scheduled visits during the study period.
Exclusion criteria included other neurological or psychiatric disorders that could affect cognitive function.
Outcomes
The primary outcome of the study was the change in cognitive function, specifically processing speed, as measured by the SDMT component of the BICAMS. Secondary outcomes included changes in verbal memory and visuospatial memory, assessed by the California Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test-Revised (BVMT-R), respectively. These outcomes were evaluated at baseline and during regular follow-up visits as part of routine clinical care.
Time 0 was the first BICAMS available within 3 months before therapy start, and Time 1 and Time 2 were evaluations each carried out within a range from 6 to 9 months from the previous one.
Covariate Definition
Covariates considered in the analysis included age, sex, disease duration, baseline Expanded Disability Status Scale (EDSS) score, prior disease-modifying therapy (DMT) use, baseline magnetic resonance imaging (MRI), and baseline cognitive scores and longitudinal cognitive scores. A cerebral MRI acquired within 90 days before the treatment start was considered the baseline MRI.
These covariates were selected based on their potential influence on cognitive outcomes in multiple sclerosis and were extracted from electronic health records at baseline.
A trained neuropsychologist conducted the BICAMS assessments. EDSS was performed by neurologist (A.Z., E.D. with neurostatus certification https://www.neurostatus.net ).
Statistical Analysis
Descriptive statistics were used to summarize baseline characteristics of the study population. Changes in cognitive outcomes from baseline to follow-up were analyzed using paired t tests for normally distributed data or Wilcoxon signed-rank tests for non-normally distributed data. Post hoc comparison was done with Bonferroni test. Cohen’s d was employed to assess the effect sizes of these differences across various time points. Cohen’s d is a statistical measure used to quantify the effect size, or the standardized difference between two means. The strength of agreement was interpreted according to Landis and Koch benchmarks [ 17 ], where κ values are categorized as follows: poor ( κ < 0.00), slight ( κ 0.00–0.20), fair ( κ 0.21–0.40), moderate ( κ 0.41–0.60), substantial ( κ 0.61–0.80), and almost perfect ( κ 0.81–1.00).
A multiple linear regression model was employed to assess the impact of various clinical and demographic factors on changes in SDMT z -scores from baseline to follow-up. The dependent variable was the change in SDMT Z -score, while independent variables included age (continuous variable), sex (as categorical, 0 = male, 1 = female), disease duration: continuous variable (years), previous DMTs (continuous variable, number), EDSS at baseline (ordinal), relapses in previous 12 months (continuous variable, number), baseline MRI activity (categorical variable, 0 = no, 1 = yes), baseline SDMT Z-score.
The model’s goodness-of-fit was evaluated using the R -squared and adjusted R -squared values.
Statistical significance was set at a p value of < 0.05. The statistical analysis was conducted using Python 3.8 with the pandas and statsmodels libraries.
Ethical approval
The study protocol was approved by the local ethics committee (Comitato Etico Bari). All patients signed a written informed consent to participate in the study. The current report does not contain any individual or identifying information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
Results
A total cohort of 67 patients, 50 (74.6%) female, was enrolled. Mean time on ozanimod was 17.7 ± 3.0 months. Baseline characteristics are shown in Table 1 .
Table 1 Baseline demographics and clinical characteristics Demographics All cohort ( n = 67) Sex, female, n (%) 50 (74.6%) Age, years, mean ± SD 47.8 ± 11.1 Patients with comorbidities, n (%) 29 (43.3%) Disease characteristics Lag time, years, median (IQR) 1.0 (0.3–3.1) Disease duration, years, median (IQR) 13.5 (7.1–21.8) Baseline EDSS , median (IQR) 2.5 (2.0–4.0) Patients naive to DMTs 7 (10.4%) No. of previous DMTs, mean ± SD 1.9 ± 1.2 Patients with relapses in previous 24 months before ozanimod prescription, n (%) 35 (52.2%) Patients with Gadolinium enhancing lesions within 12 months before ozanimod prescription, n (%) 11 (16.4%) Time on treatment, months, mean ± SD 17.7 ± 9.0 DMTs disease modifying therapies, EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, IQR interquartile range, n number, SD standard deviation
Baseline demographics and clinical characteristics
DMTs disease modifying therapies, EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, IQR interquartile range, n number, SD standard deviation
Table 2 shows BICAMS scores for investigated timings (0, 1, 2) in our cohort.
