Does cognitive dysfunction correlate with neurofilament light polypeptide levels in the CSF of patients with multiple sclerosis?

Objective To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS. Methods This observational case–control study included patients with MS. CSF levels of NfL were determined using enzyme-linked immunosorbent assay. Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population. Results Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (–0.34 ± 1.13). Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72). An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = –0.944). Conclusions This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples.

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Cognitive deficits in multiple sclerosis correlate with changes in fronto-subcortical tracts

Multiple Sclerosis Journal ◽

10.1177/1352458507084270 ◽

2008 ◽

Vol 14 (3) ◽

pp. 364-369 ◽

Cited By ~ 66

Author(s):

M. Roca ◽

T. Torralva ◽

F. Meli ◽

M. Fiol ◽

ML Calcagno ◽

...

Keyword(s):

Multiple Sclerosis ◽

Iowa Gambling Task ◽

Diffusion Tensor ◽

Verbal Learning ◽

Apparent Diffusion Coefficients ◽

Fiber Tracts ◽

Multiple Sclerosis Disease ◽

Apparent Diffusion ◽

Learning Test ◽

Serial Addition

Cognitive function and diffusion tensor imaging were assessed in a group of 12 patients with early relapsing—remitting multiple sclerosis (disease duration ≤3 years), and mild clinical disability (expanded disability status scale ≤2), as well as in 12 control subjects. Patients showed impairment in immediate logical memory and delayed recall with the Rey auditory verbal learning test. No significant differences in classical executive tests were observed. In contrast, differences were found for specific executive tests including IOWA Gambling Task, multiple errands test hospital version (MET) and Hotel Task, as well as in Paced-Auditory Serial Addition Test (PASAT). Significant correlation was found between PASAT performance and FA measures ( r = 0.64, P = 0.03), the apparent diffusion coefficients and the MET ( r = 0.72, P = 0.01), as well as in one subtask of Hotel ( r = -0.68, P = 0.02). Thus, executive deficits can best be appreciated at early stages of MS when a more specific battery of tests is used for patient evaluation. In this series, test failures observed correlated with changes in fronto-subcortical fiber tracts. Multiple Sclerosis 2008; 14: 364—369. http://msj.sagepub.com

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Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study

Multiple Sclerosis Journal ◽

10.1177/13524585211048397 ◽

2021 ◽

pp. 135245852110483

Author(s):

Brian M Sandroff ◽

Robert W Motl ◽

Maria Pia Amato ◽

Giampaolo Brichetto ◽

Jeremy Chataway ◽

...

Keyword(s):

Physical Activity ◽

Multiple Sclerosis ◽

Cardiorespiratory Fitness ◽

Vigorous Physical Activity ◽

Verbal Learning ◽

Progressive Multiple Sclerosis ◽

Aerobic Exercise Training ◽

California Verbal Learning Test ◽

Z Scores ◽

Learning Test

Background: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. Objective: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. Methods: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. Results: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = −0.01; r = −0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test–Revised (BVMT-R; r = −0.14; r = −0.14) z-scores controlling for age, sex, and education. MVPA and SDMT ( r = 0.05), CVLT-II ( r = −0.07), and BVMT-R ( r = 0.01) z-scores were not significantly correlated. Conclusion: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.

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Inflammatory Markers May Inform the Effects of Electroconvulsive Therapy on Cognition in Patients with Depression

Neuropsychobiology ◽

10.1159/000515931 ◽

2021 ◽

pp. 1-9

Author(s):

Jan-Baptist Belge ◽

Linda Van Diermen ◽

Bernard Sabbe ◽

Manuel Morrens ◽

Violette Coppens ◽

...

Keyword(s):

