Serial Addition Research Articles

The symbol digit modalities test and the paced auditory serial addition test involve more than processing speed

BackgroundSlowed processing speed is the most frequently reported cognitive deficit for people with multiple sclerosis (MS). However, measures used to assess processing speed may also recruit other cognitive abilities. The present objective was to determine the contributions of different cognitive functions to performance on two commonly used processing speed measures: the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). MethodsAdults with relapsing-remitting MS (n = 70) and controls (n = 72) completed the SDMT, PASAT, and multiple measures assessing processing speed, working memory, and learning. Hierarchical regression analyses were used to examine the contributions of MS, processing speed, working memory, learning, and all possible interactions among factors to SDMT and PASAT scores. ResultsProcessing speed and working memory generally contributed to performance on the SDMT and PASAT, with learning additionally contributing to SDMT performance. However, significant interactions revealed processing speed did not influence PASAT performance for individuals with high working memory ability whereas processing speed became increasingly more important as working memory declined to average and low levels. Further, processing speed was associated with SDMT performance for patients with MS but not controls. ConclusionsThese findings support a multifactorial interpretation of the SDMT and PASAT, which facilitates their usefulness as screening measures for cognitive decline but prevents them from identifying which specific cognitive functions are affected.

An Exploratory Study on the Effect of Virtual Environments on Cognitive Performances and Psychophysiological Responses.

Research shows that reduced exposure to natural contexts is associated with an increase in psychophysical disorders. Recent evidence suggests that even a brief experience in natural scenarios can positively affect people's health and well-being. However, natural contexts are not always easily accessible. This study investigates the effects of natural and indoor virtual environments (VREs) on psychophysiological and cognitive responses. Following a within-subject design, 34 healthy participants were exposed to two VREs (i.e., a forest and a living room) in a counterbalanced order through a head-mounted display (Oculus Rift). Participants were asked to explore the scenarios and execute a modified version of the Paced Auditory Serial Addition Test. Physiological parameters (heart rate, skin conductance level [SCL], and respiration rate) were recorded during the whole session. After the exposure to VREs, participants filled a set of visual analog scales to rate their subjective experience of presence, relaxation, and stress. Participants reported a higher perceived sense of relaxation in the virtual forest. Moreover, their SCLs were significantly higher in this environment, showing that the forest elicited higher physiological arousal than the living room. Furthermore, their SCLs were significantly higher during the attentional task in the virtual living room. The results suggest that a natural virtual environment can make people feel more relaxed and physiologically engaged than an indoor scenario. The latter instead can be linked to a performing venue, as reported for real contexts. However, these changes were not related to modulations of attentional performance.

The neurocognitive implications of depression and socioeconomic status in people with HIV

ABSTRACT Objective This cross-sectional study investigates the independent and interactive effects of depression and socioeconomic status (SES) on neurocognition in a diverse sample of people with HIV (PWH). Method The sample of 119 PWH (71% Latinx, 27% female) completed comprehensive neurocognitive and psychosocial evaluations and were separated into two groups: those with a history of depression diagnosis (n = 47) and those without (n = 72). Results The results of regression analyses indicated that lifetime depression was not associated with lower SES nor with worse neurocognitive performance on any neurocognitive outcome. However, a significant main effect of SES was observed on the Hopkins Verbal Learning Test (total), indicating that higher SES was associated with better verbal learning performance (B= .11, SE = .05, p< .02). Lastly, the results revealed an interactive effect of lifetime depression and SES, such that individuals with depression and higher SES performed better on tests of attention/working memory (i.e., WAIS-III Letter-Number Sequencing, B= .08, SE = .04, p< .02; Paced Auditory Serial Addition Test, B= .39, SE = .16, p< .02). Conclusions Depression and SES appear to play an important role in the neurocognitive performance of PWH. Specifically, higher SES appears to have a protective effect on attention/working memory among PWH only if they have co-morbid history of lifetime depression.

