But this isn't about how much sex you need to have to prevent cognitive decline, SO WHAT THE FUCK GOOD IS THIS?
Sex differences in predictors for cognitive decline and dementia in people with stroke or transient ischemic attack in the PROGRESS trial
Jessica Gonghttps://orcid.org/0000-0001-6027-76401, Katie Harris1, Christophe Tzourio2,3, Stephen Harrap4, Sharon Naismith5,6, Craig S Anderson7,8,9, John Chalmershttps://orcid.org/0000-0002-9931-05801, and Mark Woodward1,10
Background
Background
Stroke and transient ischemic attack confer greater risk of cognitive decline and dementia.
Aims
We used data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a blood pressure-lowering randomized controlled trial in stroke/transient ischemic attack. We evaluated overall and sex-specific differences in treatment effects for cognitive decline/dementia, as well as associations with vascular and stroke-specific predictors,considering death as a competing risk.
Methods
Multinomial logistic regression was used to estimate overall and sex-specific odds ratios (OR) (95% confidence intervals (CI)) for treatment effects and predictors associated with the risk of cognitive decline/dementia, and the women-to-men ratio of odds ratio (RORs).
Results
Over a median four years, 763 cognitive decline/dementia (30.9% women) were recorded in 5888 participants. Women had lower odds of cognitive decline/dementia than men (OR 0.78, 95%CI 0.63–0.95). Active treatment was associated with lower odds of cognitive decline/dementia (0.84, 0.72–0.98), with no evidence of sex difference. Higher education (0.96,0.94–0.98 (per year)) and baseline Mini-Mental State Examination (MMSE)) were associated with lower odds of cognitive decline/dementia (0.84,0.82–0.86 (per point higher)). Higher diastolic blood pressure (1.11,1.02–1.20 (per 10 mmHg)), low estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (1.27,1.03–1.58), and peripheral arterial disease (1.78,1.26–2.52) were associated with higher odds of cognitive decline/dementia. APOE ɛ4 was not associated with cognitive decline/dementia (1.05 (0.85–1.30)). Low eGFR was more strongly associated with cognitive decline/dementia in women than men (RORs, 1.60 (1.03–2.48)). Diabetes was more strongly associated with men than women.
Conclusions
Several risk factors were associated with cognitive decline/dementia in people with prior stroke/transient ischemic attack, with notable sex differences. Long-term cognitive sequelae of stroke should be considered to strengthen joint prevention strategies for stroke, cognitive decline, and dementia.
Trial Registration: This trial was not registered because enrolment began before 1 July 2005.
Keywords
Stroke, dementia, cognitive decline, sex difference, competing risk
1George Institute for Global Health, University of New South Wales, Sydney, Australia
2Bordeaux Population Health Research Center, Bordeaux University, INSERM, Bordeaux, France
3Hospital Center Bordeaux University, Bordeaux, France
4Department of Physiology, University of Melbourne, Melbourne, Australia
5School of Psychology, University of Sydney, Sydney, Australia
6Brain and Mind Centre, University of Sydney, Sydney, Australia
7George Institute China, Peking University Health Science Center, Beijing, China
8Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, Australia
9Heart Health Research Center, Beijing, China
10George Institute for Global Health, Imperial College London, London, UK
Corresponding author(s):
Jessica Gong, George Institute for Global Health, University of New South Wales, Level 5/1 King Street, Newtown, NSW 2042, Australia. Email: jgong@georgeinstitute.org.au
Stroke and transient ischemic attack (TIA) are linked to worse cognition, accelerated cognitive decline (CD), and dementia.1,3–5 Epidemiological and genetic studies suggest overlapping susceptibility factors between CD, dementia, and stroke.6 There are also reciprocal interactions between cerebrovascular disease and neurodegeneration at a pathological level.1,7,8
The Oxford Vascular Study (OxVasc) provided some clarity on how individual characteristics may predict these adverse outcomes.6 Yet, several questions remain, including predictors for cognitive impairment not satisfying criteria for dementia and the generalizability to other ethnicities.9 Death may preclude the development of dementia or CD,7 but this important consideration of death as a competing risk has not been widely incorporated in prior studies of poststroke CD/dementia.
