Cognitive function in multiple sclerosis: A long-term look on the bright side.

BACKGROUND: Multiple sclerosis (MS) may lead to cognitive decline over-time.
OBJECTIVES: Characterize cognitive performance in MS patients with long disease duration treated with disease modifying drugs (DMD) in relation to disability and determine the prevalence of cognitive resilience.
METHODS: Cognitive and functional outcomes were assessed in 1010 DMD-treated MS patients at least 10 years from onset. Cognitive performance was categorized as high, moderate or low, and neurological disability was classified according to the Expanded Disability Status Scale (EDSS) as mild, moderate or severe. Relationship between cognitive performance and disability was examined.
RESULTS: After a mean disease duration of 19.6 (SD = 7.7) years, low cognitive performance was observed in 23.7% (N = 239), moderate performance in 42.7% (N = 431), and 33.7% (N = 340) had high cognitive performance, meeting the definition of cognitively resilient patients. Within the group of patients with low cognitive performance, severe disability was observed in 50.6% (121/239), while in the group of patients with high cognitive performance, mild disability was observed in 64.4% (219/340). Differences between the group of patients with high cognitive performance and severe disability (4.5%) and the group of patients with low cognitive performance and mild disability (5.0%) were not accounted for by DMD treatment duration.
CONCLUSIONS: The majority of DMD treated MS patients did not have cognitive decline that could impair their quality of life after disease of extended duration.

Introduction

Cognitive impairment has been reported to occur in 40–65% of patients with multiple sclerosis (MS) and can present even in early phases of the disease [1-4]. We have previously reported the profile of cognitive decline in a large cohort of 1500 MS patients showing that cognitive performance was below the normative average for cognitively intact individuals of similar age and education, with information processing speed and executive function most frequently impaired [5]. Cognitive impairment was significant only at disease duration greater than five years suggesting the existence of an early therapeutic window [5]. However, the effects of disease modifying drugs (DMD) on cognitive impairments in MS have not been thoroughly studied [6], though several DMD have demonstrated a beneficial effect on cognitive performance [7] and spared brain atrophy [8-10], thus showing the potential to decrease cognitive decline.

Progression of cognitive decline in MS over time is variable, and it is not yet clear why some patients are cognitively resilient, while others decline within a short period of time. Prevalence of cognitive resilience in MS may explain variability across patients in profile of cognitive decline, and such resilience may signify a less active or even benign disease, and/or improved ability to recover during the active disease process.

In the current study, we characterized cognitive performance in DMD treated MS patients with disease duration longer than 10 years. We computed prevalence of patients with high, moderate and low cognitive performance and evaluated the relationship between cognitive status and neurological disability.

Methods

Study design and participants

This was a retrospective analysis of cross-sectional data obtained from RRMS and SPMS patients treated and followed at the Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. Demographic, clinical and cognitive data were extracted from the Sheba MS Center computerized database. The following criteria were applied to extract data for the current analyses: Inclusion criteria: (1) diagnosis of definite MS according to the revised McDonald criteria [11]; (2) cognitive assessment after at least 10 years from disease onset; (3) neurological examination with Expanded Disability Status Scale (EDSS) [12] within 3 months of the cognitive assessment; (4) treatment with DMD for at least 6 moths. Exclusion criteria: (1) primary progressive disease course; (2) corticosteroid treatment up to 3 months prior to the cognitive assessment; (3) known psychiatric illnesses (including major depression or anxiety) or dementia; (4) alcohol or drug abuse; (5) severe impairment of the upper limbs and/or visual impairment precluding performance of the computerized cognitive assessment. This was determined as a part of the cognitive test. Patients with severe upper limb dysfunction like paralysis or tremor that were not able to hold the computer-mouse were technically excluded from preforming the test. Similarly, at the beginning of the cognitive test visual acuity is assessed and patients that could not read the instructions were technically excluded from performing the test.

