Introduction
The number of individuals with stroke is rising globally, along with the accompanying burden of disease and disability. Cognitive impairment and dementia after stroke are highly prevalent as shown in many hospital-based cohorts and population-based studies around the world Reference De Ronchi, Palmer and Pioggiosi1–Reference Srikanth, Quinn, Donnan, Saling and Thrift8 and are major contributors to post-stroke disability, poor quality of life, mortality, and societal costs. Reference Tatemichi, Desmond, Stern, Paik, Sano and Bagiella3,Reference Tatemichi, Paik, Bagiella, Desmond, Pirro and Hanzawa9–Reference Rockwood, Brown, Merry, Sketris and Fisk11 Mortality after stroke is declining, which will increase the potential for more survivors to experience cognitive decline. Reference Ukraintseva, Sloan, Arbeev and Yashin12,Reference Joundi, Smith, Yu, Rashid, Fang and Kapral13
However, whether cognitive decline promotes functional decline after stroke has not been well elucidated. Cognitive decline is hypothesized to mediate functional decline in the general population and in those with minor cognitive impairment or dementia. Reference Carles, Taddé and Berr14–Reference Zahodne, Manly, MacKay-Brandt and Stern16 While studies have shown an acute decline in cognitive and functional ability after stroke, recent evidence has pointed to an ongoing accelerated decline in the years following a stroke compared to the pre-stroke rate. Reference Levine, Galecki and Langa17 These studies have shown both functional decline and cognitive decline occurring simultaneously after stroke, Reference Levine, Wadley and Langa6 but whether cognitive decline mediates the relationship with functional decline in the pre-dementia phase has not been well characterized among stroke survivors. It is plausible that cognitive decline is a significant mediator of the relationship between stroke and functional decline, given the importance of cognition function in activities of daily living, Reference Carles, Taddé and Berr14 but the presence and degree of mediation by cognition decline is unknown. Given the evidence of such mediation in non-stroke survivors and the prominence of cognitive impairment after stroke, we hypothesize that cognitive decline is a mediator of functional decline among community-dwelling stroke survivors. A better understanding of these factors would aid in targeting cognitive decline as a key component of functional loss after stroke.
We sought to determine if, and to what degree, cognitive decline was a mediator of stroke-related functional decline in a population-based sample of community dwellers in Canada.
Methods
Participants
The Canadian Longitudinal Study on Aging (CLSA) is a study of approximately 50,000 individuals who were between the age of 45 and 85 years at entry with plans to follow them for over 20 years. Reference Raina, Wolfson and Kirkland18 The CLSA consists of a Tracking Cohort (N = 21,241), in which questions are administered over telephone, and a Comprehensive cohort (N = 30,097), in which participants are assessed in person at one of eleven data collection sites across Canada. We used data from the Comprehensive cohort due to the more detailed cognitive assessments. The CLSA collects a wide range of data including detailed information on sociodemographics, health and functional status, and social supports, as well as physical measurements in the Comprehensive cohort such as blood pressure, body mass index, and motor function (see https://www.clsa-elcv.ca/researchers/data-collection for the description of the data collection overview and tools). Data are available from the CLSA (www.clsa-elcv.ca) for researchers who meet the criteria for access to de-identified CLSA data. For the current study, participants were included if they had baseline (2011–2015) and follow-up (2015–2018) assessments complete including neuropsychological testing at both time points (Figure 1).
Figure 1: Participant flowchart.