Further, while sex is an important effect modifier for many diseases including stroke and dementia,10 sex differences in risk factors for CD/dementia have not been explored in stroke/TIA. A study in a general population, free of stroke at baseline, found that several risk factors are more strongly associated with incident stroke in women than men.11 Considering the commonality of risk factors for stroke and dementia, sex can have a fundamental influence on their reciprocal relationship.
Aims
Given these evidence gaps, our study examined the overall, and sex differences in, effects of blood pressure (BP)-lowering treatments, major vascular and stroke-specific predictors associated with CD/dementia in people with prior stroke/TIA, including death as a competing risk, using the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) randomized controlled trial (RCT).
Methods
Study design and participants
The main results from PROGRESS have been described elsewhere.12,13 In brief, PROGRESS was an RCT of 6105 individuals recruited from 172 collaborative centers in 10 countries (Australia, New Zealand, China, Japan, England, Ireland, France, Belgium, Italy, and Sweden) from 1995 to 1997. Participants were eligible to enter the study, with a history of cerebrovascular disease, including stroke/TIA (but not subarachnoid hemorrhage) in the previous five years. Participants were required to have no contraindication or clear indication for angiotensin-converting enzyme inhibitors use. After a four-week run-in period, participants were randomized to active treatment; a flexible regimen of perindopril (4 mg daily) for all participants, with/without the addition of indapamide (2.5 mg daily/2 mg in Japan); or matching placebo(s). Ethical approvals were obtained from institutional ethics committees of each collaborating center, and all participants provided written informed consent.
Measurement of putative risk factors
At study baseline, information about participant’s sex, birth date, age at highest level of education attained, ethnicity, and region of residence were collected; a history of concurrent diseases, including diabetes (insulin and non-insulin dependent), myocardial infarction, atrial fibrillation, and peripheral arterial disease (PAD); lifestyle habits including alcohol use and smoking were self-reported. Weight and height measurements were taken, and body mass index (BMI) was calculated. Repeated BP measurements were averaged to define baseline BP. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine measured at baseline, using the updated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation14,15 and defined as low if <60 ml/min/1.73 m2. The Mini-Mental State Examination (MMSE)16 was administered to assess cognitive function.
Stroke at baseline was categorized as (1) TIA/amaurosis fugax; (2) unknown stroke; (3) ischemic stroke only; (4) hemorrhagic stroke only; (5) ischemic and hemorrhagic stroke. Barthel Index of Activities of Daily Living (BI)17 was used to assess disability, with higher BI indicating less disability. Poststroke dependency and recovery were assessed through the Lindley Questions18: “In the last two weeks has the patient required regular help with everyday activities?” (dependency question) and “Does the patient feel that he or she has fully recovered from previous cerebrovascular events?” (recovery question).
Lymphocytes were isolated from peripheral blood for subsequent DNA extraction and genotyping for APOE polymorphism (http://www.genevcanvas.org).19 APOE was characterized as one of the six genotypes: ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, or ɛ4/ɛ4. APOE ɛ4 status was recorded positive for ɛ3/ɛ4 or ɛ4/ɛ4 genotype.
Assessment of cognitive function, CD, and dementia
Both CD and dementia were pre-specified secondary outcomes in PROGRESS.
Cognitive function was assessed using MMSE at baseline, six-, and 12-month visits, then annually until end of the follow-up (Supplementary Figure 1). CD was defined as a three-point or more decrement on MMSE between baseline and last recorded score.
A two-phase screening and assessment process were implemented for dementia diagnosis over follow-up. If the participant screened positive for possible dementia, they were referred for formal diagnostic clinical assessment by a specialist experienced in diagnosing dementia. The clinical assessment for ascertaining dementia was conducted through interviews. Information was gathered via a checklist based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria.19
For all cases that screened positive for dementia, the diagnosis made by the local specialist were further reviewed by a central Dementia Adjudication Committee comprising two neurologists. Dementia was defined as “certain dementia” or “fairly certain dementia” based on the adjudication. All screen-negative cases were classified as “no dementia.” Further details of the CD/Dementia assessment are presented in the supplementary methods.