Each patient record was coded anonymously to ensure confidentiality during statistical analyses. For patients with multiple cognitive assessments, an automated algorithm randomly selected data from one visit so that each patient is represented only once in the study dataset. The study was approved by the Sheba Medical Center IRB Ethics Committee.

Cognitive assessment

Cognitive performance was assessed with a battery of computerized tests (NeuroTrax Corporation, Medina, NY, USA). The NeuroTrax cognitive battery has been previously validated in MS patients showing good discriminant and construct validity as compared to conventional cognitive assessment [3, 13], and incorporates alternate forms that minimize learning on follow‐ups. The battery is easily administered, and testing included the following cognitive domains: memory (verbal and nonverbal), executive function, attention, information processing speed, visual spatial processing, verbal function and motor skills. Each cognitive score was standardized relative to age-/education-stratified cognitively intact norms and scaled to an IQ-style scale (mean: 100, SD: 15). Domain scores were computed as the average scores from particular tests (see [3,5] for more details). A global cognitive score (GCS) was computed as the average of the cognitive domains scores. Testing time was approximately 45 min. The computerized cognitive battery has shown good test-retest reliability and construct validity relative to paper-based tests, including the frequently used Neuropsychological Screening Battery for MS, NSBMS, [3], as well as sensitivity to effects of DMD in MS [7].

Group categorization

Cognitive performance was categorized by GCS as “high” (GCS >100), “moderate” (GCS 85–100) or “low” (GCS<85). Neurological disability was classified according to EDSS score as “mild” (EDSS ≤3), "moderate” (EDSS 3.5–5.5), or "severe" (EDSS ≥6.0).

Statistical analysis

Descriptive statistics were used to summarize demographic, clinical and cognitive variables. Between groups differences were evaluated by the chi-square test for categorial variables and by analysis of variance (ANOVA) for continuous variables. Analyses were carried out using SPSS Version 25.0 (IBM Corporation, Armonk, NY, USA). Two-tailed statistics were used, and significance level was set to p<0.05.

Results

We analyzed data obtained from 1010 relapsing-remitting (RRMS) and secondary-progressive (SPMS) patients, 700 females, 310 males, mean age 49.3 (SD = 11.0) years, all treated with DMD for a mean period of 9.2 (SD = 5.6) years. Demographic, neurologic and cognitive data subdivided by cognitive performance group are shown in Table 1. After a mean disease duration of 19.6 (SD = 7.7) years, low cognitive performance was found in 23.7% (N = 239) of patients, moderate performance in 42.7% (N = 431), and 33.7% (N = 340) had high cognitive performance attaining scores above average for cognitively intact individuals of similar age and education. Generally, lesser cognitive impairment was associated with lesser disability (Fig 1). As expected, significant differences between the low, moderate and high cognitive groups were found for all cognitive measures. Neurological disability by EDSS score and the functional system disability scores (except for visual functional score) were significantly higher in the groups with low and moderate cognitive performance as compared to patients with high cognitive performance.

Table 1

Demographic and clinical data for MS patients with long disease duration subdivided by cognitive performance.

