Factors associated with improvement or decline in cognitive function after an ischemic stroke in Korea: the Korean stroke cohort for functioning and rehabilitation (KOSCO) study

Cerebrovascular stroke is considered one of the main causes of dementia [1‐3]. It may decrease quality of life in addition to causing other neurological deficits [4]. Post-stroke dementia is defined as a presence of dementia identified at 3 months after an acute stroke [5]. Reasons for a stroke patient to develop dementia are still insufficiently understood. It is not always a direct consequence of cerebrovascular lesions, and, in some cases, post-stroke dementia has a progressive course, suggesting a degenerative rather than a vascular origin [6, 7]. In previous autopsy series, 10 to 15% of dementias occurring after a stroke were found to be due to a combination of vascular and Alzheimer’s disease [8, 9].

Despite consensus that strokes are associated with an increased risk of post-stroke dementia, the data regarding prevalence at 3 months post-stroke are still conflicting, with reports ranging from 6% to more than 50% [10‐14]. In addition, cognitive function may vary (either improve or decline) years after a stroke. Snaphaan et al. reported that post-stroke memory dysfunction varied from 23 to 55% at 3 months after a stroke, and this declined from 11 to 31% at 1 year after a stroke. Declined cognitive function may change. A previous cohort study showed 33% of patients with mild cognitive impairments diagnosed in the first 6 months after a stroke showed improvement at 1 year. Several prospective studies have identified delayed improvement in cognitive function after strokes using various diagnostic assessment tools for dementia [15-17].

The pathophysiology of delayed cognitive change after a stroke is multifactorial, and the prevalence rate of post-stroke dementia is higher among older patients [18, 19]. Previous studies have tracked cognitive changes to identify the factors associated with delayed improvement or a decline in cognitive function after stroke. However, no large-scale study has been conducted to investigate the pattern of post-stroke cognitive changes, identify the risk factors, or compare age-related differences using repeated administration of the most commonly used screening tool.

Therefore, we conducted a prospective cohort study in conjunction with the Korean Stroke Cohort for Functioning and Rehabilitation (KOSCO) to identify 1) the prevalence of delayed cognitive impairment; patients progress to either converter, stable, or reverter group after ischemic stroke and 2) clinical and demographic factors associated with improvement or decline in cognitive function between 3 months and 12 months after ischemic stroke. The present study is the first to involve a large and well-characterized Korean cohort, a battery of short cognitive and functional assessments, and a 1-year follow-up.

A total of 2,625 patients (older patients = 1,431) with first time ischemic stroke were included in this study. Among these patients, 1,735 (66.1%) (older patients = 835 (58.4%)) were classified as NCG, while 890 patients (33.9%) (older patients = 596 (41.6%)) were the ICG at 3 month K-MMSE assessment. Although, percentage of normal and declined cognitive function was similar for older patients at 3 months and 12 months, percentage of normal cognition group was slightly increased and percentage of declined cognition groups was decreased in total patients (Fig. 2). Among NCG, 1,460 (82.4%) (older patients = 612 (73.3%)) were stable group, 93 patients (5.4%) (older patients = 79 (9.5%)) were converter group, and 212 patients (12.2%) (older patients = 144(17.2%)) were reverter group at 12 months onset. Among ICG, 472 patients (53.0%) (older patients = 336 (56.4%)) were stable group, 321 patients (36.1%) (older patients = 183(30.7%)) were converter group, and 97 patients (10.9%) (older patients = 77 (12.9%)) were reverter group (Table 2) (Figs. 3, 4). To analyze the cognitive change from 3 month to 12 month, the proportion stable group was dominant in NCG and converter group was higher in ICG.

Among NCG of total patients, hypertension, and cortical or multiple level involvement was dominant in reverter group, male sex, lower onset age, higher education level were dominant in stable group. In addition, functional assessments in stable group including NIHSS, mRS, FIM, K-MBI, FAC, GDS, and EQ-5D at 3 months were significantly better in scores compared to other groups. For the tendency of ICG of total patients, onset age, hypertension history was higher, education level was lower in reverter group. All functional assessments at 3 months showed better scores in converter groups and worse scores in reverter group (Table 3). Among separated older patients, male sex, lower onset age were dominant in stable group, educational level was lower in reverter group. Functional assessments including NIHSS, mRS, FIM, K-MBI, FAC, GDS, and EQ-5D, at 3 months showed better scores in stable group compared to others. In addition, proportion of receiving rehabilitation therapy at 3 months was lower and all functional l assessments showed better scores in converter group compared to others (Table 4).