Statistical analysis
Baseline characteristics by sex were summarized using mean (standard deviation) or median (interquartile interval) for continuous variables, and number (percentage) for categorical variables. Odds ratios (ORs) were estimated using multinomial regression models, with outcomes defined as (0) neither CD nor dementia nor death (reference); (1) CD or dementia, regardless of whether the participants died before the end of follow-up; (2) the competing risk of death preceding CD or dementia. Since the onset of CD and dementia are highly insidious, time to event models may not be reliable.
The effect of BP-lowering treatment in PROGRESS on the risk of CD and dementia has been reported elsewhere5; the present study expands on this by reporting the effects of randomized treatment effects, and a comprehensive list of genetic, cardiometabolic, and stroke-specific predictors by sex and considers competing risk of death. Randomized treatment effects (overall and by combination or single-drug therapy) on the risk of CD/dementia remain unadjusted, consistent with the original statistical analysis plan.12
The association between each predictor with CD/dementia was explored in two sets of model adjustment: (1) “basic-adjusted” models, adjusted for sex, age, education, region, and randomized treatment; (2) “fully-adjusted” models, in addition to basic adjustments, different sets of a priori covariates (MMSE, systolic blood pressure (SBP), BMI, smoking, alcohol use, diabetes) were included to avoid over-adjustment, for each predictor. The specific adjustment strategy for each model is presented in the supplementary methods.
To address effect modification by sex, associations between predictors and multinomial outcomes were investigated by sex-disaggregated analyses, and the interaction term between each predictor and sex was used to obtain the respective women-to-men ratio of ORs (RORs).20
Given the robust dementia adjudication in PROGRESS, differential effects of treatments and predictors on CD and dementia as stand-alone multinomial outcomes were examined, defined as (0) had neither CD nor dementia (reference category); (1) had CD only without dementia; (2) had dementia (including CD); (3) death preceding any CD or dementia during the study, using the aforementioned adjustment strategies.
Since the present study focuses on CD and dementia as outcomes of interest, results on death were not presented. Complete case analyses were undertaken and performed in RStudio Version 4.0.3 (R Core Team, 2020).
Results
Baseline characteristics
A total of 5888 participants with at least two MMSE measurements were included in the present analyses. At baseline, more men than women had ever smoked, were current alcohol drinkers, and had prior myocardial infarction and PAD; more women had low eGFR than men (Table 1). Further details on ethnicity by region of residence (Asian residence or non-Asian residence) were outlined (Supplementary Table 1).
Follow-up
During four years’ (median) follow-up, 763 CD/dementia (30.9% women) (CD: n = 610, 31.1% women; dementia: n = 394, 32.2% women; CD and dementia: n = 241, 33.6% women) and 392 deaths were recorded (19.4% women) (Table 1). A time chart of PROGRESS was provided (Supplementary Figure 1).
Trial Registration: This trial was not registered because enrolment began before 1 July 2005.
