https://orcid.org/0009-0009-9630-6453
Figures
Abstract
Introduction
Post-stroke cognitive impairment (PSCI) and dementia may have a significant impact on stroke recurrence and long-term functional outcomes of patients.
Aim
To investigate the potential link between PSCI and dementia, and stroke recurrence, mortality, and poor functional outcomes of stroke survivors.
Methods
A systematic search across Medline, Google Scholar, and Science Direct databases was done for studies that evaluated the association of PSCI and dementia with long-term stroke outcomes. The results were expressed as pooled hazard ratios (HR) with 95% confidence intervals (CI), and heterogeneity was assessed using the I2 statistic and the Chi-square test. Subgroup analyses were performed based on the sample size, geographical location, follow-up, and type of dementia/cognitive impairment. Study quality was evaluated using the Newcastle Ottawa Scale (NOS).
Results
The meta-analysis included thirteen studies. Of them, ten studies (n = 4036) reported a significant association between PSCI and stroke recurrence, with a pooled HR of 1.33 (95% CI: 1.14–1.55, I2 = 84.6%). Subgroup analysis revealed a statistically significant association between PSCI and stroke recurrence across various subrgoups. Four studies (n = 1944) demonstrated that patients with PSCI had a higher risk of poor functional outcome, with a pooled HR of 1.68 (95% CI: 1.16–2.05, I2 = 80.0%). However, the multivariate analysis did not detect a significant association between PSCI and stroke mortality, with a pooled HR of 1.50 (95% CI: 0.94–2.40, I2 = 45.9%).
Conclusions
The study showed that PSCI was associated with 33% increased stroke recurrence and 68% higher rate of poor functional outcome. Our findings underscore the adverse impact of PSCI on stroke recurrence and functional outcomes, emphasizing the importance of early detection and targeted interventions to mitigate the cognitive impairment burden in stroke survivors.
Citation: Yu J, Wang J (2024) Effect of post-stroke cognitive impairment and dementia on stroke recurrence and functional outcomes: A systematic review and meta-analysis. PLoS ONE 19(12): e0313633. https://doi.org/10.1371/journal.pone.0313633
Editor: Pengpeng Ye, National center for chronic and non-communicable diesease prevention and control, CHINA
Received: June 11, 2024; Accepted: October 28, 2024; Published: December 3, 2024
Copyright: © 2024 Yu, Wang. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files. This study is a meta-analysis and systematic review. All of the literature for analysis were summarized in Table 1. The relevant papers can be publicly retrieved from the following databases: PubMed, Science Direct, Google Scholar, and Scopus databases.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Stroke is a leading cause of mortality and disability worldwide and an important public health issue [1]. In 2019, stroke remained the third most common cause of disability (5.7 percent of total disability-adjusted disability years [DALYs]) and the second most common cause of death worldwide (11.6% of total deaths) [2]. Recent studies have also reported that this burden has substantially increased since 1990 [2]. Stroke is also associated with a significant burden on the healthcare system due to its association with numerous long-term physical and cognitive complications in survivors [3].
Stroke is the leading cause of mortality in China, where the latest China stroke surveillance report, 2021 has stated that approximately 12.5% (95% CI 12.4–12.5%) of stroke survivors are left disabled [4, 5]. It is estimated that Post-stroke cognitive impairment (PSCI) is considered one of the main stroke complications. PSCI encompasses a spectrum of cognitive deficits ranging from mild impairment to post-stroke dementia (PSD), significantly compromising patients’ quality of life and functional independence [6]. It is defined as impairment of any of the six cognitive subgroups—visuoconstruction, attention, verbal memory, language, visual memory, and visuomotor function [7].
Studies have reported that PSCI prevalence rates range from 20% to 80%, underscoring its pervasive impact on stroke outcomes [8]. Dementia is a syndrome with a variety of underlying causes, overlapping symptoms, and diverse pathologies that impair the behavioral and cognitive capacities of patients [9]. Studies show that about 25% of stroke survivors develop PSD [10]. Moreover, estimates suggest a threefold increase in dementia incidence in patients after stroke [11]. This cognitive decline, associated with stroke, not only exacerbates functional disability but also amplifies the risk of recurrent stroke, thereby creating a vicious cycle of neurological deterioration [12].
While there is a body of research on the prevalence of PSCI and dementia in patients with stroke, studies that specifically focus on long-term follow-up of patients with PSCI/dementia and stroke are scarce. This study aims to evaluate the effect of PSCI and PSD on mortality, recurrence, and functional outcomes of stroke survivors.