Episodic Memory ◽

Cognitive Functioning ◽

Electroconvulsive Therapy ◽

Inflammatory Markers ◽

Verbal Learning ◽

Potential Biomarker ◽

Tnf Α ◽

Autobiographic Memory ◽

Learning Test ◽

Verbal Episodic Memory

Introduction: The neurobiological mechanisms underlying the acute cognitive effects of electroconvulsive therapy (ECT) remain poorly understood. Prior research has shown that proinflammatory cytokines such as IL-6, TNF-α, IL1-β, and IL-10 may interfere with cognitive functioning. Interestingly, immunomodulation is one of the proposed modes of action of ECT. This study investigates whether changes of peripheral levels of IL-6, TNF-α, IL1-β, and IL-10 are related to changes in cognitive functioning following ECT. Methods: In the week before and 1 week after an acute course of ECT, 62 patients suffering from depression underwent a neuropsychological evaluation to assess their processing speed using the Symbol Digit Substitution Test (SDST), verbal episodic memory using the Hopkins Verbal Learning Test-Revised (HVLT-R), and their retrospective autobiographic memory using the Autobiographical Memory Interview (AMI) with the peripheral inflammatory markers being measured at the same 2 time points. Results: Patients improved drastically following ECT, while their main performance on both the HVLT-R and AMI declined and their SDST scores remained stable. The levels of IL-6 and IL1-β had both decreased, where the decrease in IL-6 was related to the decrease in HVLT-R scores. Higher baseline IL-10 levels were associated with a more limited decrease of the HVLT-R scores. Conclusion: Our findings tentatively suggest that the effects of ECT on verbal episodic memory may be related to the treatment’s immunomodulatory properties, most notably due to decreased IL-6 levels. Moreover, baseline IL-10 appears to be a potential biomarker to predict the effects of ECT on verbal episodic memory. Whilst compelling, the results of this study should be interpreted with caution as, due to its exploratory nature, no correction for multiple comparisons was made. Further, a replication in larger cohorts is warranted.

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The Impact of Cognitive Dysfunction on Locomotor Rehabilitation Potential in Multiple Sclerosis

Journal of Central Nervous System Disease ◽

10.1177/1179573519884041 ◽

2019 ◽

Vol 11 ◽

pp. 117957351988404

Author(s):

Stijn Denissen ◽

Alexander De Cock ◽

Tom Meurrens ◽

Luc Vleugels ◽

Ann Van Remoortel ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Word Association ◽

Verbal Learning ◽

Cognitive Status ◽

Attentional Deficits ◽

Ambulatory Patients ◽

The Impact ◽

Locomotor Rehabilitation

Background: Cognitive dysfunction is a frequent manifestation of multiple sclerosis (MS) but its effect on locomotor rehabilitation is unknown. Objective: To study the impact of cognitive impairment on locomotor rehabilitation outcome in people with MS. Methods: We performed a retrospective analysis involving ambulatory patients with MS who were admitted for intensive, inpatient, multidisciplinary rehabilitation at the National Multiple Sclerosis Center of Melsbroek between the years 2012 and 2017. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used to determine the cognitive status of subjects as either impaired (COG–) or preserved (COG+). Locomotor outcome was compared between groups with the difference in 6-minute walk test (6MWT) measured at admission and discharge (Δ6MWT). In addition, individual test scores of the BRB-N for attention (Paced Auditory Serial Addition Test 2” and 3”), visuospatial learning/memory (7/24 Spatial Recall Test), verbal learning/memory (Selective Reminding Test) and verbal fluency (Controlled Oral Word Association Test) were correlated to the Δ6MWT. Results: A total of 318 complete and unique records were identified. Both groups showed a significant within-group Δ6MWT during hospitalization (COG+: 47.51 m; COG–: 40.97 m; P < .01). In contrast, Δ6MWT values were comparable between groups. The odds of achieving a minimal clinical important difference on the 6MWT did not differ significantly between both groups. Only attention/concentration was significantly correlated with Δ6MWT (r = 0.16, P = .013). Conclusion: Cognitive impairment based on BRB-N results appears not to impede locomotor rehabilitation in ambulatory patients with MS. Attentional deficits are correlated to the extent of locomotor rehabilitation, suggesting the presence of a subtle effect of cognition.

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Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis

Multiple Sclerosis Journal ◽

10.1177/1352458515574148 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1761-1770 ◽

Cited By ~ 60

Author(s):

S Modvig ◽

M Degn ◽

H Roed ◽

TL Sørensen ◽

HBW Larsson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Optic Neuritis ◽

Light Chain ◽

Oligoclonal Bands ◽

Enzyme Linked Immunosorbent Assay ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. Objective: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). Methods: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6–19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. Results: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI ( p=0.0001), chitinase 3-like 1 ( p=0.0033) and age ( p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale ( p=0.0111) and nine-hole-peg-test ( p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test ( p=0.0150). Conclusion: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event.

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Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial

Multiple Sclerosis Journal ◽

10.1177/1352458510367662 ◽

2010 ◽

Vol 16 (6) ◽

pp. 715-723 ◽

Cited By ~ 57

Author(s):