Keywords
Stroke, dementia, cognitive decline, sex difference, competing risk
1George Institute for Global Health, University of New South Wales, Sydney, Australia
2Bordeaux Population Health Research Center, Bordeaux University, INSERM, Bordeaux, France
3Hospital Center Bordeaux University, Bordeaux, France
4Department of Physiology, University of Melbourne, Melbourne, Australia
5School of Psychology, University of Sydney, Sydney, Australia
6Brain and Mind Centre, University of Sydney, Sydney, Australia
7George Institute China, Peking University Health Science Center, Beijing, China
8Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, Australia
9Heart Health Research Center, Beijing, China
10George Institute for Global Health, Imperial College London, London, UK
Corresponding author(s):
Jessica Gong, George Institute for Global Health, University of New South Wales, Level 5/1 King Street, Newtown, NSW 2042, Australia. Email: jgong@georgeinstitute.org.au
Introduction
In 2019, the World Stroke Organization called for joint prevention of dementia and stroke.1 Current trends in global burdens of dementia and stroke projected 200 million stroke survivors and 106 million people with dementia by 2050,2 with 30 million incident stroke and five million deaths from dementia every year thereafter.2Stroke and transient ischemic attack (TIA) are linked to worse cognition, accelerated cognitive decline (CD), and dementia.1,3–5 Epidemiological and genetic studies suggest overlapping susceptibility factors between CD, dementia, and stroke.6 There are also reciprocal interactions between cerebrovascular disease and neurodegeneration at a pathological level.1,7,8
The Oxford Vascular Study (OxVasc) provided some clarity on how individual characteristics may predict these adverse outcomes.6 Yet, several questions remain, including predictors for cognitive impairment not satisfying criteria for dementia and the generalizability to other ethnicities.9 Death may preclude the development of dementia or CD,7 but this important consideration of death as a competing risk has not been widely incorporated in prior studies of poststroke CD/dementia.
Further, while sex is an important effect modifier for many diseases including stroke and dementia,10 sex differences in risk factors for CD/dementia have not been explored in stroke/TIA. A study in a general population, free of stroke at baseline, found that several risk factors are more strongly associated with incident stroke in women than men.11 Considering the commonality of risk factors for stroke and dementia, sex can have a fundamental influence on their reciprocal relationship.
Aims
Given these evidence gaps, our study examined the overall, and sex differences in, effects of blood pressure (BP)-lowering treatments, major vascular and stroke-specific predictors associated with CD/dementia in people with prior stroke/TIA, including death as a competing risk, using the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) randomized controlled trial (RCT).
Methods
Study design and participants
The main results from PROGRESS have been described elsewhere.12,13 In brief, PROGRESS was an RCT of 6105 individuals recruited from 172 collaborative centers in 10 countries (Australia, New Zealand, China, Japan, England, Ireland, France, Belgium, Italy, and Sweden) from 1995 to 1997. Participants were eligible to enter the study, with a history of cerebrovascular disease, including stroke/TIA (but not subarachnoid hemorrhage) in the previous five years. Participants were required to have no contraindication or clear indication for angiotensin-converting enzyme inhibitors use. After a four-week run-in period, participants were randomized to active treatment; a flexible regimen of perindopril (4 mg daily) for all participants, with/without the addition of indapamide (2.5 mg daily/2 mg in Japan); or matching placebo(s). Ethical approvals were obtained from institutional ethics committees of each collaborating center, and all participants provided written informed consent.
Measurement of putative risk factors
At study baseline, information about participant’s sex, birth date, age at highest level of education attained, ethnicity, and region of residence were collected; a history of concurrent diseases, including diabetes (insulin and non-insulin dependent), myocardial infarction, atrial fibrillation, and peripheral arterial disease (PAD); lifestyle habits including alcohol use and smoking were self-reported. Weight and height measurements were taken, and body mass index (BMI) was calculated. Repeated BP measurements were averaged to define baseline BP. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine measured at baseline, using the updated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation14,15 and defined as low if <60 ml/min/1.73 m2. The Mini-Mental State Examination (MMSE)16 was administered to assess cognitive function.
Stroke at baseline was categorized as (1) TIA/amaurosis fugax; (2) unknown stroke; (3) ischemic stroke only; (4) hemorrhagic stroke only; (5) ischemic and hemorrhagic stroke. Barthel Index of Activities of Daily Living (BI)17 was used to assess disability, with higher BI indicating less disability. Poststroke dependency and recovery were assessed through the Lindley Questions18: “In the last two weeks has the patient required regular help with everyday activities?” (dependency question) and “Does the patient feel that he or she has fully recovered from previous cerebrovascular events?” (recovery question).