Possible evidence of near transfer effects after adaptive working memory training in persons with multiple sclerosis

BackgroundCognitive deficits, especially in working memory (WM) and information processing (IP) efficiency, are common in people with multiple sclerosis (PwMS). Few studies have examined the efficacy of n-back training in improving these two cognitive functions in PwMS. In the present study, we examined the effects of an intensive n-back training program by measuring the gains on the trained task (2- and 3-back tasks), but we also studied possible near transfer effects to other tests that assess WM and IP, as well as far transfer effects or improvements in other cognitive functions. MethodsA sample consisting of 35 PwMS with different cognitive statuses. All the participants underwent an adaptive n-back training for 10 days (60 min/day), and they were neuropsychologically assessed at baseline (D1) and after training (D10). The effectiveness of the training was tested: (1) by using mean-based comparisons and Cohen's d values; (2) by estimating and comparing the quartile values of the D1 and D10 distributions. Two indexes of improvement in individual performance were calculated, the net score improvement index (NSI) and the percent of maximum possible individualized improvement (PMPI). ResultsRepeat practice improves 2- and 3-back performance, showing more correct responses (CR) and lower reaction times (RT) on D10 compared to D1. These results were corroborated by the NSI and PMPI scores, but the gains after training were more statistically significant for the 3-back (observing higher CR and lower RT after training) than for the 2-back (observing gains in CR, but not in RT). We also observed a possible transference of this improvement on the n-back task to other WM/IPS tests. Specifically, statistically significant pre-post training differences were found in the values in three quartiles of the Paced Auditory Serial Addition Test (PASAT; q25, p < 0.03; q50, p < 0.001; q75, p < 0.002) and of the Symbol Digit Modalities Test (SDMT; q25, p < 0.03; q50, p < 0.001; q75, p < 0.001) as well as in two quartiles of the Letter-Number Sequencing Task (LNST; q50, p < 0.004; q75 p < 0.001), and in one quartile of the Digit Backwards Span Test (DSBT; q75, p < 0.001). Reliable change analyses confirmed these performance improvements on the PASAT, SDMT, and LNST. ConclusionsThis study confirmed that the intensive and adaptive n-back training produced improvements in the trained task in PwMS with different cognitive statuses. Furthermore, these gains were not only observed on the trained task, but they seemed to be also transferred to other tests that measured WM and IP functions.

Improvement in the multiple sclerosis functional composite score by multi-function swing suspension training program

BackgroundPhysical activity has been considered as a promising approach to slow down the disease process in Multiple Sclerosis (MS) patients. The functional impairments of MS have been studied in detail, while evidence of the efficacy of exercise training interventions on the Multiple Sclerosis functional composite (MSFC) score in these patients is limited. The aim of this study was to investigate the improvement in MSFC score by multi-function swing suspension training program (MFSST) in the women with MS. MethodsThe patients were divided into two groups as the intervention and control groups. A total of 47 MS patients completed the MSFC components at baseline and after the intervention: the timed 25-foot walk (T25FW); the 9-hole peg test (9HPT); and paced auditory serial addition test (PASAT). Z scores were created for each test based on control means. ResultsThe MSFC score, 9HPT, T25FW, and PASAT showed a significant increment in comparison with the baseline levels in the four, six, and eight weeks following the first exercise session (all p<0.05). These differences in the control group were not significant. The improvement in the MSFC score and the component Z-scores in the intervention groups was found from the fourth week onwards. ConclusionsThe study findings highlight that the progression of MS disability can be partially compensated by physical exercise. Overall, these results indicate that MFSST can be used as an effective treatment method in patients suffering from MS. Longer (years) exercise studies with larger samples of MS patients, with different MS subtypes, and of different sex, are needed to evaluate the effect of other types of exercise interventions on the MSFC score in MS patients with different disabilities.

The impact of visual cross-modal conflict with semantic and nonsemantic distractors on working memory task: A functional near-infrared spectroscopy study.