Neuropsychological Testing and Normative Scores
Cognitive tests include a modified Rey Auditory Verbal Learning Test immediate recall after one learning trial (REY I) and 5-minute delayed recall (REY II), the Mental Alternation Test (MAT), Animal Fluency (AF), the Controlled Oral Word Association Test (COWAT; total score of the letters F, A, and S), and the Victoria Stroop Test with the Interference ratio (defined as the performance on the “color” task divided by performance on the “dot” task). Scores for the Stroop test were reversed to be compatible with the other tests. The neuropsychological tests are described in more detail elsewhere. Reference Tuokko, Griffith, Simard and Taler19,Reference Tuokko, Griffith and Simard20
We generated normed neuropsychological scores in multiple steps. First, for each neuropsychological test, each participant’s raw score was transformed into standardized scores (mean 0 and SD 1) based on comparisons with the healthy normative subsample. Normative comparisons require correction because measurement of cognitive function can be biased; for example, few years of education can make someone who is cognitively intact appear impaired because the cognitive tests capture educational status in addition to cognitive status. Full regression models did not reduce measurement bias (e.g., due to education), instead stratification and regression models for demographic corrections were the only method that reduced measurement bias. Reference O’Connell, Kadlec and Griffith21 In other words, any analysis that includes demographic variables as covariates in regression models will not remove measurement bias in the cognitive tests. The standardized normed scores in CLSA were adjusted for language of administration (French/English), age, sex, and years of formal education using stratification and regression models (hybrid regression models). Reference O’Connell, Kadlec and Griffith21 Second, scores were normed for baseline and follow-up separately, and then, third, reliable change scores were calculated. Reliable change scores account for error in measurement, regression to the mean, aging, and expected practice effects based on the performance of the subsample of participants who were healthy at baseline and first follow-up (O’Connell et al., in preparation). For this paper, reliable change scores were calculated for the composite memory (REYI and REYII), composite executive function (AF, MAT, COWAT, Stroop), and overall cognitive composite for participants with complete data for tests included in the respective composite scores.
Functional Status
The Older Americans Resources and Services (OARS) Multidimensional Assessment scale Reference Fillenbaum and Smyer22,Reference George and Fillenbaum23 was used to assess functional decline between baseline and follow-up. The OARS questionnaire obtains information about seven activities of daily living (dressing, feeding, taking care of appearance, walking, getting out of bed, bathing, trouble getting to the bathroom in time) and seven instrumental activities of daily living (using the telephone, ability to travel, shopping/groceries, housework, taking medicine, handling money, and meal preparation). Reference Fillenbaum24 We calculated the total number of times the respondent indicated that they need help with an activity or are completely unable to do an activity. Our primary outcome was the numerical change in the number of dependent activities from baseline to follow-up. We also assessed the outcome as any increase in dependence versus no increase in dependence.
Stroke and Other Covariates
Prior history of stroke was the primary exposure. This variable was obtained from self-report. For stroke and other co-morbidities, participants were asked to respond yes/no to the question: “Has a doctor ever told you that you have (the chronic condition)?”
Covariates included age, sex, education, self-reported co-morbidities of heart disease, peripheral vascular disease, high blood pressure, diabetes, smoking, rural residence, ethnicity, income, marital status, physical activity, fruit and vegetable consumption, and calculated body mass index. Categorization of variables is shown in Table 1. Physical activity was measured with the Physical Activity Scale for the Elderly (PASE). Reference Washburn, Smith, Jette and Janney25 PASE evaluates physical activity over the last 1 week and includes leisure, occupational, and household activities, ranging from 0 to 793 where a higher score indicates more activity. The PASE score was the only variable not collected at baseline, as it was collected as part of a maintaining contact questionnaire 18 months after the baseline assessment.