Lymphocytes were isolated from peripheral blood for subsequent DNA extraction and genotyping for APOE polymorphism (http://www.genevcanvas.org).19 APOE was characterized as one of the six genotypes: ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, or ɛ4/ɛ4. APOE ɛ4 status was recorded positive for ɛ3/ɛ4 or ɛ4/ɛ4 genotype.
Assessment of cognitive function, CD, and dementia
Both CD and dementia were pre-specified secondary outcomes in PROGRESS.
Cognitive function was assessed using MMSE at baseline, six-, and 12-month visits, then annually until end of the follow-up (Supplementary Figure 1). CD was defined as a three-point or more decrement on MMSE between baseline and last recorded score.
A two-phase screening and assessment process were implemented for dementia diagnosis over follow-up. If the participant screened positive for possible dementia, they were referred for formal diagnostic clinical assessment by a specialist experienced in diagnosing dementia. The clinical assessment for ascertaining dementia was conducted through interviews. Information was gathered via a checklist based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria.19
For all cases that screened positive for dementia, the diagnosis made by the local specialist were further reviewed by a central Dementia Adjudication Committee comprising two neurologists. Dementia was defined as “certain dementia” or “fairly certain dementia” based on the adjudication. All screen-negative cases were classified as “no dementia.” Further details of the CD/Dementia assessment are presented in the supplementary methods.
Statistical analysis
Baseline characteristics by sex were summarized using mean (standard deviation) or median (interquartile interval) for continuous variables, and number (percentage) for categorical variables. Odds ratios (ORs) were estimated using multinomial regression models, with outcomes defined as (0) neither CD nor dementia nor death (reference); (1) CD or dementia, regardless of whether the participants died before the end of follow-up; (2) the competing risk of death preceding CD or dementia. Since the onset of CD and dementia are highly insidious, time to event models may not be reliable.
The effect of BP-lowering treatment in PROGRESS on the risk of CD and dementia has been reported elsewhere5; the present study expands on this by reporting the effects of randomized treatment effects, and a comprehensive list of genetic, cardiometabolic, and stroke-specific predictors by sex and considers competing risk of death. Randomized treatment effects (overall and by combination or single-drug therapy) on the risk of CD/dementia remain unadjusted, consistent with the original statistical analysis plan.12
The association between each predictor with CD/dementia was explored in two sets of model adjustment: (1) “basic-adjusted” models, adjusted for sex, age, education, region, and randomized treatment; (2) “fully-adjusted” models, in addition to basic adjustments, different sets of a priori covariates (MMSE, systolic blood pressure (SBP), BMI, smoking, alcohol use, diabetes) were included to avoid over-adjustment, for each predictor. The specific adjustment strategy for each model is presented in the supplementary methods.
To address effect modification by sex, associations between predictors and multinomial outcomes were investigated by sex-disaggregated analyses, and the interaction term between each predictor and sex was used to obtain the respective women-to-men ratio of ORs (RORs).20
Given the robust dementia adjudication in PROGRESS, differential effects of treatments and predictors on CD and dementia as stand-alone multinomial outcomes were examined, defined as (0) had neither CD nor dementia (reference category); (1) had CD only without dementia; (2) had dementia (including CD); (3) death preceding any CD or dementia during the study, using the aforementioned adjustment strategies.
Since the present study focuses on CD and dementia as outcomes of interest, results on death were not presented. Complete case analyses were undertaken and performed in RStudio Version 4.0.3 (R Core Team, 2020).
Results
Baseline characteristics
A total of 5888 participants with at least two MMSE measurements were included in the present analyses. At baseline, more men than women had ever smoked, were current alcohol drinkers, and had prior myocardial infarction and PAD; more women had low eGFR than men (Table 1). Further details on ethnicity by region of residence (Asian residence or non-Asian residence) were outlined (Supplementary Table 1).
Follow-up
During four years’ (median) follow-up, 763 CD/dementia (30.9% women) (CD: n = 610, 31.1% women; dementia: n = 394, 32.2% women; CD and dementia: n = 241, 33.6% women) and 392 deaths were recorded (19.4% women) (Table 1). A time chart of PROGRESS was provided (Supplementary Figure 1).
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