Cross-modal conflicts arise when information from multisensory modalities is incongruent. Most previous studies investigating audiovisual cross-modal conflicts have focused on visual targets with auditory distractors, and only a few studies have focused on auditory targets with visual distractors. Moreover, no study has investigated the differences in the impact of visual cross-modal conflict with semantic and nonsemantic competition and its neural basis. This cross-sectional study aimed to characterize the impact of 2 types of visual cross-modal conflicts with semantic and nonsemantic distractors through a working memory task and associated brain activities. The participants were 33 healthy, right-handed, young male adults. The paced auditory serial addition test was performed under 3 conditions: no-distractor and 2 types of visual distractor conditions (nonsemantic and semantic distractor conditions). Symbols and numbers were used as nonsemantic and semantic distractors, respectively. The oxygenated hemoglobin (Oxy-Hb) concentration in the frontoparietal regions, bilateral ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex, and inferior parietal cortex (IPC) were measured during the task under each condition. The results showed significantly lower paced auditory serial addition test performances in both distractor conditions than in the no-distractor condition, but no significant difference between the 2 distractor conditions. For brain activity, a significantly increased Oxy-Hb concentration in the right VLPFC was only observed in the nonsemantic distractor condition (corrected P = .015; Cohen d = .46). The changes in Oxy-Hb in the bilateral IPC were positively correlated with changes in task performance for both types of visual cross-modal distractor conditions. Visual cross-modal conflict significantly impairs auditory working memory task performance, regardless of the presence of semantic or nonsemantic distractors. The right VLPFC may be a crucial region to inhibit visual nonsemantic information in cross-modal conflict situations, and bilateral IPC may be closely linked with the inhibition of visual cross-modal distractor, regardless of the presence of semantic or nonsemantic distractors.

The association between body mass index, demographic and clinical characteristics with cognitive performance in patients with neuromyelitis optica spectrum disorder.

Background: Cognitive dysfunction is one of the problems that patients with neuromyelitis optica spectrum disorder (NMOSD) suffer from. We aimed to assess the association between demographic and clinical features as well as body mass index (BMI) and cognitive function in patients with NMOSD. Methods: A cross-sectional study was performed on 41 patients with definite diagnosis of NMOSD. Serum status of neuromyelitis optica immunoglobulin G (NMO-IgG) was determined using enzyme-linked immunosorbent assay (ELISA) method. Cognitive function was assessed by Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery which is validated for Persian people before and North American Adult Reading Test (NAART). Results: The mean score of NAART test was higher in participants with normal weight compared with overweight patients (40.47 ± 3.51 vs. 36.00 ± 5.74, P = 0.02). Current age was negatively correlated with Delis-Kaplan Executive Function System (D-KEFS)-Sorting (P = 0.05, r = -0.30). The correlation of duration of disease and cognitive performance was not significant (P > 0.05). Higher physical disability based on Expanded Disability Status Scale (EDSS) was correlated with lower results in Brief Visuospatial Memory Test-Revised (BVMT-R) (P < 0.01, r = -0.50), California Verbal Learning Test-second edition (CVLT-II)-Delayed Recall (P = 0.02, r = -0.35), and Symbol Digit Modalities Test (SDMT) (P = 0.03, r = -0.33) subtests of MACFIMS. Annual relapse rate was indirectly correlated with CVLT-II (P = 0.03, r = -0.34) and CVLT-II-Delayed Recall (P = 0.01, r = -0.38). Male participants obtained better scores in Paced Auditory Serial Addition Test (PASAT) subtest (P = 0.05). NMO-IgG seropositive patients had poorer performance in terms of CVLT-II-Delayed Recall, Controlled Oral Word Association Test (COWAT), and D-KEFS-Descriptive (P < 0.05). Participants with bachelor and master education degrees showed significantly better results compared to those with high school degree (P < 0.05). Conclusion: Investigating the clinical and demographic factors affecting cognitive impairment can increase the awareness of health care providers for early diagnosis of cognitive impairment in patients with NMOSD and increase the quality of health services.

Cognitive assessment of Brazilian patients with multiple sclerosis: weighing the impact of disability and depressive symptoms.

The aim of this study was to compare the cognitive status of patients with MS with age, sex, and schooling matched controls and to evaluate the potential influence of clinical parameters on cognition. A total of 35 patients with MS (mean±SD age 37.9 years±11.44, M/F: 12/23) and 33 healthy controls (mean±SD age 38.8 years±12.6, M/F: 12/21) were enrolled in this study. All subjects underwent a structured clinical assessment and the cognitive tools are as follows: Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Rey Auditory Verbal Learning Test (RAVLT), Digit Span, and Verbal Fluency Tests (letters F, A, and S and animal category). Psychopathology was assessed with the Mini International Neuropsychiatric Interview and the Beck Depression Inventory (BDI). The Expanded Disability Status Scale (EDSS) was used for patients. Patients performed worse than controls in almost all tests, with approximately 70% of patients presenting cognitive impairment. The most affected cognitive domain was episodic memory (45.7%), followed by verbal fluency (42.8%) and information processing speed (22.8%). SDMT was inversely correlated with disease severity, as assessed by the EDSS. Depression did not influence cognitive performance in this cohort. Cognitive dysfunction is common among patients with MS. While motor impairment was associated with information processing speed, depression did not influence cognitive performance.

