Sex Differences in Poststroke Cognitive Impairment

A Multicenter Study in 2343 Patients With Acute Ischemic Stroke

Lieza G. Exalto, PhD; Nick A. Weaver, MD; Hugo J. Kuijf, PhD; Hugo P. Aben, MD; Hee-Joon Bae, PhD; Jonathan G. Best, MD; Régis Bordet, PhD; Christopher P.L.H. Chen, MD; Ruben S. van der Giessen, PhD; Olivier Godefroy, MD, PhD; Bibek Gyanwali, MD; Olivia K.L. Hamilton, PhD; Saima Hilal, PhD; Irene M.C. Huenges Wajer, PhD; Jonguk Kim, MD; L. Jaap Kappelle, PhD; Beom Joon Kim, PhD; Sebastian Köhler, PhD; Paul L.M. de Kort, PhD; Peter J. Koudstaal, PhD; Jae-Sung Lim, MD; Stephen D.J. Makin, PhD; Vincent C.T. Mok, MD; Robert J. van Oostenbrugge, PhD; Martine Roussel, PhD; Julie Staals, PhD; Maria del C. Valdés-Hernández, PhD; Narayanaswamy Venketasubramanian, MBBS; Frans R.J. Verhey, PhD; Joanna M. Wardlaw, PhD; David J. Werring, PhD; Xin Xu, PhD; Martine J.E. van Zandvoort, PhD; J. Matthijs Biesbroek, PhD; Francesca M. Chappell, PhD; Geert Jan Biessels, PhD

Disclosures

Stroke. 2023;54(9):2296-2303..

Abstract and Introduction

Abstract

Background: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women.

Methods: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278).

Results: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61–0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45–0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17–1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively).

Conclusions: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Graphic Abstract: A graphic abstract is available for this article.

Introduction

Poststroke cognitive impairment (PSCI) is a common consequence of ischemic stroke, and a leading cause of long-term disability and reduced quality of life.^[1] PSCI occurs in approximately half of stroke survivors within the first year.^[2,3] Early detection of PSCI can facilitate tailored rehabilitation and informed planning for long-term needs.^[4]

Accumulative evidence indicates that functional outcomes of stroke are worse in women compared with men. A review on sex differences in stroke outcomes showed that women experience more activity limitations, worse quality of life, and more poststroke depression than men.^[5] Whether women and men differ with regard to PSCI is less clear,^[5] since only limited and heterogeneous studies are available,^[6–10] which differ in the definition of PSCI and cognitive assessment protocols. Most studies used a global measure of cognitive functioning, measured with screening tests like the Montreal Cognitive Assessment (MoCA). This reflects clinical practice, as a screening test is more readily available and quicker than multidomain cognitive assessment. Moreover, it remains unclear whether the cognitive profile of PSCI, that is, affected cognitive domains, differs between women and men. In Alzheimer dementia, differences in cognitive profile between women and men have previously been shown, therefore such differences might also apply to other forms of cognitive impairment, such as PSCI.^[11]

We aimed to investigate sex differences in the occurrence and type of PSCI in patients with acute ischemic stroke. As a secondary objective, we explored sex differences in the sensitivity and specificity of cognitive screening tools to identify PSCI.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline Characteristics Total Study Sample and Stratified by Sex
Characteristics	All	Women	Men	P value
Characteristics	(n=2434)	(n=913)	(n=1430)	P value
Demographic characteristics
Age in years, mean (SD)	66.2±11.8	68.3±12.3	64.9±11.3	<0.001
Education level (STROKOG), n (%)				<0.001
Less than high school	1297 (55)	648 (71)	649 (45)
High school completion	462 (20)	138 (15)	325 (23)
Technical/college diploma	226 (10)	63 (7)	163 (11)
University or higher	357 (15)	64 (7)	293 (21)
Clinical characteristics
NIHSS, median [IQR] (n=2091)	2 [1–5]	3 [1–5]	2 [1–5]	0.26
IQCODE, median [IQR] (n=1532)	3.1 [3–3.4]	3.2 [3–3.5]	3.1 [3–3.4]	<0.001
Medical history
Hypertension*	1527 (67)	616 (69)	911 (66)	0.07
Hyperlipidemia*	978 (43)	374 (42)	604 (43)	0.62
Diabetes*	640 (28)	240 (27)	400 (29)	0.33
History of stroke†‡	261 (11)	97 (11)	164 (12)	0.60
Brain imaging
Imaging timing, n days after event, median [IQR]*	5 [2–28]	5 [2–15]	5 [2–30]	0.43
Normalized acute infarct volume in mL, median [IQR]	2.8 [0.9–14.4]	2.8 [1.0–12.7]	2.8 [0.9–15.8]	0.70
Infarct type§				0.002
Small subcortical	720 (31)	315 (35)	405 (28)
Other	1623 (69)	598 (66)	1025 (72)
Cognitive testing
Timing cognitive assessment, n days after event, median [IQR]	101 [71–168]	102 [74–167]	101 [69–168]	0.65