Variable	Cognitive performance				p-value
	All	HighGCS>100	Moderate 85≤GCS≤85	LowGCS<85
Count (%)	1010	340 (33.7)	431 (42.7)	239 (23.7)
Age, y	49.3 (11.0)	49.2 (11.0)	49.7 (11.3)	48.6 (10.4)	0.423
Gender
Female, n	700	219	318	163	0.017*a,b,c
Male, n	310	121	113	76
MS Type (RR/SP)	812/198	298/42	352/79	162/77	<0.001*a,c
Disease duration, y	19.6 (7.7)	18.6 (6.9)	19.8 (8.2)	20.8 (7.8)	0.113
Education, y	14.5 (2.4)	15.0 (2.5)	14.3 (2.3)	14.0 (2.4)	<0.001*a,c
DMD treatmentduration, y	9.2 (5.6)	9.2 (5.5)	9.2 (5.6)	9.1 (5.6)	0.979
EDSS	3.8 (2.2)	2.8 (2.0)	3.8 (2.2)	5.1 (2.1)	<0.001*a,b,c
Pyramidal	2.3 (1.4)	1.7 (1.3)	2.3 (1.4)	3.0 (1.3)	<0.001*a,b,c
Cerebellar	1.3 (1.2)	0.8 (0.9)	1.3 (1.1)	2.0 (1.2)	<0.001*a,b,c
Brainstem	0.6 (0.9)	0.4 (0.7)	0.5 (0.8)	1.0 (1.0)	<0.001*a,c
Sensory	1.1 (1.2)	0.8 (1.0)	1.2 (1.2)	1.4 (1.2)	<0.001*a,b,c
Bowel & Bladder	1.3 (1.2)	0.9 (1.0)	1.3 (1.2)	1.8 (1.3)	<0.001*a,b,c
Visual	0.4 (0.9)	0.4 (0.9)	0.4 (0.9)	0.5 (1.0)	0.245
Cerebral	0.3 (0.8)	0.1 (0.4)	0.3 (0.8)	0.6 (1.1)	<0.001*a,b,c
Global cognitive score	92.8 (14.0)	106.2 (4.0)	93.6 (4.3)	72.4 (9.9)	<0.001*a,b,c
Memory	92.9 (17.9)	105.2 (6.6)	95.0 (11.8)	71.6 (19.0)	<0.001*a,b,c
Executive function	93.0 (15.8)	106.8 (8.7)	92.6 (8.6)	73.7 (13.3)	<0.001*a,b,c
Visual spatial	97.8 (18.9)	110.6 (1.4)	96.6 (15.4)	81.2 (19.8)	<0.001*a,b,c
Verbal function	93.6 (20.4)	104.4 (8.4)	94.8 (15.4)	73.3 (27.2)	<0.001*a,b,c
Attention	91.9 (17.3)	104.9 (6.3)	93.7 (9.2)	69.4 (17.4)	<0.001*a,b,c
Processing speed	93.6 (17.9)	107.4 (12.0)	91.3 (12.6)	71.2 (12.9)	<0.001*a,b,c
Motor skills	92.2 (17.2)	104.2 (8.9)	91.3 (12.7)	71.3 (17.7)	<0.001*a,b,c

GCS = Global cognitive score; DMD = Disease modifying drugs

*abetween high and low cognitive performance

bbetween low and moderate cognitive performance

cbetween high and moderate cognitive performance.

Fig 1

Correlation between cognitive performance and disability.

No significant differences between cognitive performance groups were observed for age and DMD treatment duration.

The relationship between cognitive performance and disability status in the entire cohort (Fig 2), further elucidates the association between disability and cognitive decline.

Fig 2

Cognitive performance in relation to disability levels.

Among patients with high cognitive performance, 64.4% (219/340) had mild disability and can therefore be considered to have a benign MS disease pattern under DMD treatment. Among patients with moderate cognitive performance, 44% (190/431) had mild disability, and among patients with low cognitive performance, 50.6% (121/239) had a high level of disability. Analysis of patients with ‘inconsistency’ between cognitive performance and disability status demonstrated that 4.5% (46/1010) had high cognitive performance in spite of severe disability, while 5.0% (50/1010) had low cognitive performance in spite of mild disability. The majority of patients with high cognitive performance and severe disability had SPMS and more years of education as compared to patients with low cognitive performance and mild disability, and the difference between these groups could not be accounted for by DMD treatment duration, Table 2.

Table 2

Groups with ‘inconsistency’ between cognitive performance and disability.