Menopausal symptoms and hormone therapy in women with multiple sclerosis: A baseline-controlled study

BackgroundDepression, sleep disturbances, and cognitive difficulties impair the quality of life in people with multiple sclerosis (MS). Similar symptoms are also frequent during the menopausal transition. In clinical practice, it is important to consider the multifactorial causes of these overlapping symptoms and the potential benefits of menopausal hormone therapy (MHT). The objective of this study was to evaluate vasomotor symptoms (VMS), mood, sleep, and cognition of menopausal women with and without MS at baseline and during one year of MHT. MethodsIn this prospective baseline-controlled study, peri- and early postmenopausal participants with (n=14) and without (n=13) MS received MHT containing 1 or 2 mg of estradiol and cyclical 10 mg dydrogesterone for one year. VMS frequency, depressive symptoms (measured by Beck Depression Inventory), insomnia severity (Insomnia Severity Index), and cognitive performance (Paced Auditory Serial Addition Test; PASAT, Symbol Digit Modalities Test; SDMT) were evaluated at baseline and at 3 and 12 months of treatment. Differences in the outcome measures between groups at baseline were assessed using the Mann-Whitney U test. Changes during follow-up compared to baseline within groups were evaluated by Wilcoxon Signed Ranks Test. P < 0.05 was considered for statistical significance. MS activity was monitored by clinical assessment and brain MRI at baseline and at 12 months. ResultsDepressive symptoms were more common in MS group, while vasomotor and insomnia symptoms were equally common. During follow-up with MHT, VMS frequency decreased in both groups. Depressive symptoms decreased at 3 months (p = 0.031 with MS; p = 0.024 without MS) and the reduction was sustained at 12 months (p = 0.017; p = 0.042, respectively). Alleviation in insomnia symptoms was seen in participants without MS at 3 months (p = 0.029) and in those participants with MS suffering insomnia at baseline (p = 0.016 at 3 months; p = 0.047 at 12 months). Both groups improved their performance in PASAT, but no significant change was observed in SDMT. MS activity at baseline was mainly stable, and no increase in activity was detected during MHT. ConclusionImprovements in vasomotor, depressive, and insomnia symptoms observed during one year of MHT are encouraging and suggest that larger placebo-controlled studies of MHT in women with MS are warranted. Cognitive implications were inconclusive because the findings in PASAT likely result from practice effect. MHT did not show any adverse effect on MS activity and increasing safety data will hopefully facilitate patient recruitment for future studies.

Combined progressive functional exercise effect on contactin-1 and contactin-2 level in mildly disabled persons with multiple sclerosis

BackgroundAlthough contactin-1 and contactin-2 are known as two proteins involved in axonal regeneration, it is unclear whether these proteins are induced by exercise in persons with multiple sclerosis (PwMS). ObjectiveThe aim of this study was to determine the serum levels of contactin-1 and contactin-2 in PwMS and to investigate the change of these markers with exercise. MethodsA total of 60 participants with relapsing-remitting MS were divided into groups by stratified randomization. The progressive functional exercise was applied to the intervention group. Participants in the control group continued the treatments and lives of the routines. Participants' contactin-1 and contactin-2, cognitive performance and aerobic capacities were evaluated. ResultsThe comparison of the pre-and post-study values of contactin-1 and contactin-2 showed significant differences only in the intervention group. The contactin-1 and contactin-2 values were similar between the groups before the exercise, whereas a significant difference was found in favor of the intervention group after the exercise. Paced Auditory Serial Addition Test-3 value increased significantly only in the intervention group. ConclusionWith this study, it was shown for the first time that contactin-1 and contactin-2, which play an important role in axonal regeneration and axonal organization, can be increased by exercise.

Evaluation of Stress and Cognition Indicators in a Puzzle Game: Neuropsychological, Biochemical and Electrophysiological Approaches.