Table 1: Baseline characteristics of those with memory scores comparing people with and without stroke
Statistical Analysis
Presence of stroke was the independent variable, standardized cognitive decline was the mediator, and functional decline was the dependent variable. Figure 2 shows the hypothetical model where stroke is related to functional decline directly, as well as indirectly through cognitive decline. We first tested the three components of the pathway independently using linear regression – the association between stroke and cognitive decline (path a; first component of the indirect effect), the association between cognitive decline and functional decline (path b; second component of the indirect effect), and the association between stroke and functional decline (path c’; the direct effect). The simple association between stroke and functional decline is measured by path c, which is contrasted with path c’ where cognitive decline is modeled as a mediator removing some of the variance in the association between stroke and functional decline. Mediation was completed using the “medsem” package in Stata, which provides two approaches to the statistical analysis of mediation. The first approach to mediation was first developed by Baron & Kenny. Reference Baron and Kenny26 Structural equation modeling is used to simultaneously estimate regression coefficients for the three pathways. If all three pathways are statistically significant (steps 1–3), and c’ is reduced to zero after controlling for the mediation (step 4), then there is “full mediation.” If steps 1–3 are met but step 4 is not, there is “partial mediation.” The statistical significance of the reduction in path c’ after controlling for the mediator is determined using the Sobel test. Reference Sobel27 Medsem employs the modified approach of the above steps for use with structural equation modeling. Reference Iacobucci, Saldanha and Deng28
Figure 2: Theoretical causal model for mediation of the relationship between stroke and function decline by cognitive decline. a: association between stroke and cognitive decline; b: association between cognitive decline and functional decline; c’: association between stroke and functional decline in presence of mediator; c: association between stroke and functional decline without mediator present; a * b = indirect effect; a * b + c’ = total effect.
The second approach is based on Zhao et al., Reference Zhao, Lynch and Chen29 in which mediation can be determined solely with a bootstrap test of the indirect effect (pathways a and b), and is thought to be a better option than the Sobel test. If the confidence intervals do not include the value of zero, the indirect effect is significant. If the bootstrap test of the indirect effect is significant but path c’ remains significant after controlling for the mediator, there is partial mediation. If the bootstrap test of the indirect effect is significant and path c’ no longer significant after controlling for the mediator, there is full mediation. Medsem uses the Monte Carlo approach, an alternative to bootstrapping which is less computationally intensive. Reference Jose30–Reference Kenny33
We used both the Baron & Kenny and the Zhao approaches and compared for compatibility. We computed the presence and degree of mediation for each cognitive domain and for both functional outcomes separately. We estimated the proportion mediated by cognitive decline by calculating the proportion of the bootstrapped indirect effect (a * b) divided by the total effect (a * b + c’).
Lastly, to verify the unique role of cognition in mediation versus other control variables we replaced cognitive decline with the following potential mediators in different domains: change in depression status using the Center for Epidemiologic Studies Depression scale (CES-D-10), change in systolic blood pressure, change in Timed Get Up and Go Test, and change in Social Support Scale from baseline to follow-up. The CES-D-10 is a 10-item Likert scale questionnaire assessing depressive symptoms in the past week. Reference Andresen, Malmgren, Carter and Patrick34 It includes three items on depressed affect, five items on somatic symptoms, and two on positive affect. Options for each item range from “rarely or none of the time” (score of 0) to “all of the time” (score of 3). Total scores can range from 0 to 30. Higher scores suggest greater severity of symptoms. The Social Support Scale was adapted from the Medical Outcomes Study Social Support Survey Reference Sherbourne and Stewart35 and has 19 items which address tangible social support, affection, positive social interaction, and emotional or informational support. An overall social support score is obtained by averaging the responses over all 19 items and transforming the score into a 0–100 scale, where higher score indicates better social support. The Timed Get Up and Go Test measures the time taken to stand up and walk a distance of 3 m, turn around, walk back to the chair, and sit down again.
In a separate sensitivity analysis, the associations with functional decline were assessed with logistic regression using a dichotomous outcome of any increase in dependence. In the main models, we adjusted for age, sex, education, heart disease, peripheral vascular disease, high blood pressure, diabetes, smoking, body mass index, rural residence, and ethnicity. Although cognitive scores were normed by age, sex, and education, these variables were included to ensure that the direct causal relationship between stroke and functional decline was appropriately adjusted for confounders. In a sensitivity analysis, we excluded age, sex, and education. In the full model, additional adjustment was made for income, marital status, physical activity, and fruit and vegetable consumption. In additional sensitivity analyses we (1) reversed the order of cognitive and functional impairment, to test whether functional change is a mediator of cognitive change, (2) assessed whether baseline cognition mediates functional change, and (3) changed the independent variable to Parkinson’s disease or myocardial infarction.