Data are presented as mean±SD, n (%), or median [IQR]. Comparison between the sex strata by Student t (mean), Mann-Whitney U test (median), χ² for n (%) are reported as P value (unadjusted). IQCODE indicates Informant Questionnaire on Cognitive Decline in the Elderly; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; STROKOG, Stroke and Cognition; and TIA, transient ischemic attack.
*Missing in <3%.
†Missing in <1%
‡Clinical diagnosis of TIA or stroke.
§Small subcortical infarcts are defined as single supratentorial infarcts without cortical involvement, with lesion volume of ≤4.19 mL (ie, a sphere of ≤2 cm diameter); other infarct type include both supra and infratentorial large subcortical (>4.19 mL) and cortical infarcts (any volume).

Table 2. PSCI and Impairment of the Cognitive Domains
	Assessed in*	Impairment, n (%)			Women-to-men mean Δ (95% CI)
	Total n: women/men	All	Women	Men	Difference unadjusted	Difference age adjusted
PSCI	2343: 913/1430	1188/2343 (51%)	464/913 (51%)	724/1430 (51%)	0.2% (−4 to 4)	−1% (−5 to 4)
AEF	2195: 807/1388	375 (17%)	159 (20%)	216 (16%)	4% (1 to 7)†	3% (0.2 to 7)†
Speed	2091: 791/1300	360 (17%)	147 (19%)	213 (16%)	2% (−1 to 1)	2 (−2 to 5)
Language	2304: 906/1398	374 (16%)	178 (20%)	196 (14%)	6% (3 to 9)†	5% (2 to 8)†
Verbal mem.	2286: 889/1397	605 (27%)	207 (23%)	398 (29%)	−5% (−9 to −2)†	−6% (−10 to −3)†
VS functions	1875: 734/1141	509 (27%)	214 (29%)	295 (26%)	3% (−1 to 7)	2% (−3 to 6)
VS memory	806: 312/494	98 (12%)	35 (11%)	63 (13%)	−2% (−6 to 3)	−1% (−6 to 4)

Sex difference calculated as women-to-men adjusted for age. AEF indicates attention and executive functioning; speed, information processing speed; PSCI, poststroke cognitive impairment; and VS, visuospatial.
*The number of available tests and domains could differ between cohorts, but data on a minimum of 3 cognitive domains was needed to rule out PSCI.
†Significant differences (P<0.05).

Authors and Disclosures

Lieza G. Exalto, PhD, Nick A. Weaver, MD, Hugo J. Kuijf, PhD, Hugo P. Aben, MD, Hee-Joon Bae, PhD, Jonathan G. Best, MD, Régis Bordet, PhD, Christopher P.L.H. Chen, MD, Ruben S. van der Giessen, PhD, Olivier Godefroy, MD, PhD, Bibek Gyanwali, MD, Olivia K.L. Hamilton, PhD, Saima Hilal, PhD, Irene M.C. Huenges Wajer, PhD, Jonguk Kim, MD, L. Jaap Kappelle, PhD, Beom Joon Kim, PhD, Sebastian Köhler, PhD, Paul L.M. de Kort, PhD, Peter J. Koudstaal, PhD, Jae-Sung Lim, MD, Stephen D.J. Makin, PhD, Vincent C.T. Mok, MD, Robert J. van Oostenbrugge, PhD, Martine Roussel, PhD, Julie Staals, PhD, Maria del C. Valdés-Hernández, PhD, Narayanaswamy Venketasubramanian, MBBS, Frans R.J. Verhey, PhD, Joanna M. Wardlaw, PhD, David J. Werring, PhD, Xin Xu, PhD, Martine J.E. van Zandvoort, PhD, J. Matthijs Biesbroek, PhD*, Francesca M. Chappell, PhD* and Geert Jan Biessels, PhD

Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, the Netherlands (L.G.E., N.A.W., I.M.C.H.W., L.J.K., M.J.E.v.Z., J.M.B., G.J.B.). Image Sciences Institute, University Medical Center Utrecht, the Netherlands (H.J.K.). Department of Neurology, Elisabeth Tweesteden Hospital, Tilburg, the Netherlands (H.P.A., P.L.M.d.K.). Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea (H.-J.B., J.K., B.J.K.). Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, United Kingdom (J.G.B., D.J.W.). Université Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-Lille, France (R.B.). Department of Pharmacology, National University of Singapore (C.P.L.H.C., S.H., X.X.). Memory, Aging and Cognition Center, National University Health System, Singapore, Singapore (C.P.L.H.C., B.G., S.H., X.X.). Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands (R.S.v.d.G., P.J.K.). Department of Neurology, Amiens University hospital, Laboratory of Functional Neurosciences, Jules Verne Picardy University, France (O.G., M.R.). Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (O.K.L.H., M.d.C.V.-H., J.M.W.). UK Dementia Research Institute at the University of Edinburgh, United Kingdom (O.K.L.H., M.d.C.V.-H., J.M.W.). Saw Swee Hock School of Public Health, National University of Singapore and National University Health System (S.H.). Experimental Psychology, Helmholtz Institute, Utrecht University, the Netherlands (I.M.C.H.W., M.J.E.v.Z.). Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, the Netherlands (S.K., F.R.J.V.). Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (J.-S.L.). Centre For Rural Health, Institute of Applied Health Sciences, University of Aberdeen, United Kingdom (S.D.J.M.). Division of Neurology, Department of Medicine and Therapeutics (V.C.T.M.) and Therese Pei Fong Chow Research Centre for Prevention of Dementia, Margaret Kam Ling Cheung Research Centre for Management of Parkinsonism, Gerald Choa Neuroscience Centre (V.C.T.M.), The Chinese University of Hong Kong. Department of Neurology, Maastricht University Medical Center, the Netherlands (R.J.v.O., J.S.). Raffles Neuroscience Centre, Raffles Hospital, Singapore, Singapore (N.V.). Department of Neurology, Diakonessenhuis Hospital, Utrecht, the Netherlands (J.M.B.). Social and Public Health Sciences Unit (F.M.C.) and MRC/CSO Social and Public Health Sciences Unit, School of Health and Wellbeing (O.K.L.H.), University of Glasgow, United Kingdom.

Correspondence to
Lieza G. Exalto, PhD, Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the Netherlands. Email l.g.exalto-@umcutrecht.nl

*J.M. Biesbroek and F.M. Chappell contributed equally

Disclosures
Dr Aben reports grants from ZonMW (grant number 842003011). Dr Chen reports grants from the National Medical Research Council (NMRC) of Singapore and National University of Singapore. Dr Godefroy reports grants from Amiens University Hospital and the French Ministry of Health, during the last 5 years Dr Godefroy has served on scientific advisory boards and as a speaker for Novartis, CSL-Behring, Biogen, Genzyme, Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, Covidien, Teva Santé, and Astra Zeneca. Dr Hamilton is supported by the Medical Research Council (MC_UU_00022/2) and the Scottish Chief Scientist Office (SPHSU17). Dr Köhler reports grants from Nederlandse Organisatie voor Wetenschappelijk Onderzoek and grants from ZonMw. Dr Wardlaw reports grants from the Wellcome Trust, Row Fogo Charitable Trust, and the UK Medical Research Council. Dr Werring has received: grant funding from the Stroke Association and British Heart Foundation; speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and NovoNordisk; and consultancy fees from Bayer and NovoNordisk. Dr Biessels reports grants from ZonMW and Hartstichting. The other authors report no conflicts.