Video games have significant and diverse effects on stress and cognitive systems based on the game style. The effect of this media on the central nervous system is significant because of its repetition. Nowadays, video games have become an important part of human life at different ages, and therefore, assessing their effects (good and bad) on stress factors, cognition, and behavior can be an important help in understanding the nature of these games and managing their impact on humans. Consequently, this study aimed to investigate the effect of a puzzle game on the player's stress and cognitive indicators in neuropsychological, biochemical, and electrophysiological approaches. A total of 44 participants were entered into the study and randomly assigned to control and experimental groups. Our interventions were watching (control group) and playing (experimental group) the game. Salivary biomarkers (cortisol and alpha-amylase) were measured using the enzyme-linked immunosorbent assay method. Electrophysiological assessment of attention and stress was performed using electroencephalography. Neuropsychological assessments for the evaluation of mental health, mental fatigue, sustained attention, and reaction time were conducted using paced auditory serial addition test. All tests were administered before and after the interventions. The findings revealed that the salivary cortisol and alpha-amylase significantly reduced after playing the game. There were significantly higher levels of attention after playing the game. Mental health and sustained attention significantly increased after game playing. It can conclude that puzzle-style computer games can strengthen and empower the perceptual-cognitive system and suppress the stress system of players. Therefore, they can be used purposefully as a positive cognitive therapy approach.

Trail Making Test Could Predict Impairment in Cognitive Domains in Patients with Multiple Sclerosis: A Study of Diagnostic Accuracy.

Cognitive impairment (CI) and executive dysfunction (ED) are prevalent in patients with multiple sclerosis (PwMS). The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) is the gold standard neuropsychological battery (NPB) for detecting CI. Delis-Kaplan Executive Function System (DKEFS) NPB evaluates ED. We aimed to find practical test(s) from DKEFS with acceptable diagnostic utility for early detection of impairment in cognitive and executive domains. Cognitive and executive tasks, physical disability, and depression scores of 30 PwMS were assessed (17 women, age: 38.1). Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Controlled Oral Word Association Test (COWAT) from MACFIMS and Trail Making Test (TMT), Design Fluency Test (DFT), and Verbal Fluency Test (VFT) from DKEFS were selected. The association between patients' characteristics and performance in tests, and diagnostic accuracy of DKEFS tests in detecting impairment in cognitive tasks were evaluated, using Pearson correlation and receiver operator characteristic curve analyses, respectively. A significant correlation was found between disease duration and SDMT and TMT subtests. Expanded Disability Status Scale was significantly related to SDMT, VFT-switching, and TMT subtests. Beck Depression Inventory was significantly related to DFT. TMT-switching detected abnormalities in SDMT and PASAT with 100% sensitivity, 93.3% (for SDMT), and 85.7% specificity (for PASAT). TMT-letter showed 100% sensitivity and 90% specificity in identifying abnormalities in COWAT. TMT, particularly the switching condition, is a practical paper-based test that could predict impairment in cognitive tasks. Clinicians may use TMT as a screening tool among PwMS.

A streamlined method for pressurized extraction and fractionation of leaf lipids

Plant leaf lipids are complex mixtures, which may include n-alkanes, n-alkanols, fatty acids, phenolic compounds, phytosterols, terpenes, flavonoids, and alkaloids. Many of these compounds are also widely distributed in sediments and soils, preserving molecular and isotopic information that aids the study of past climatic and ecological variables. Sample preparation typically requires multi-step extraction and fractionation procedures, making it impractical to process large numbers of samples in most laboratories. This study reports a streamlined method of leaf lipid extraction, cleanup and fractionation on commercial pressurized solvent extraction systems. A method using solid-phase adsorbents placed within the sample cell during total lipid extraction, eliminating the need for subsequent cleanup procedures, is referred to as solid phase in-cell cleanup (SPIC). Additionally, we demonstrate the feasibility of lipid fractionation according to functional group chemistries by combining in-cell solid-phase adsorption with a serial addition of protic solvents, which we refer to as solid phase in-cell fractionation (SPIF). We applied SPIC to angiosperm leaves, Morus celtidifolia, and SPIF to gymnosperm leaves of Juniperus ashei and lacustrine sediment. Molecular yields were measured by gas chromatography–mass spectrometry and compared to traditional gravity-fed silica gel column fractionation. The SPIC yields of n-alkanes, n-alkanols, and n-alkanoic acids from M. celtidifolia leaves were greater than traditional silica gel column fractionation by 37%, 83% and 59%, respectively. SPIF was highly effective in separating hydrocarbons and alcohols from the corresponding acids. The time for using SPIC/SPIF was 1.8-fold less per sample than that involved in using traditional columns.