Analyses were conducted in Stata 17.0 (College Station, TX).
Results
In the analytic sample, there were 22,648 individuals for which memory change scores could be derived from baseline to follow-up (325 with stroke) and 17,613 individuals with executive functioning change scores (241 with stroke; See flowchart in Figure 1). The number of people who died between baseline and follow-up was 390 (1.4%) for the non-stroke group and 19 (4.4%) for the stroke group. Median follow-up time was 2.9 years (interquartile range 2.8–3.1). Median reported time between stroke and participation in the CLSA was 6 years (IQR 2–14). Baseline characteristics for those with and without stroke in the memory sample are shown in Table 1. Those with stroke were older, less likely to be female, and more likely to have co-morbidities, lower income, and lower physical activity. Those with stroke were also more likely to have any increase in activity dependence at follow-up compared to baseline (19.7% vs. 8.1%, p < 0.001). Histograms for standardized cognitive change scores are shown in Figure 3, with a shift to greater cognitive decline in those with stroke.
Figure 3: Cognitive change scores among those with and without stroke for memory (A), executive function (B), and combining both (C).
History of stroke was significantly associated with functional decline (adjusted odds ratio [aOR] 2.31, 95% CI 1.80–2.97; Table 2). Change in cognitive performance was also significantly associated with functional decline (memory aOR 1.24 per 1 SD decline, 95% CI 1.18–1.30; executive aOR 1.25, 95% CI 1.19–1.32; and overall aOR 1.27, 95% CI 1.20–1.34). Results from the full model were similar (Table 2). History of stroke was also associated with significantly lower cognitive scores at baseline and follow-up, as well as greater decline in cognitive scores between baseline and follow-up (Table 3).
Table 2: Associations between stroke and cognitive change with functional loss
Changes in cognitive scores are continuous variables (standardized change scores), and odds ratios are per 1 SD lower change score.
Main model adjusted for age, sex, education, heart disease, peripheral vascular disease, high blood pressure, diabetes, smoking, body mass index, rural residence, and ethnicity, and full model additionally adjusted for income, marital status, physical activity, and fruit and vegetable consumption.
Table 3: Association between stroke and cognitive performance
Estimates represent change in SD for cognitive performance in presence of stroke.
Main model adjusted for age, sex, education, heart disease, peripheral vascular disease, high blood pressure, diabetes, smoking, body mass index, rural residence, and ethnicity, and full model additionally adjusted for income, marital status, physical activity, and fruit and vegetable consumption.
There was significant mediation of the relationship of stroke with functional decline by memory, executive, and overall cognitive decline (Table 4). The relation between stroke and functional decline was partially mediated by declines in memory, but this was small (at 5% in the fully adjusted model). Declines in executive function mediated 13% of the relation between stroke and functional decline and overall cognition mediated 22% of the relation between stroke and functional decline. Results remained similar in the full model and when removing age, sex, and education from the model (as these variables were adjusted for in the use of normed cognitive scores). In the sensitivity analysis, substituting the cognitive mediator for other control variables, or reversing the order of cognitive and functional change resulted in no significant mediation. Lastly, there was no mediation when substituting stroke for Parkinson’s disease or myocardial infarction. The results for both mediation methods (Baron & Kenny and Zhao) were compatible for all analyses.
Table 4: Mediation of stroke-functional decline relationship by cognitive decline
The estimate of indirect effect represents the product of the coefficients of path a (association between stroke and cognitive decline) and path b (association between cognitive decline and functional decline). The total effect represents the estimate of indirect effect + the estimate for path c’ (association between stroke and functional decline). The amount of mediation is the indirect effect divided by the total effect.
