Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus

John G. Hanly; Alexandra Legge; Lyna Kamintsky; Alon Friedman; Javeria A. Hashmi; Steven D. Beyea; John Fisk; Antonina Omisade; Cynthia Calkin; Tim Bardouille; Chris Bowen; Kara Matheson; Marvin J. Fritzler

doi:10.1136/lupus-2022-000668

Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus

John G. Hanly, Alexandra Legge, Lyna Kamintsky, Alon Friedman, Javeria A. Hashmi, Steven D. Beyea, John Fisk, Antonina Omisade, Cynthia Calkin, Tim Bardouille, Chris Bowen, Kara Matheson, Marvin J. Fritzler

Medicine

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Objective Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. Methods Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. Results There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. Conclusions Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

Original language	English
Article number	e000668
Journal	Lupus Science and Medicine
Volume	9
Issue number	1
DOIs	https://doi.org/10.1136/lupus-2022-000668
Publication status	Published - Jun 15 2022

Bibliographical note

Funding Information:
Contributors All authors participated in the collection of research data, data analysis, or writing and critical review of the manuscript. JGH is the author acting as guarantor, Funding This study was supported by the Canadian Institutes of Health Research (CIHR; MOP88526 and PJT148896, CIHR project grant 168878), Nova Scotia Health Research Foundation (NSHRF; MED-EST-2015-10067), Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN 04293-17 and RGPIN/05684-2016), Brain Canada (BC; PSG2015-3780), Mitacs (grant IT23320), Nova Scotia Research Fund, National MS Society, Research Nova Scotia, and consultation and distribution royalties from MAPI Research Trust. The funders of the study had no role in study design, patient recruitment, data collection, analysis and interpretation, or publication.

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

ASJC Scopus Subject Areas

Immunology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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Hanly, J. G., Legge, A., Kamintsky, L., Friedman, A., Hashmi, J. A., Beyea, S. D., Fisk, J., Omisade, A., Calkin, C., Bardouille, T., Bowen, C., Matheson, K., & Fritzler, M. J. (2022). Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus. Lupus Science and Medicine, 9(1), Article e000668. https://doi.org/10.1136/lupus-2022-000668

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title = "Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus",

abstract = "Objective Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. Methods Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. Results There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. Conclusions Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies. ",

author = "Hanly, {John G.} and Alexandra Legge and Lyna Kamintsky and Alon Friedman and Hashmi, {Javeria A.} and Beyea, {Steven D.} and John Fisk and Antonina Omisade and Cynthia Calkin and Tim Bardouille and Chris Bowen and Kara Matheson and Fritzler, {Marvin J.}",

note = "Funding Information: Contributors All authors participated in the collection of research data, data analysis, or writing and critical review of the manuscript. JGH is the author acting as guarantor, Funding This study was supported by the Canadian Institutes of Health Research (CIHR; MOP88526 and PJT148896, CIHR project grant 168878), Nova Scotia Health Research Foundation (NSHRF; MED-EST-2015-10067), Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN 04293-17 and RGPIN/05684-2016), Brain Canada (BC; PSG2015-3780), Mitacs (grant IT23320), Nova Scotia Research Fund, National MS Society, Research Nova Scotia, and consultation and distribution royalties from MAPI Research Trust. The funders of the study had no role in study design, patient recruitment, data collection, analysis and interpretation, or publication. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = jun,

day = "15",

doi = "10.1136/lupus-2022-000668",

language = "English",

volume = "9",

journal = "Lupus Science and Medicine",

issn = "2053-8790",

publisher = "BMJ Publishing Group",

number = "1",

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TY - JOUR

T1 - Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus

AU - Hanly, John G.

AU - Legge, Alexandra

AU - Kamintsky, Lyna

AU - Friedman, Alon

AU - Hashmi, Javeria A.

AU - Beyea, Steven D.

AU - Fisk, John

AU - Omisade, Antonina

AU - Calkin, Cynthia

AU - Bardouille, Tim

AU - Bowen, Chris

AU - Matheson, Kara

AU - Fritzler, Marvin J.

N1 - Funding Information: Contributors All authors participated in the collection of research data, data analysis, or writing and critical review of the manuscript. JGH is the author acting as guarantor, Funding This study was supported by the Canadian Institutes of Health Research (CIHR; MOP88526 and PJT148896, CIHR project grant 168878), Nova Scotia Health Research Foundation (NSHRF; MED-EST-2015-10067), Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN 04293-17 and RGPIN/05684-2016), Brain Canada (BC; PSG2015-3780), Mitacs (grant IT23320), Nova Scotia Research Fund, National MS Society, Research Nova Scotia, and consultation and distribution royalties from MAPI Research Trust. The funders of the study had no role in study design, patient recruitment, data collection, analysis and interpretation, or publication. Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022/6/15

Y1 - 2022/6/15

N2 - Objective Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. Methods Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. Results There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. Conclusions Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

AB - Objective Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. Methods Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. Results There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. Conclusions Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

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Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus

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