Consistent Effects of Hypoglycemia on Cognitive Function in People With or Without Diabetes.

OBJECTIVEHypoglycemia poses an immediate threat for cognitive function. Due to its association with acute cognitive impairment, the International Hypoglycemia Study Group (IHSG) defines a blood glucose level <3.0 mmol/L as “level 2 hypoglycemia.” In the current study we investigated whether having diabetes, type of diabetes, or hypoglycemia awareness moderates this association.RESEARCH DESIGN AND METHODSAdults with type 1 diabetes with normal (n = 26) or impaired (n = 21) hypoglycemic awareness or with insulin-treated type 2 diabetes (n = 15) and age-matched control subjects without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic-hypoglycemic glucose clamp (2.80 ± 0.13 mmol/L [50.2 ± 2.3 mg/dL]). At baseline and during hypoglycemia, calculation ability, attention, working memory and cognitive flexibility were measured with the Paced Auditory Serial Addition Test (PASAT) and the Test of Attentional Performance (TAP).RESULTSFor the whole group, hypoglycemia decreased the mean ± SD proportion of correct answers on the PASAT by 8.4 ± 12.8%, increased reaction time on the TAP Alertness task by 32.1 ± 66.6 ms, and increased the sum of errors and omissions on the TAP Working Memory task by 2.0 ± 5.5 (all P < 0.001). Hypoglycemia-induced cognitive declines were largely irrespective of the presence or type of diabetes, level of symptomatic awareness, diabetes duration, or HbA1c.CONCLUSIONSIHSG level 2 hypoglycemia impairs cognitive function in people with and without diabetes, irrespective of type of diabetes or hypoglycemia awareness status. These findings support the cutoff value of hypoglycemia <3.0 mmol/L (<54 mg/dL) as being clinically relevant for most people with diabetes.

Improved prediction of early cognitive impairment in multiple sclerosis combining blood and imaging biomarkers.

Disability in multiple sclerosis is generally classified by sensory and motor symptoms, yet cognitive impairment has been identified as a frequent manifestation already in the early disease stages. Imaging- and more recently blood-based biomarkers have become increasingly important for understanding cognitive decline associated with multiple sclerosis. Thus, we sought to determine the prognostic utility of serum neurofilament light chain levels alone and in combination with MRI markers by examining their ability to predict cognitive impairment in early multiple sclerosis. A comprehensive and detailed assessment of 152 early multiple sclerosis patients (Expanded Disability Status Scale: 1.3 ± 1.2, mean age: 33.0 ± 10.0 years) was performed, which included serum neurofilament light chain measurement, MRI markers (i.e. T2-hyperintense lesion volume and grey matter volume) acquisition and completion of a set of cognitive tests (Symbol Digits Modalities Test, Paced Auditory Serial Addition Test, Verbal Learning and Memory Test) and mood questionnaires (Hospital Anxiety and Depression scale, Fatigue Scale for Motor and Cognitive Functions). Support vector regression, a branch of unsupervised machine learning, was applied to test serum neurofilament light chain and combination models of biomarkers for the prediction of neuropsychological test performance. The support vector regression results were validated in a replication cohort of 101 early multiple sclerosis patients (Expanded Disability Status Scale: 1.1 ± 1.2, mean age: 34.4 ± 10.6 years). Higher serum neurofilament light chain levels were associated with worse Symbol Digits Modalities Test scores after adjusting for age, sex Expanded Disability Status Scale, disease duration and disease-modifying therapy (B = −0.561; SE = 0.192; P = 0.004; 95% CI = −0.940 to −0.182). Besides this association, serum neurofilament light chain levels were not linked to any other cognitive or mood measures (all P-values > 0.05). The tripartite combination of serum neurofilament light chain levels, lesion volume and grey matter volume showed a cross-validated accuracy of 88.7% (90.8% in the replication cohort) in predicting Symbol Digits Modalities Test performance in the support vector regression approach, and outperformed each single biomarker (accuracy range: 68.6–75.6% and 68.9–77.8% in the replication cohort), as well as the dual biomarker combinations (accuracy range: 71.8–82.3% and 72.6–85.6% in the replication cohort). Taken together, early neuro-axonal loss reflects worse information processing speed, the key deficit underlying cognitive dysfunction in multiple sclerosis. Our findings demonstrate that combining blood and imaging measures improves the accuracy of predicting cognitive impairment, highlighting the clinical utility of cross-modal biomarkers in multiple sclerosis.