Variable	Low cognitive performance & Mild disability	High cognitive performance &Severe disability	p-value
Number	50	45
Age, y	47.2 (10.0)	56.6 (8.4)	0.082
Gender (F/M)	38/12	29/16	0.191
MS type (RR/SP)	49/1	11/34	<0.001
Disease duration, y	19.5 (6.8)	23.7 (8.1)	0.789
Education, y	13.8 (2.2)	15.6 (2.5)	0.002
DMD treatment duration, y	8.7 (5.2)	10.4 (5.1)	0.120

Data are presented as mean (SD)

Discussion

Our study assessed the frequency of cognitive impairment in a large cohort of DMD- treated RRMS and SPMS patients after nearly 20 years of illness. Notably, we observed a much lower rate of cognitive impairment than previously reported in the literature. Most studies assessing cognitive performance in MS estimated frequency of cognitive decline, particularly in the domains of attention, processing speed and working memory, to be within the range of 40% to 60% over the lifespan, but these studies were performed mainly in patients who did not receive DMD [4, 14]. It is not surprising that cognitive impairment would be less than in the pre-DMD treatment era, due to effective disease modification and greater ascertainment of milder cases of MS.

The use of DMD significantly changed the pattern of MS progression. These medications modulate the inflammatory immune response and lead to decreased disease activity by reducing relapse rate and delaying disability progression. Consequently, these treatments lead to better cognitive protection [15]. The safety-risk profile of DMD in MS is favorable. Possible side effects vary between treatments and include injection-site reactions, increased risk for infections, gastrointestinal symptoms, flushing, autoimmune thyroid disorders and elevated liver enzymes [16].

In our cohort of patients treated with DMD for a relatively long period, only 23.7% had low cognitive performance, while 33.7% had high cognitive performance attaining scores above average for cognitively intact individuals of similar age and education. This group of patients, that after a long disease duration of almost 20 years, maintained their cognitive skills, can be defined as ‘cognitively resilient’ patients. The term resilience is derived from the Latin words salire (to leap or jump), and resilire (to spring back). When applied to cognition it denotes the capacity of the brain to resist deteriorating processes or injuries [17,18]. Cognitive resilience literature has focused on specific contexts in which individuals differ in their capabilities to withstand or overcome brain insults and to explain the difference in the patterns of cognitive decline associated with aging and neurodegenerative diseases [19]. Various predisposing interacting factors may contribute to the road map for brain resilience, including education, gender, prior brain injuries, family history, participation in cognitively stimulating activities, physical exercise, social relationships and apoE genotype [20-24]. In young patients with a chronic long-lasting disease like MS, characterizing differences between cognitive subgroups in relation to clinical variables may afford new insights into active neuroplasticity mechanisms and thus suggest plasticity facilitating treatments to enhance cognitive resilience. Our findings suggest a reason for optimism relative to the previously reported studies. Furthermore, we found that approximately 75% of RRMS and SPMS patients (i.e., “moderate” and “high” cognitive performance groups combined) do not have low levels of cognitive function that may compromise quality of life, social interactions, employment prospects and work performance [25].

It is of note that different DMD may have varying effects on cognitive performance, that during the long-term study period, patients switched DMD, and that treatment duration under each DMD varied; however, in spite of these limitations that make it difficult to assess the contribution of each DMD to cognitive performance, our findings are encouraging in suggesting that overall, long-term treatment with DMD affords significant beneficial effects in the maintenance of normal brain function.

As anticipated, increased neurological disability correlated with lower cognitive performance, indicating that cognitive function is an integral clinical feature of MS and directly related to neurological disability. Neurological disability by the EDSS score and functional system disability scores were significantly higher in the groups with low and moderate cognitive performance as compared to patients with high cognitive performance. No difference was found for visual functional score between the groups, probably because visual impairment was an exclusion criterion. However, no significant differences between high, moderate and low cognitive performance groups were observed for age and DMD treatment duration, suggesting that differences in cognitive performance may be attributable to differential disease activity. More aggressive disease activity characterized by increased rate of relapses and post-relapse residual disability [26] may lead to worse cognitive performance and higher disability despite treatment with DMD; this more aggressive group comprised 12.0% of the cohort. In contrast, 21.7% of the patients had high cognitive performance and low level of disability and can therefore be considered to have benign MS [27, 28]. Cognitive resilience in these patients probably signifies MS resilience, e.g., resilience to the disease pathogenic mechanisms. These patients have low disability and therefore also manifest with less cognitive impairment, suggesting that cognition as a part of the functional neurological spectrum of MS, is better preserved in patients with less active disease. Indeed, it is expected that patients with a benign disease course, probably presenting as good responders to DMD treatment, will be resilient to disability and cognitive decline even after many years of disease.