In our study, total the percentage of cognitive impairment group did not change at 12 months compared to 3 months assessment. Otherwise, the percentage of cognitive impairment at 3 months, the percentage of patients in the reverter group, and the percentage of patients transferring from the NCG to the ICG at 12 months were higher in older patients compared to total group analysis (Table 2) (Fig. 2). Influencing factors for delayed cognitive change were discretely determined in the NCG and ICG of total and older patients. Hypertension history and onset age, sex, education level were somewhat repeated influencing factors. Although presence of atrial fibrillation, smoking, alcohol history showed statistical significance, large difference of number of patients between groups made it difficult to define it as meaningful result. Another unique aspect of our study is that we included functional assessment since it could influence on patients’ delayed cognitive function. Patients with better functional assessment scores not only in cognitive field but in all other domains including activities of daily living, motor function, mobility and gait, general functional level, quality of life at 3 month tend to have less cognitive decline and more cognitive improvement from 3 month to 12 month. Otherwise, stroke characteristics including ischemic type, location, treatment characteristics showed no significant difference between the groups. Patients in the ICG-RG that were aged >65 years received more rehabilitation therapy. Moreover, compared to the other patient groups, the patients in the ICG-SG received less cognitive therapy, which was a component of the rehabilitation therapy. We believe that unlike the other factors, the administration of rehabilitation treatment depended on the cognitive status of the patient; however, rehabilitation was not a factor that improved cognitive function.

Stroke severity, onset age, pre-stroke cognitive function, level of education, and bilateral lesions are well-known factors associated with development of post-stroke dementia [33‐36]. In contrast, a cohort study of younger stoke patients (mean age, 60 years) showed that more than 30% of the patients with mild cognitive impairments between 0 and 6 months were classified as cognitively intact by 12 to 18 months [16]. For older patients (mean age, 80.4 ± 3.8), about 50% of the patients experienced an improvement in MMSE at 15 months [17]. As the prognosis of stroke varies according to the patient’s age at onset, identifying the factors affecting cognitive changes by age might aid in both preventing secondary cognitive decline, and enhancing post-stroke cognitive function. In our study, separating patients by age, cognitive function at 3 month, and aspect of cognitive change to find the propensity of each prevalence and influencing factors was meaningful. Also, compared to other cross sectional studies, our study analyzed delayed post stroke cognitive function and focused on amount and aspect of cognitive change from 3 month to 12 month and its influencing factors.

To carry this analysis further, we examined the differences in the MMSE scores among the groups by using the cutoff score of <24 points, conventionally accepted for the diagnosis of significant cognitive impairment, i.e., dementia [37]. Previous studies have established more than 3 points of MMSE variability as a significant change for improvement or decline in cognitive function.

MMSE is the most frequently applied test for dementia screening. A systematic review and meta-analysis examining cognitive tests to detect dementia found 10,263 cases of dementia identified from 36,080 participants in 108 cohort studies. The result reported a sensitivity of 0.81 and a specificity of 0.89 for the MMSE [38]. The MMSE requires only 5–10 min to evaluate various cognitive domains (orientation, memory, language, attention, visuospatial) and is practical to use serially and routinely [39].

The overall prevalence of dementia in subjects aged greater than 65 in Korea is estimated to be 9.2%. In addition, the pooled age-specific prevalence of dementia is estimated to increase with each 5-year age band (65–69 years) [40]. This result is much higher than the estimated overall prevalence of dementia in Asian people [41]. We analyzed our data by separating patients older than 65 y/o to compare the age factors. The percentages of normal cognitive group and cognitive impaired patients and mean MMSE scores showed significant differences between total and older patient groups. In particular, the percentage of patients in the reverter group was higher and the converter group was lower at 12 months in older patient group, and their average MMSE showed differences by age. Otherwise, in older ICG, less factors were significant compared to other groups. This finding may be due to the lower percentage of patients when compared to the entire study population and NCG.

First, we only used a MMSE to test cognitive function. Although there are 40 other more detailed tests for dementia diagnosis in healthcare settings, we required multi-domain, serial functional assessments for screening and detecting post stroke cognitive decline. Also, MMSE was optimal for our insurance benefits and medical policy which can be done consecutively for our large-scale cohort study [40].

Second, we excluded patients with pre-stroke cognitive decline, but we had no objective assessment data on which to base our exclusions. Instead, patients’ pre-stroke cognitive function was determined by administered questionnaires and face-to-face interviews. Additional studies, such as volumetric analysis by MRI/MRA scans, may be valuable to investigate and compare the severity of stroke among the groups.

Third, we excluded patients who are not capable of 1 year follow up examination including functional assessments which could make selection bias. However, it could be a strength of this cohort study which differs from others and it may suggest more objective data for stroke survivors.

The prevalence of cognitive impairment at 3 month showed difference between total and older patient groups. To analyze the cognitive change from 3 month to 12 month, the proportion stable group was dominant in NCG and converter group was higher in ICG. By investigating the influencing factors from each group, we were able to identify the early predictors including the age factor.