JF Lovera ◽

E. Frohman ◽

TR Brown ◽

D. Bandari ◽

L. Nguyen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Free Recall ◽

Controlled Trial ◽

Neuropsychiatric Symptoms ◽

Verbal Learning ◽

Self Report ◽

California Verbal Learning Test ◽

Cognitive Improvement ◽

Learning Test

Background: Memantine, an NMDA antagonist, is effective for moderate to severe Alzheimer’s disease. Objective: Determine whether memantine improves cognitive performance (CP) among subjects with multiple sclerosis (MS) and cognitive impairment (CI). Methods: This double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov NCT00300716) compared memantine 10 mg twice a day (4 week titration followed by 12 weeks on the highest tolerated dose) with placebo. The primary outcome was the change from baseline to exit on the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test-II (CVLT-II) Long Delay Free Recall (LDFR). Secondary outcomes included additional neuropsychological tests; self-report measures of quality of life, fatigue, and depression; and family/caregiver reports of subjects’ CI and neuropsychiatric symptoms. Results: The differences between the groups on the change on the PASAT (placebo—memantine = 0.0 correct responses, 95% CI 3.4, 3.4; p = 0.9) and on CVLT-II LDFR (placebo—memantine =—0.6 words, 95% CI —2.1, 0.8; p = 0.4) as well as on the other cognitive tests were not significant. Subjects on memantine had no serious adverse events (AEs) but had more fatigue and neurological AEs as well as, per family members’ reports, less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo. Conclusion: Memantine 10 mg twice a day does not improve CP in subjects with MS, ages 18—65, without major depression, who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II (total recall or delayed free recall).

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Monitoring disease activity in multiple sclerosis using serum neurofilament light protein

Neurology ◽

10.1212/wnl.0000000000004683 ◽

2017 ◽

Vol 89 (22) ◽

pp. 2230-2237 ◽

Cited By ~ 117

Author(s):

Lenka Novakova ◽

Henrik Zetterberg ◽

Peter Sundström ◽

Markus Axelsson ◽

Mohsen Khademi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Single Molecule ◽

Enzyme Linked Immunosorbent Assay ◽

Neurofilament Light ◽

Median Serum ◽

Relapsing Remitting ◽

Before And After ◽

Paired Serum ◽

Highly Correlated

Objective:To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).Methods:NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.Results:In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6–32.7) ng/L to 15.7 (IQR 9.6–22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).Conclusions:Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.

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Cerebrospinal Fluid Biomarker for Alzheimer Disease Predicts Postoperative Cognitive Dysfunction

Anesthesiology ◽

10.1097/aln.0000000000000953 ◽

2016 ◽

Vol 124 (2) ◽

pp. 353-361 ◽

Cited By ~ 51

Author(s):

Lisbeth Evered ◽

Brendan Silbert ◽

David A. Scott ◽

David Ames ◽

Paul Maruff ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cognitive Dysfunction ◽

Postoperative Cognitive Dysfunction ◽

Adverse Outcomes ◽

Reliable Change Index ◽

Enzyme Linked Immunosorbent Assay ◽

Neurofilament Light ◽

Cut Point ◽

Significant Difference

Abstract Background Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD. Methods CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid β1–42 (Aβ1–42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods. Results POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Aβ1–42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes. Conclusions Low CSF Aβ1–42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD.

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Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000749 ◽

2020 ◽

Vol 7 (4) ◽

pp. e749 ◽

Cited By ~ 4

Author(s):

Marie-Christine Reinert ◽

Pascal Benkert ◽

Jens Wuerfel ◽

Zuzanna Michalak ◽

Esther Ruberte ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Treatment Response ◽

Single Molecule ◽

Light Chain ◽

Interferon Beta ◽

Class Iii ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Potential Biomarker

ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001).ConclusionssNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.

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The correlation between EDSS and cognitive impairment in MS patients. Assessment of a Brazilian population using a BICAMS version

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20160151 ◽

2016 ◽

Vol 74 (12) ◽

pp. 974-981 ◽

Cited By ~ 5

Author(s):

Marco A. G. de Caneda ◽

Maria Cecília A. de Vecino

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Neuropsychological Tests ◽

Verbal Learning ◽

Therapeutic Interventions ◽

California Verbal Learning Test ◽

Cognitive Evaluation ◽

Disability Status ◽

Learning Test

ABSTRACT Multiple sclerosis (MS) may present with a cognitive impairment as disabling as the physical disabilities. Therefore, routine cognitive evaluation is pivotal. Valid and reliable neuropsychological tests are essential in follow-up and to define future therapeutic interventions. Objectives To investigate the correlation between the disabilities of MS patients and their cognitive impairment assessed by the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Methods Forty patients with definitive diagnoses of MS were selected. The correlation coefficient (r) between the Expanded Disability Status Scale (EDSS) and the neuropsychological tests of BICAMS were calculated. Results The correlation was clinically substantial and significant with r = 0.55 (p < 0.01) in the Symbol Digit Modalities Test (SDMT), 0.54 (p < 0.01) in the Brief Visuospacial Memory Test (BVMT) and 0.40 (p < 0.05) in the California Verbal Learning Test (CVLT). Conclusion BICAMS has easy and satisfactory application and evaluation for routine visits and presents a significant correlation with the EDSS. Its use may be indicated for screening and monitoring of cognitive impairment in patients with MS.

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