More intriguing is to understand the groups for which cognitive performance and disability were inconsistent, i.e., patients who after a long-term follow-up present with high cognitive performance and severe disability (4.5%), or patients with low cognitive performance and mild disability (5.0%). We believe that these minority groups may have a different anatomical pattern of central nervous system involvement. Patients with cognitive resilience but severe disability probably have more pronounced spinal cord involvement, either cervical, thoracic or both [29], while patients with low cognitive performance and mild disability likely will have more distinct brain atrophy and a higher brain lesion load, with lesser cervical or thoracic spinal cord involvement [30, 31].

In our cohort, 33.7% of patients were cognitively resilient. These patients had intact cognitive performance despite an extended disease duration, and the majority were also neurologically protected, reflected by a relatively low EDSS score. One of the mechanisms that accounts for cognitive resilience may be preserved brain functional reserve. In accordance, Rocca et al., [32] reported that relatively mild grey matter damage was associated with a favorable clinical course in patients with benign MS. Sumowski et al., [33] have suggested that the level of cerebral efficiency prior to disease affords a ‘cognitive reserve’ against disease-related cognitive impairment, such that when cognitive processing is challenged by a brain disease, individuals with greater cerebral efficiency are better able to withstand the insult and will not develop cognitive impairment. Indeed, in our cohort, educational level was higher in patients with high cognitive performance as compared to patients with moderate and low cognitive performance.

Although our study is retrospective and cross-sectional and included only relapsing-remitting and secondary progressive patients, it encompasses a large number of patients, and to the best of our knowledge, this is the first study that evaluates “real-world” experience of DMD treatments on cognitive performance in MS patients. We could not evaluate the effects of individual DMD on cognitive performance as patients changed treatments, and the treatment period for each medication varied. However, the main strength of our study is in elucidating the relationship between cognitive performance and disability in MS patients after a long disease duration.

We suggest that pre-disease intellectual enrichment reflected by educational level contributes to better cognitive reserve and better cognitive resilience in MS patients. Furthermore, a cognitive sparing effect can be enhanced by DMD treatment leading to a high rate of MS patients without cognitive decline even after many years from onset.

18 Jun 2019

PONE-D-19-14839

Cognitive function in multiple sclerosis: A long-term look on the bright side

PLOS ONE

Dear Prof ACHIRON,

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The manuscript reports on the cognitive performance in individuals with long history of MS treated with DMD in relation to disability and cognitive resilience.

Overall, there needs to be consistencies in terminologies throughout the manuscript. Low cognitive, moderate cognitive, and high cognitive performance or severe cognitive, moderate cognitive, and low cognitive impairments. Specifically, define cognitive resilience in light of the terminology you choose. These will facilitate better comprehension of the manuscript.

Abstract: Apart from the inconsistency in terminologies, this section is well-written.

Introduction: Short and succinct.

Methods: Reads well.

Results: Page 6, end of the first paragraph: As shown in Table 1, there was also no significant difference in visual functions. This fact needs to be included in the narrative as well.

Figure 1 is exactly the same information as in Table 2. Either one, plus the narrative should be sufficient.

Discussion: Page 7, end of the first paragraph: Can you discuss some of side effects of DMDs?

Page 9: beginning of the second paragraph: If this is a prospective study, how is it possible that data was collected prospectively?