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis.

Background and ObjectivesThe relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS).MethodsWe included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status.ResultsAfter 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = −21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = −2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = −3.58, p = 0.029).DiscussionSmoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

Antitumor activity of T cells expressing a novel anti-folate receptor alpha (FOLR1) costimulatory antigen receptor (CoStAR) in a human xenograft murine solid tumor model and implications for in-human studies.

2535 Background: ITIL-306 is an autologous tumor-infiltrating lymphocyte (TIL) therapy that integrates T-cell receptor (TCR)-specific antigen recognition (Signal 1) with robust costimulation via the novel CoStAR transgene upon engagement with FOLR1 (Signal 2; Sukumaran, et al. JITC. 2021;9:198). Here, we assessed IL-2 independent effector function by anti-FOLR1 CoStAR T cells in vitro and evaluated activity in a novel, more representative murine solid tumor model. Methods: For in vitro studies, healthy donor T cells were manufactured to express anti-FOLR1 CoStAR or left nontransduced (NTD). Product cells were stimulated with a single (Day [D]0; ±IL-2) or serial (D0, 7, 14, 21; no IL-2) addition of target cells expressing membrane-anchored OKT3 (Signal 1) and FOLR1 (Signal 2). T-cell activation and proliferation were measured. For in vivo studies, the carcinoembryonic antigen (CEA)-positive (Signal 1) H508 cell line was engineered to express FOLR1 (Signal 2) and injected into 6 mice/group (D–21). NTD or healthy donor T cells expressing HLA-A*02-restricted anti-CEA TCR only, anti-FOLR1 CoStAR only, or dual TCR+CoStAR were given intravenously (D0), and compared with PBS control. Tumor growth, survival, and T-cell expansion were assessed in 2 donors to D96. Results: After single and serial stimulation, only anti-FOLR1 CoStAR T cells showed sustained proliferation without exogenous IL-2. PD-1 positivity was low ( &lt; 10%) on anti-FOLR1 T cells up to D24. In vivo, T-cell persistence on D14 was increased in dual TCR+CoStAR vs anti-CEA TCR only mice ( P&lt;.001) and all other groups ( P&lt;.01-.001). Tumor growth up to D58 was significantly lower in dual TCR+CoStAR ( &lt;.5 cm3) vs all other groups (each &gt; 2 cm3; P&lt;.0001). Survival was significantly longer in dual TCR+CoStAR ( P&lt;.01) vs all other groups; only dual TCR+CoStAR mice were alive at D58, with 5/6 alive at D96. The second donor showed similar tumor control irrespective of exogenous IL-2 in responder mice, with &gt; 50% alive at D96, and robust T-cell expansion in dual TCR+CoStAR mice. Conclusions: When combined with TCR-specific binding, CoStAR significantly enhanced T-cell proliferation, persistence, and antitumor activity in vivo vs TCR alone, resulting in tumor control and prolonged survival. Effects were not observed with CoStAR alone, underscoring that signaling through CoStAR alone does not induce T-cell effector function. The sustained proliferation of anti-FOLR1 CoStAR T cells without exogenous IL-2 support in vitro and in vivo supports a clinical TIL regimen free of high-dose IL-2. These results suggest that CoStAR may improve the clinical performance and benefit/risk profile of TILs, whereby fewer toxicities are expected with the removal of post-TIL IL-2 support. This will be explored in an upcoming first-in-human clinical study with ITIL-306.