Materials and methods
A systematic search across PubMed, Science Direct, Google Scholar, and Scopus databases was done for studies published up to March 2024. Studies reporting on the effect of PSCI and PSD on selected clinical outcomes among patients with any type of stroke were reviewed by two independent authors. The review was done with the latest “Preferred reporting items for systematic reviews and meta-analyses (PRISMA)” framework [13]. The review was prospectively registered in PROSPERO (CRD42024528158). Data were extracted separately, and any conflicts of extracted information were resolved by mutual consensus. Ethical approval was not applicable since data was extracted from freely available sources. We included only articles in English in our review.
Inclusion and exclusion criteria
- Population: Adult patients (>18 years of age) who presented with any type of stroke (except for Transient ischemic attacks (TIA) and intra-cerebral hemorrhages) were included as the study population. Only patients who presented with acute stroke were included, while patients who were on rehabilitative therapy were excluded. Studies that included patients diagnosed with dementia or cognitive impairment before stroke were excluded.
- Exposure: The exposure of interest was post-stroke cognitive impairment and dementia. We accepted any recommended definition of dementia or cognitive impairment used by the individual studies.
- Outcome: Our primary outcome of interest was stroke recurrence during the follow-up period. Our secondary outcomes include poor functional outcomes and all-cause mortality.
- Study design: We included all analytical studies (prospective, retrospective, and cross-sectional studies).
Search strategy
We utilized medical subject heading (MeSH) terms such as: “Stroke” OR “Cerebrovascular accident” AND “Dementia” OR “Cognitive impairment” AND “Functional outcomes” OR “Mortality” OR “Recurrence” AND “Observational studies” OR “Cohort studies” OR “Prospective studies” among the included databases. The references of included studies were also reviewed to look for similar studies focusing on the same research question. The detailed search strategy is also explained in S1 Table.
Data extraction and management
The two authors independently extracted data, including author details, publication year, study design, sample size, geographical location, inclusion criteria, definition of cognitive impairment/dementia, tools used to classify cognitive impairment/dementia, etc.
Statistical analysis
We performed all statistical analyses using STATA 14.2. The collected data were double-checked for data entry errors and verified for completeness. We summarized primary (recurrence) and secondary outcomes (functional outcome and mortality) as hazards ratio (HR) with 95% confidence interval (CI). Estimates were pooled using the random effects model and Mantel-Haenszel method due to considerable clinical and high statistical heterogeneity. The effect sizes were pooled separately if univariate and multivariate estimates of HRs were provided in the individual studies. The results, in the form of pooled effect sizes, were visually depicted through forest plots. To assess publication bias, we employed funnel plots to check for the asymmetry of the funnel plot and verified it using Egger’s test [14] A p-value of less than 0.05 was considered indicative of statistical significance.
Assessment of heterogeneity
Heterogeneity was measured using the I2 test, categorizing percentages into ranges: 0%–40% indicating possibly no heterogeneity, 30%–60% suggesting moderate heterogeneity, 50%–90% denoting substantial heterogeneity, and 75%–100% indicating considerable heterogeneity.
Quality assessment of included studies
The quality of the included studies was evaluated using the Newcastle Ottawa Scale (NOS) [15]. This scale assesses study quality based on three criteria: ascertainment of outcomes, selection of study groups, and comparability. In the selection and outcome categories, a study can receive a maximum of one star for each numbered item. For comparability, a maximum of two stars can be assigned. Therefore, the NOS allows for a maximum score of nine for each study.
Results
Study selection
The initial literature search identified a total of 6112 articles. Of them, 5429 duplicates were removed, and another 617 studies were excluded as ineligible during the secondary screening. Of the remaining 66 studies, 29 free full-text articles were retrieved. Finally, 13 articles that met eligibility criteria were included in our systematic review and meta-analysis [6, 16–27]. Ten articles reported on the effect of PSCI and/or dementia on stroke recurrence [16, 18–23, 25–27], six reported on the association of PSCI and/or dementia with mortality [6, 16, 21, 23–25], and four reported on the effect of PSCI and/or dementia on functional outcome [17, 18, 24, 27]. The PRISMA 2020 flow diagram is explained in Fig 1.
Characteristics of the included studies
General characteristics of the included studies are detailed in Table 1. Of the 13 included studies, seven were from Asia, three were from America, and three were from Europe. The included studies had sample sizes ranging from 66 to 1528, and all 13 reported results in the English language. Four studies reported on dementia, while the nine had information on PSCI. We attempted to contact the authors individually to obtain the free full texts, and the articles were excluded if we failed to receive any response from the authors even after two consecutive mail attempts.
Excluded studies
Of the 29 full-text articles extracted, 17 were excluded during secondary screening. Nine studies were excluded because they had different study participants, and eight were reported in languages other than English.