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28 Jun 2019

23.6.2019

Dear Editor

Enclosed please find our revised manuscript PONE-D-19-14839 entitled “Cognitive performance in multiple sclerosis: A Long-term look on the bright side”, which we submit after revision after we addressed the points raised during the review process as follows:

Comment 1. Overall, there needs to be consistencies in terminologies throughout the manuscript. Low cognitive, moderate cognitive, and high cognitive performance or severe cognitive, moderate cognitive, and low cognitive impairments.

Specifically, define cognitive resilience in light of the terminology you choose. These will facilitate better comprehension of the manuscript.

Response: As suggested, we have better defined the cognitive terminologies throughout the manuscript, using the terminology of low cognitive, moderate cognitive, and high cognitive performance.

Accordingly, we have defined cognitive resilience as patients with high cognitive performance after a long-disease duration.

Comment 2. Results: Page 6, end of the first paragraph: As shown in Table 1, there was also no significant difference in visual functions. This fact needs to be included in the narrative as well.

Response: We added to the narrative the fact that there was no significant difference in visual function, Results end of first paragraph..

Comment 3. Figure 1 is exactly the same information as in Table 2. Either one, plus the narrative should be sufficient.

Response: We omitted Table 2 and added the data to the narrative. Accordingly we changed the order of the figures (Figure 1is now Figure 2, and Figure 2 is now Figure 1), and explained in the narrative the numbers of the inconsistency groups.

Comment 4. Discussion: Page 7, end of the first paragraph: Can you discuss some of side effects of DMDs?

Added to the Discussion.

Comment 5. Page 9: beginning of the second paragraph: If this is a prospective study, how is it possible that data was collected prospectively?

We mentioned that the study was retrospective cross-sectional, but the data was collected prospectively – as we wanted to highlight the point that patients were evaluated on an on-going basis prospectively. As it seems confusing we omitted the term prospectively.

.

I hope you will find the revised version merit for publication in PlosOne.

With respects

Anat Achiron, MD, PhD

Sheba Medical Center

Tel-Hashomer, 52621, Israel.

Tel: 972-3-5303932; Fax: 972-3-5348186

Email: Anat.Achiron@sheba.health.gov.il

Submitted filename: Achiron.PlosOne.Response to Reviewers.docx

Click here for additional data file.

8 Aug 2019

PONE-D-19-14839R1

Cognitive function in multiple sclerosis: A long-term look on the bright side

PLOS ONE

Dear Prof ACHIRON,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Sep 22 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Abiodun E. Akinwuntan, PhD, MPH, MBA

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Good job responding to the comments. Consistency in terminologies has made the manuscript easier to read and understand.

The few corrections needed are:

Page 6: Consider adding "disability" in the sentence with: Neurological disability by EDSS score and the functional system "disability" scores (except for visual functional score) were …..

Page 6, last paragraph: Table 2 shows 45/1010 while the narrative reports 45/1010 for high cognitive performance and severe disability. Which is correct?

Page 7, second paragraph in "Discussion": Consider changing the sentence to "The use of DMD significantly changed the pattern of MS progression."

Overall, check all citations and references for accuracy.

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Reviewers' comments:

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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6. Review Comments to the Author

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Reviewer #1: Thank you for the opportunity to evaluate the manuscript PONE-D-19-14839R1 “Cognitive function in multiple sclerosis: a long-term look on the bright side”. I was not involved in the first review round and will therefore critique the manuscript from a fresh perspective.

This retrospective study includes a large number (n = 1010) of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS. The main aim was to describe cognitive functioning in those patients who had received at least 10 years of disease modifying drug treatment and to correlate cognitive impairments with long term disability. The authors found that the majority of patients with MS did not have cognitive decline. The authors discuss the findings in light of cognitive resilience and long-term quality of life.

Overall, I enjoyed reading the manuscript. The manuscript is topical, timely, and well-written and contributes to the body of knowledge. My major comments are:

1. The discussion around cognitive resilience could be strengthened. Devote at least a paragraph explaining what cognitive resilience is, how it can be captured, what predisposing factors contribute to cognitive resilience, and how that may impact disability and quality of life. Provide references.