Discussion
In this cohort study, we found that history of stroke was associated with both cognitive decline and functional decline over a median of 3 years of follow-up among community dwellers. Furthermore, cognitive performance was a significant mediator of the relation between stroke and functional decline. The greatest mediation proportion of 22% was observed for overall cognitive change, which is a composite of the tests measuring memory and executive functioning. Our results suggest that recognizing and preventing cognitive decline in stroke survivors may help preserve function.
Cognitive decline and dementia after stroke are well recognized. The OXVASC study demonstrated an incidence for post-event dementia of 34.4% among survivors of major stroke and 8.2% in those with minor stroke at 1 year, with risk increasing into 5-year follow-up. Reference Pendlebury and Rothwell5 The population-based REGARDS study in the US showed that participants with stroke had accelerated and persistent cognitive decline over 6 years. Reference Levine, Galecki and Langa17 Cognitive deficits are even present in long-term follow-up among younger individuals with stroke, Reference Schaapsmeerders, Maaijwee and van Dijk36 and among those with TIA. Reference van Rooij, Kessels, Richard, Leeuw and van Dijk37,Reference van Rooij, Schaapsmeerders and Maaijwee38 The relationship between cognition and function is less clear. Functional decline is also known to occur progressively after stroke, as the proportion of patients with functional independence after stroke declines yearly. Reference Dhamoon, Moon and Paik39 Furthermore, a number of studies have shown both functional decline and cognitive decline simultaneously after stroke. Reference Levine, Galecki and Langa17 A clinical trial on nitric oxide in stroke showed cognition was associated with functional impairment in cross-sectional associations. Reference Ankolekar, Renton and Sare10 Observational studies have shown that cognitive impairment is independently associated with dependent living after adjustment for age, physical impairment, and other factors. Reference Tatemichi, Desmond, Stern, Paik, Sano and Bagiella3 This is compatible with the fact that baseline cognitive impairment predicts rate of functional decline in people with dementia. Reference Atchison, Massman and Doody40 However, whether longitudinal decline in cognition is related to decline in functional impairment is not well understood. Furthermore, it is unknown whether cognitive decline mediates the greater functional decline seen in people with stroke compared to those without stroke.
Our study found that cognitive decline was a mediator of functional decline attributable to prior stroke. The degree of mediation from executive function decline was greater than for memory decline, in keeping with evidence that executive control and is more important than episodic memory for activities of daily living. Reference Royall, Palmer, Chiodo and Polk41,Reference Pillai, Bonner-Jackson, Walker, Mourany and Cummings42 Although there was “full mediation” in the mediation model by overall cognitive decline, the degree of mediation overall was only 22%. There are multiple potential explanations for the moderate amount of mediation. Firstly, cognitive testing under structured conditions likely incompletely captures cognitive function required for daily tasks. The challenges of neuropsychological tests predicting daily function are well known (i.e., the evidence for ecological validity is lacking Reference Howieson43 ). Second, only memory and executive function were tested; other domains such as social cognition, visuospatial function, and praxis were not specifically tested and are important for activities of daily living. Third, other factors may be important mediators of functional decline, including frailty and sarcopenia, impact of recurrent stroke and other co-morbidities, inflammation and post-stroke neurodegeneration. Reference Srikanth, Quinn, Donnan, Saling and Thrift8,Reference Lo, Crawford and Desmond44–Reference Wallace, Theou, Godin, Andrew, Bennett and Rockwood47 Changes in psychological health, motor function, and loss of social supports may also have importance, although we found no mediation by surrogate measures of these items. While the mechanisms of post-stroke cognitive decline in the chronic phase of stroke are unknown, possible pathways include accelerated brain atrophy, Reference Brodtmann, Khlif, Egorova, Veldsman, Bird and Werden48 induction of accelerated amyloid deposition possibly through interference with amyloid clearance pathways, Reference Garcia-Alloza, Gregory and Kuchibhotla49 as well as inflammatory changes. Reference Doyle, Quach and Solé50 These alterations may impact on cognitive test performance and daily function in overlapping but also independent ways. Nevertheless, in our analysis there was no reciprocity between functional and cognitive decline. Our results support the directionality of the hypothesized model that cognitive changes are one of the causal mechanisms by which functional decline occurs after chronic stroke. In contrast, cognitive decline was not mediated functional decline within the median 3 years of follow-up of our study. This further emphasizes the potential of cognitive vulnerability and impairment as a primary target to prevent functional decline after stroke.