Effect of PSCI and/or dementia on recurrence among stroke patients
Ten studies (n = 4036) reported the association (univariate) between PSCI and/or dementia and recurrence among stroke patients. Patients with any form of PSCI had a 33% higher risk of stroke recurrence during the follow-up period (pooled HR of 1.33, 95% CI: 1.14–1.55, with high heterogeneity I2 = 84.6, p-value <0.001) [Fig 2]. Only three studies reported on the multivariate-adjusted estimates, showing a non-significant association (pooled HR of 1.37, 95% CI: 0.81–2.32, with high heterogeneity I2 = 87.9, p-value <0.001) [S1 Fig] Due to high heterogeneity, subgroup analysis was done based on the region, type of exposure, and sample size. The results showed that studies conducted in the Asian subcontinent and reporting the effect of cognitive impairment with no dementia on recurrence had a statistically significant association, with very low heterogeneity [S2–S4 Figs]
Effect of PSCI and/or dementia on functional outcome among stroke patients
Four studies (n = 1944) reported the association between PSCI and/or dementia and functional outcomes in stroke patients. Patients with any form of PSCI had a 2.68 times higher risk of having poor functional outcomes during the follow-up period (pooled HR of 2.68, 95% CI: 1.76–4.09, with high heterogeneity I2 = 80.0, p-value <0.001) [Fig 3]. Three studies reported on the multivariate-adjusted estimates and showed that patients with any form of PSCI had 54% higher hazards of having poor functional outcomes after adjusting for known confounders (pooled HR of 1.54, 95% CI: 1.16–2.05, with very low heterogeneity I2 = 18.2, p-value 0.30) [S5 Fig]
Effect of PSCI and/or dementia on mortality among stroke patients
Six studies (n = 3323) reported the association between PSCI and/or dementia and mortality in stroke patients. Any form of PSCI was associated with 2.25 times higher risk of mortality (pooled HR of 2.25, 95% CI: 1.38–3.67, with high heterogeneity I2 = 78.1, p-value <0.001). [Fig 4] Four studies reported on the multivariate-adjusted estimates, with a non-significant association (pooled HR of 1.50, 95% CI: 0.94–2.40, with moderate heterogeneity I2 = 45.9, p value 0.13) [S6 Fig]
Publication bias and risk of bias
Presence of publication bias for association between exposure and recurrence was detected on funnel plot and Egger test (p value 0.01) [Fig 5]. Table 1and S2 Table summarizes risk of bias in the included studies, as assessed by NOS checklist for observational studies. The difference in effect estimates for various outcomes with respect to risk of bias scores is shown in S7 Fig.
Discussion
Our meta-analysis included 13 studies that investigated the impact of post-stroke cognitive impairment (PSCI) and post-stroke dementia (PSD) on stroke recurrence, functional outcomes, and mortality. We observed the diagnosis of PSCI and/or dementia in stroke survivors was associated with considerably poorer functional outcomes, even after adjusting for known confounders. Our results also showed a significant association between PSCI and mortality and stroke recurrence. However, this association became insignificant in multivariable analysis. Our results provide new insights into the complex relationship between PSCI, stroke recurrence, and long-term outcomes, contributing to the growing body of research on post-stroke care.
The analysis of 10 studies (n = 4036) revealed that stroke patients with PSCI or dementia had a 33% higher risk of stroke recurrence during the follow-up period. These results were in line with the study by Hanon et al., which reported data over a 12-year follow-up [28]. In addition, a study by Cumming et al. showed that cognitive impairment is linked to poor quality of life at one-year follow-up [29]. Together, these results suggest that while cognitive impairment may indicate a higher risk of recurrence, other factors—such as vascular risk profiles, medication adherence, and the severity of the initial stroke—may contribute significantly to this risk [30, 31]. The observed high heterogeneity indicates that individual study differences, including population characteristics, study design, and methods of cognitive impairment assessment, play a role in the variability of results. Subgroup analyses provided additional insights, showing that studies conducted in the Asian subcontinent and those focused on cognitive impairment without associated dementia showed a statistically significant link to recurrence, with lower heterogeneity. This regional variation underscores the importance of considering geographic factors and sociocultural determinants in understanding the relationship between cognitive impairment and stroke outcomes [6]. Several underlying pathophysiological mechanisms can explain the observed association between PSCI and stroke recurrence. Cognitive impairment following stroke often results from cerebral vascular damage, including small vessel disease, cortical infarcts, and white matter lesions [32]. These structural alterations disrupt neural networks involved in executive function, attention, and memory, predisposing patients to impaired cerebrovascular autoregulation and increased susceptibility to recurrent ischemic events [33]. The ischemic cascade triggers excitotoxicity, oxidative stress, inflammation, and apoptosis, resulting in neuronal death and tissue damage. Following cerebral ischemia, inflammatory processes are initiated, with microglia and astrocytes releasing pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 [34, 35]. This inflammation worsens neuronal damage and contributes to cognitive decline. Furthermore, post-stroke cognitive impairment was shown to be related to white matter lesions, such as leukoaraiosis and lacunar infarcts, that may cause executive dysfunction and slower cognitive processing [36]. Additionally, cognitive impairment may compromise compensatory mechanisms such as cognitive reserve and neuroplasticity, rendering individuals more vulnerable to neurological insult and subsequent stroke recurrence [20].