2. The leap from good performance on cognitive tests to “cognitive resilience” needs better argumentation. The authors report that 33.7% are cognitive resilient because they score well on cognitive tests despite long disease duration. However, they also have mild disability. It is logical to assume that those with mild disability will also have less cognitive impairments. The 33.7% with good performance in cognitive tests reported here do well because they are generally less disabled; not necessarily because they show better cognitive resilience. You could also argue then that these individuals have better physical resilience, or respond better to disease modifying treatment. It would be more important to focus on the persons who show high cognitive performance despite moderate to severe disability, e.g., those individuals reported in Table 2.

I have few minor comments:

3. How were the three groups of cognitive performance and the three groups of neurological disability determined. Please provide references on the categorization of cognitive performance and neurological disability.

4. Please add in the limitations section that this study included only relapsing-remitting and secondary progressive MS.

5. Please elaborate on exclusion criterion 5. How was it determined from chart review whether a patient had severe upper limb or visual impairment?

6. On that note, visual performance did not differ between the three groups (Table 1), probably because visual impairment was an exclusion criterion. Please add this to the discussion.

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Reviewer #1: Yes: Hannes Devos

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10 Aug 2019

Comment 1. Page 6: Consider adding "disability" in the sentence with: Neurological disability by EDSS score and the functional system "disability" scores (except for visual functional score) were …..

Response: Corrected

Comment 2. Page 6, last paragraph: Table 2 shows 45/1010 while the narrative reports 45/1010 for high cognitive performance and severe disability. Which is correct?

Response: The title column in Table 2 shows: High cognitive performance & Severe disability, so essentially both are the same and correct.

Comment 3. Page 7, second paragraph in "Discussion": Consider changing the sentence to "The use of DMD significantly changed the pattern of MS progression."

Response: corrected.

Comment 4. check all citations and references for accuracy.

Response: We checked all citations and references to ensure accuracy.

Review Comments to the Author

1. The discussion around cognitive resilience could be strengthened. Devote at least a paragraph explaining what cognitive resilience is, how it can be captured, what predisposing factors contribute to cognitive resilience, and how that may impact disability and quality of life. Provide references.

Response: We have added to the Discussion a paragraph explaining what cognitive resilience is, how it can be captured, what predisposing factors contribute to cognitive resilience, and how that may impact disability and quality of life. In accordance we have provide references as follows:

The term resilience was derived from the Latin words salire (to leap or jump), and resilire (to spring back). When applied to cognition it stands for the capacity of the brain to resist deteriorating processes or injuries (SternY. What is cognitive reserve? Theory and research applications of the reserve concept. J Int Neuropsychol Soc 2002; 8:448–460. McEwen BS. In pursuit of resilience: stress, epigenetics, and brain plasticity. Ann N Y Acad Sci. 2016;1373:56-64). Cognitive resilience literature has focused on specific contexts in which individuals differ in their capabilities to withstand or overcome brain insults and to explain the difference in the patterns of cognitive decline associated with aging and neurodegenerative diseases (de Frias CM, Dixon RA, Bäckman L. Use of memory compensation strategies is related to psychosocial and health indicators. J Gerontol B Psychol Sci Soc Sci. 2003;58:12-22.). Various predisposing interacting factors may contribute to the road map for brain resilience including education, gender, prior brain injuries, family history, participation in cognitively stimulating activities, physical exercises, social relationships and apoE genotype. (Christensen H1, Hofer SM, Mackinnon AJ, Korten AE, Jorm AF, Henderson AS. Age is no kinder to the better educated: absence of an association investigated using latent growth techniques in a community sample. Psychol Med. 2001;31:15-28. Kirk-Sanchez NJ, McGough EL. Physical exercise and cognitive performance in the elderly: current perspectives. Clin Interv Aging. 2014;9:51-62. Hofer SM, Christensen H, Mackinnon AJ, Korten AE, Jorm AF, Henderson AS, Easteal S. Change in cognitive functioning associated with apoE genotype in a community sample of older adults. Psychol Aging. 2002;17:194-208. Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287:742-8. Seeman TE, Lusignolo TM, Albert M, Berkman L. Social relationships, social support, and patterns of cognitive aging in healthy, high-functioning older adults: MacArthur studies of successful aging. Health Psychol. 2001;20:243-55.). In young patients with a chronic long-lasting disease like MS, characterizing differences between cognitive subgroups in relation to clinical variables may afford new insights into the on-going neuroplasticity mechanisms and in accordance suggest plasticity‐facilitating treatments to enhance cognitive resilience.