Table 2 Cognitive test scores over time Test Metric T0 Mean ± SD T1 Mean ± SD T2 Mean ± SD Effect size (Cohen’s d ) p value a p value b Overall p SDMT Raw score 44.8 ± 12.7 49.2 ± 12.2 49.2 ± 12.1 0.35 Z -score − 0.6 ± 1.1 − 0.1 ± 1.1 − 0.1 ± 1 0.42 0.0143* 0.0125* 0.0003* BVMT-R Raw score 21.5 ± 7.6 23.5 ± 7.3 23.5 ± 7.3 0.26 Z -score − 0.3 ± 0.9 − 0.1 ± 0.9 − 0.1 ± 0.9 0.17 0.6155 0.6014 0.1926 CVLT-II Raw score 45.2 ± 10.1 47.4 ± 8.5 45.2 ± 10 0.00 Z -score − 0.3 ± 1.1 − 0.1 ± 0.9 − 0.3 ± 1 0.01 1.00 1.00 0.9490 Effect sizes calculated using Cohen’s d between T0 and T2 SDMT Symbol Digit Modalities Test, BVMT-R Brief Visuospatial Memory Test-Revised, CVLT-II California Verbal Learning Test-II, SD standard deviation a p values for pairwise comparisons: T1 with T0, Bonferroni corrected b p values for pairwise comparisons: T2 with T0, Bonferroni corrected *Statistically significant
Cognitive test scores over time
Effect sizes calculated using Cohen’s d between T0 and T2
SDMT Symbol Digit Modalities Test, BVMT-R Brief Visuospatial Memory Test-Revised, CVLT-II California Verbal Learning Test-II, SD standard deviation
a p values for pairwise comparisons: T1 with T0, Bonferroni corrected
b p values for pairwise comparisons: T2 with T0, Bonferroni corrected
*Statistically significant
The analysis indicates a significant improvement in SDMT Z -scores from Time 0 to Time 1, with a moderate effect size (Cohen’s d = 0.42) and a statistically significant t test result ( p overall= 0.0003) (Fig. 1 ).
Violin plots representing BICAMS Z-scores at different time points. BVMT-R brief visuospatial memory test-revised, CVLT-II California Verbal Learning Test-II, SDMT symbol digit modalities, T0 Time 0, T1 Time 1, T2 Time 2
The mean improvement in SDMT z -scores was 0.34 (SD 0.64), with improvements ranging from − 1.04 to 1.89, suggesting a meaningful cognitive benefit in the majority of treated patients.
The CVLT-II and BVMT-R tests showed minimal changes across time points.
The multiple linear regression analysis revealed that the baseline SDMT Z- score was a significant predictor of changes in SDMT Z -scores, with a coefficient of − 0.345 ( p < 0.001) (see Table 3 ). The model explained 32.4% of the variance in SDMT change ( R -squared = 0.324, adjusted R -squared = 0.287). None of the other variables (age, sex, disease duration, number of previous DMTs, baseline EDSS, relapses within 12 months from ozanimod prescription , and presence of Gadolinium enhancing lesions within 12 months from ozanimod prescription) were statistically significant predictors of SDMT change (Table 3 ).
Table 3 Multiple linear regression analysis results Variable Coefficient 95% CI Standard error p value Age − 0.015 (− 0.039, 0.009) 0.012 0.215 Sex (female) 0.234 (− 0.154, 0.622) 0.198 0.238 Disease duration − 0.021 (− 0.056, 0.014) 0.018 0.245 Previous DMTs ( n ) − 0.112 (− 0.283, 0.059) 0.087 0.198 Baseline EDSS − 0.089 (− 0.238, 0.060) 0.076 0.243 Relapses within 12 months from ozanimod prescription − 0.156 (− 0.419, 0.107) 0.134 0.245 MRI activity within 12 months from ozanimod prescription 0.078 (− 0.249, 0.405) 0.167 0.641 Baseline SDMT Z-score − 0.345 (− 0.519, − 0.171) 0.089 < 0.001* Dependent variable: change in SDMT Z -score from baseline to follow-up R -squared: 0.324, adjusted R -squared: 0.287 * F -statistic: 8.45 ( p < 0.001)
Multiple linear regression analysis results
Dependent variable: change in SDMT Z -score from baseline to follow-up
R -squared: 0.324, adjusted R -squared: 0.287
* F -statistic: 8.45 ( p < 0.001)
Discussion
Our analysis suggested that treatment with ozanimod is associated with significant improvement in cognitive performance as measured by SDMT, with 69.7% of patients showing improvement in SDMT scores. The mean improvement in SDMT z -scores was 0.34 (SD 0.64), with improvements ranging from − 1.04 to 1.89, suggesting a meaningful cognitive benefit in the majority of treated patients.