Our results also showed that PSCI is strongly associated with poor functional outcomes. These results align with the existing literature suggesting that cognitive impairment following stroke not only affects cognitive domains but also interferes with physical recovery and functional independence [36, 37].
Recommendations
The association between PSCI, dementia, and various stroke outcomes underscores the need for early detection and intervention strategies aimed at improving cognitive impairment and optimizing functional post-stroke recovery. Additionally, including cognitive outcomes in stroke trials and rehabilitation assessments could provide a more comprehensive picture of recovery. Since current stroke outcome measures, such as the Modified Rankin Scale (mRS) and Barthel Index, focus primarily on physical function and disability, they may not adequately capture the cognitive aspects of recovery. Incorporating cognitive measures, such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE), could improve the ability to predict long-term outcomes and guide individualized rehabilitation plans.
Strengths and limitations
Our study had several strengths. To the best of our knowledge, this is the first meta-analysis that has tried to establish the relationship between PSCI/dementia and specific stroke outcomes in survivors. We have also performed additional subgroup and sensitivity analysis (using NOS), adding to the limited literature available. A large sample size of the included studies adds robustness to our results and increases their generalizability. All studies were reviewed separately by the two investigators. Nevertheless, our review has a few limitations. First, there was evidence of high heterogeneity among the included studies, which might have impacted the combined results. Although subgroup analysis and sensitivity analyses were used to adjust for heterogeneity, the underlying variability in methodologies, tools used for defining cognitive impairment and dementia, and duration of follow-up should be considered when interpreting the results. Additionally, we need to acknowledge the potential impact of the publication bias on the interpretation of our results. Lastly, this review included only free full-text English-language articles, while the grey literature was excluded.
Conclusions
In summary, our systematic review and meta-analysis highlight the adverse effect of post-stroke cognitive impairment and dementia on stroke recurrence and functional outcomes. Healthcare providers should prioritize routine cognitive screening in stroke survivors, utilizing validated tools to detect early signs of cognitive impairment. Early identification of cognitive impairment will enable prompt initiation of targeted interventions, including cognitive rehabilitation, pharmacological management, patient education, and lifestyle modifications. Our study also emphasizes the need for a multidisciplinary approach to reduce the risk of adverse stroke outcomes. Future research must also focus on standardized assessment scales and adopt newer interventions to improve the cognitive function of stroke survivors.
Supporting information
S1 Fig. Forest plot showing the association between PSCI/dementia with recurrence (adjusted).
https://doi.org/10.1371/journal.pone.0313633.s001
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S2 Fig. Forest plot showing the association between PSCI/dementia with recurrence grouped by continent.
https://doi.org/10.1371/journal.pone.0313633.s002
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S3 Fig. Forest plot showing the association between PSCI/dementia with recurrence grouped by type.
https://doi.org/10.1371/journal.pone.0313633.s003
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S4 Fig. Forest plot showing the association between PSCI/dementia with recurrence grouped by sample size.
https://doi.org/10.1371/journal.pone.0313633.s004
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S5 Fig. Forest plot showing the association between PSCI/dementia with functional outcome (adjusted).
https://doi.org/10.1371/journal.pone.0313633.s005
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S6 Fig. Forest plot showing the association between PSCI/dementia with mortality (adjusted).
https://doi.org/10.1371/journal.pone.0313633.s006
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S7 Fig. Forest plot showing the association between PSCI/dementia with recurrence grouped by NOS.
https://doi.org/10.1371/journal.pone.0313633.s007
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S2 Table. Components of Newcastle-Ottawa Scale across the included studies (NOS).
https://doi.org/10.1371/journal.pone.0313633.s009
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S2 File. A numbered table of all studies identified in the literature search.
https://doi.org/10.1371/journal.pone.0313633.s011
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S3 File. All data extracted from the primary research sources for the systematic review and/or meta-analysis.
https://doi.org/10.1371/journal.pone.0313633.s012
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S4 File. The completed risk of bias and quality/certainty assessments for each study or outcome.
https://doi.org/10.1371/journal.pone.0313633.s013
(DOCX)
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