2. The leap from good performance on cognitive tests to “cognitive resilience” needs better argumentation. The authors report that 33.7% are cognitive resilient because they score well on cognitive tests despite long disease duration. However, they also have mild disability. It is logical to assume that those with mild disability will also have less cognitive impairments. The 33.7% with good performance in cognitive tests reported here do well because they are generally less disabled; not necessarily because they show better cognitive resilience. You could also argue then that these individuals have better physical resilience, or respond better to disease modifying treatment. It would be more important to focus on the persons who show high cognitive performance despite moderate to severe disability, e.g., those individuals reported in Table 2.

Response: As the Reviewer commented, indeed, cognitive resilience in patients with long disease duration and mild disability probably signifies MS resilience, e.g., resilience to the disease pathogenic mechanisms. These patients are defined as patients with benign disease course and therefore also manifest with less cognitive impairments. Our findings implicate that cognition as a part of the functional neurological spectrum of MS is better reserved in patients with less active disease, as patients with low disability were found to be more cognitively resilient.

Regarding the group of patients who show high cognitive performance despite moderate to severe disability as compared to patients with low cognitive performance despite mild disability, we have specified in the Discussion a possible explanation related to anatomical involvement. We suggest that patients with moderate to severe disability but high cognitive performance the spinal cord will be more involved as compared to patients with mild disability but with low cognitive performance that probably present widespread brain disease and relatively lower spinal cord involvement.

We have added these paragraphs to the Discussion.

minor comments:

3. How were the three groups of cognitive performance and the three groups of neurological disability determined. Please provide references on the categorization of cognitive performance and neurological disability.

Response: As specified in the Methods - Cognitive assessment, last paragraph, the three groups of cognitive performance and the three groups of neurological disability were determined according to the global cognitive score (GCS) and the Expanded Disability Status Scale (EDSS) score as follows:

Cognitive performance was categorized by GCS as “high” (GCS >100), “moderate” (GCS 85-100) or “low” (GCS<85). Neurological disability was classified according to EDSS score as “mild” (EDSS ≤3), "moderate” (EDSS 3.5-5.5), or "severe" (EDSS >6.0).

Both are referenced.

We better detailed this by adding the title of Group categorization to this paragraph.

4. Please add in the limitations section that this study included only relapsing-remitting and secondary progressive MS.

Response: Added.

5. Please elaborate on exclusion criterion 5. How was it determined from chart review whether a patient had severe upper limb or visual impairment?

Response: This exclusion criteria is determined as a part of the cognitive test. Patients that have severe upper limb dysfunction like paralysis or tremor are not able to hold the computer-mouse and therefore are technically excluded from preforming the test. Similarly, at the beginning of the cognitive test visual acuity is assessed and patients that can not read the instructions are technically excluded from performing the test.

The explanation was added to exclusion criterion 5.

6. On that note, visual performance did not differ between the three groups (Table 1), probably because visual impairment was an exclusion criterion. Please add this to the discussion.

Response: Added.

15 Aug 2019

Cognitive function in multiple sclerosis: A long-term look on the bright side

PONE-D-19-14839R2

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21 Aug 2019

PONE-D-19-14839R2

Cognitive function in multiple sclerosis: A long-term look on the bright side

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