These findings complement, in a real-world setting, the cognitive outcomes reported in ozanimod’s pivotal trials [ 15 , 18 , 19 ]. In the phase 3 SUNBEAM, ozanimod-treated patients showed greater SDMT improvement than those receiving IFN β-1a: at 12 months, the least squares mean difference in SDMT Z-scores was 0.102 (95% CI, 0.031–0.174; p = 0.0051), with a higher proportion of ozanimod-treated patients achieving clinically meaningful improvement (35.6% vs 27.9%) [ 18 ]. Extension data from DAYBREAK further supported these findings, showing sustained cognitive stability in ozanimod-treated patients over 24 months [ 19 ].
Furthermore, the ENLIGHTEN phase 3 trial of ozanimod, designed to assess cognitive processing speed over three years, has reported preliminary data suggesting cognitive stability or improvement in treated patients, with nearly half of patients showing clinically meaningful improvement in SDMT performance at one year [ 20 ]. Similar findings have been observed with other S1P receptor modulators, such as fingolimod, where real-world studies have demonstrated cognitive benefits, particularly in information processing speed measured by SDMT, and siponimod [ 21 – 24 ].
Our analysis found no significant predictive factors for cognitive improvement, including age, disease duration, or baseline EDSS. This suggests that cognitive benefits might occur independently of these traditional prognostic factors, a finding that could have important implications for treatment selection in clinical practice.
Our study has several limitations that warrant consideration. The relatively small sample size and the monocentric nature limits statistical power for detecting subtle associations or subgroup effects. The single-center nature of our study may affect generalizability, and the absence of a control group makes it challenging to definitively attribute cognitive changes to ozanimod treatment versus natural variation or practice effects.
Additionally, the cognitive profile may have been influenced by concurrent conditions, such undiagnosed psychiatric comorbidities (e.g., mood disorders), well documented in the MS population, which could have negatively impacted cognitive performance [ 25 , 26 ]. Moreover, disease heterogeneity and concurrent treatments were not explored in depth [ 27 , 28 ]. Additionally, longer follow-up periods would be valuable to assess the durability of cognitive improvements.
These limitations notwithstanding, our findings contribute to real-world evidence supporting potential cognitive benefits with ozanimod treatment in MS. The alignment of our results with both clinical trial data and emerging real-world evidence strengthens their validity and clinical relevance.
Conclusions
Future research should focus on larger, multicenter studies with longer follow-up periods to further characterize the cognitive benefits of ozanimod and identify any patient subgroups who might derive particular benefit from this treatment approach.
Acknowledgements
Contributors: Martina Iorio collaborate for data acquisition.
Author Contributions
Aurora Zanghì: conceptualization, data curation, formal analysis, writing-draft. Paola Sofia Di Filippo: conceptualization, data curation; Carlo Avolio: conceptualization, data curation. Emanuele D’Amico conceptualization, data curation, visualization, supervision, writing, original draft.
Funding
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors. The researchers were independent from funders and sponsors. All researchers could access all the data.
Data Availability
Anonymised data will be shared upon request from any qualified investigator for the sole purpose of replicating procedures and results presented in the report provided that data transfer is in agreement with EU legislation on the general data protection regulation.
Declarations
Conflict of interest
Aurora Zanghì has nothing to disclose related to the submitted manuscript. Paola Sofia Di Filippo has nothing to disclose related to the submitted manuscript. Carlo Avolio has nothing to disclose related to the submitted manuscript. Emanuele D’Amico has nothing to disclose related to the submitted manuscript.
Ethical Approval
The study protocol was approved by the local ethics committee (Comitato Etico Bari). All patients signed a written informed consent to participate in the study. The current report does not contain any individual or identifying information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
References
Associated Data
Data Availability Statement
Anonymised data will be shared upon request from any qualified investigator for the sole purpose of replicating procedures and results presented in the report provided that data transfer is in agreement with EU legislation on the general data protection regulation.