Our results confirm that stroke survivors, even in the chronic phase after stroke, have greater cognitive and functional decline compared to control counterparts. Therefore, individuals with prior stroke warrant monitoring for cognitive decline years after the event. Preventing or slowing cognitive impairment may also be an avenue toward preserving long-term function. Vascular risk factor management is associated with long-term reduced risk of cognitive impairment, including, or combination of antihypertensives, anti-thrombotics, and lipid-lowering medications. Reference Douiri, McKevitt, Emmett, Rudd and Wolfe51 Lifestyle factors such as physical activity have also been associated with post-stroke cognition. Reference Oberlin, Waiwood, Cumming, Marsland, Bernhardt and Erickson52 Further well designed prospective studies and clinical trials are needed to identify targets and treatments vascular cognitive impairment after stroke. Reference Dichgans and Zietemann53
Our study had limitations. Results were generalizable only to community-dwelling stroke or survivors in the chronic phase, without aphasia or dementia. Participants had a median time from stroke to CLSA participation of 6 years, with a wide IQR of 2–14. Rates of cognitive and functional decline and strength of mediation may vary depending on time since stroke, but our sample size was not large enough to analyze by time subgroup and this should be considered for future studies. We were unable to control for stroke features, such as stroke type, severity, location, or laterality. Selective attrition may lead to underestimation of cognitive decline as participants with the worst cognition may have dropped out or died. We did not capture the immediate post-stroke period where significant cognitive decline could occur, and participants may have already experienced a substantial amount of cognitive decline by baseline assessment, as evidenced by the lower scores at baseline among those with stroke. We could not account for recurrent stroke, which may be an important mediator of cognitive decline. Reference Srikanth, Quinn, Donnan, Saling and Thrift8 Our study also relied on self-reported stroke, which has moderate agreement with hospital-recorded stroke. Reference Jackson, Mishra, Tooth, Byles and Dobson54,Reference Engstad, Bonaa and Viitanen55
In conclusion, cognitive performance decline, particularly in the executive domain, is a mediator of functional decline in a cohort of community-dwelling chronic stroke survivors. Strategies to prevent cognitive decline after stroke to preserve function should be further studied.
Acknowledgements
This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). Funding for the CLSA is provided by the Government of Canada through the Canadian Institutes of Health Research under grant reference: LSA 94473 and the Canada Foundation for Innovation, as well as the following provinces, Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia. This research has been conducted using the CLSA datasets: Baseline Tracking Dataset version 3.6, Baseline Comprehensive Dataset version 5.0, Follow-up 1 Tracking Dataset version 2.1, and Follow-up 1 Comprehensive Dataset version 3.0, under Application ID 2006010. The CLSA is led by Drs. Parminder Raina, Christina Wolfson and Susan Kirkland.
RJ was supported by a Canadian Institutes of Health Research Fellowship Grant (MFE 164702).
Statement of Authorship
RJ was involved with the project conception, analysis, and writing of the manuscript; MO and ES were involved with analysis and critical revision of the manuscript; SP was involved with critical revision of the manuscript.
Disclosures
ES (University of Calgary) has had research services contracts with McMaster University and the Ottawa Heart Institute to analyze MRI scans collected in clinical trials.
MO has received honoraria from Roche Canada.
Disclaimer
The opinions expressed in this manuscript are the author’s own and do not reflect the views of the Canadian Longitudinal Study on Aging.