Investıgatıon of The Effect of Serum Homocysteıne Level on Cognıtıve Functıons in Multıple Sclerosıs Patıents

Objective: In this study, we aimed to investigate whether serum homocysteine level was higher in patients with MS, and evaluate the effect of this situation on cognitive functions. In addition, we aimed to determine whether high blood homocysteine level is associated with socio-demographic and clinical features and determine the affected cognitive functions with neuropsychological tests.Methods: We looked at changes in the levels of vitamin B12 and folic acid associated with high levels of serum homocysteine levels. Cognitive performance, and laboratory values of 60 cases with Relapsing-remitting MS (RRMS) patient, and 30 healthy volunteers were compared. The frontal lobe activities, information processing speed, flexibility, and the ability of the calculation, as well as cognitive functions of attention and visuospatial perception and construction of complex skills were also evaluated. For these purposes, Paced Auditory Serial Addition Test (PASAT), Line Orientation Test (LOT) and Stroop Test were used.Results: Test performance for all of the test steps were found to be defective in MS group more than the control group subjects. In addition, all steps of the test performance were found to be impaired in both patients and healthy subjects with high levels of homocysteine(p&amp;lt;0.001).Conclusion: In this study visual memory processes, visual-spatial functions, construction skills, planning, programming and executive functions were found to be significantly deteriorated and the reaction time prolonged in RRMS patients with high levels of homocysteine compared with healthy control group

018 Disease control beyond NEDA: the value of non-clinical measures to determine treatment response to natalizumab

IntroductionNo evidence of disease activity (NEDA; no relapses, MRI activity, or Expanded Disability Status Scale worsening) is considered a multiple sclerosis (MS) treatment goal. We assessed the independent contributions of NEDA components, serum neurofilament light (sNfL), brain parenchymal fraction (BPF), and other clinical outcomes in defining disease control with natalizumab.MethodsWe used AFFIRM data from 792 patients to assess change (baseline to year [Y] 2) in NEDA com- ponents, worsening of Paced Auditory Serial Addition Test, 9-Hole Peg Test, Timed 25-Foot Walk, change (Y1-Y2) in BPF, and Y2 sNfL levels. Comparisons included odds ratios (ORs) for natalizumab vs placebo and area under the receiver-operating characteristic curve (AUC).ResultsNo MRI activity (OR=9.3; AUC=0.73; P&lt;0.0001 vs. placebo), no relapses (2.7; 0.62; P&lt;0.0001), and sNfL &lt;8 pg/mL (4.1; 0.67; P&lt;0.0001) had the strongest association with natalizumab. The best-fit multivariate logistic regression model included no MRI activity (OR=7.6; 95% CI=5.0–11.5; P&lt;0.0001), sNfL (3.1; 2.2–4.5; P&lt;0.0001) and no relapses (2.1; 1.5–3.0; P&lt;0.0001).ConclusionMRI activity, sNfL, and relapses had the strongest natalizumab treatment association over 2 years in AFFIRM. sNfL may be useful in defining disease control with natalizumab.*Additional authors: Richard A. Rudick (Biogen, Cambridge, MA, USA), Al Sandrock (Biogen, Cambridge, MA, USA). Support: Biogen. Disclosures: Included on poster.g.giovannoni@qmul.ac.uk

Effects of teriflunomide treatment on cognitive performance and brain volume in patients with relapsing multiple sclerosis: Post hoc analysis of the TEMSO core and extension studies

Background: In post hoc analyses of Teriflunomide Multiple Sclerosis Oral study (TEMSO; NCT00134563), teriflunomide 14 mg significantly reduced brain volume loss (BVL) versus placebo in patients with relapsing multiple sclerosis (MS). Objective: In this post hoc analysis of TEMSO and its long-term extension (NCT00803049), we examined the relationship between teriflunomide’s effects on BVL and cognition. Methods: We analyzed data from 709 patients who received teriflunomide 14 mg in TEMSO or its extension. The change in cognitive performance, assessed using the Paced Auditory Serial Addition Test 3 (PASAT-3), was measured in subgroups stratified by BVL over 2 years (least BVL: ⩽ 0.52%; intermediate BVL: >0.52%–2.18%; most BVL: >2.18%). BVL, MRI lesions, and relapses over 2 years were evaluated as potential mediators of the effect of teriflunomide on cognition. Results: Teriflunomide 14 mg significantly improved PASAT-3 Z-scores versus placebo through year 2. In the least- and intermediate-BVL groups, significant improvements in PASAT-3 Z-score were demonstrated versus the most-BVL group over 3 years in the extension. According to the mediation analysis, 44% of the teriflunomide effect on cognition was due to effects on BVL at year 2. Conclusion: Teriflunomide improves cognition largely through its effects on BVL. Accelerated BVL earlier in the disease course may predict cognitive outcomes. ClinicalTrials.gov identifier: NCT00134563, NCT00803049