Effects of physical exercise on cognitively impaired older adults: a meta-analysis of randomized control trials


 Objectives: The main aim of this meta-analysis was to compare the effects of different physical activities on cognitive functions in older adults divided according to cognitive impairment levels. Methods: We searched Web of Science, Scopus, and PubMed for randomized control trials (RCT). A standardized mean difference (SMD) of the pre-post intervention score of global cognitive function tests were calculated by the random model in the Cochrane meta-analyses for people with cognitive impairment generally and across three levels - mild, mild to moderate, and moderate to severe cognitive impairment separately. Additionally, an unstandardized coefficient beta (B) was calculated in generalized linear models to estimate the effects of exercise, cognitive impairment severity, age, female ratio, length of intervention, and time of exercise a week on the global cognitive function. Results: Data from 26 studies involving 1,137 participants from intervention groups and 1,187 participants from control groups were analyzed. Physical exercise had a positive effect on cognitive functions in people across all levels of cognitive impairments SMD (95 % confidence interval [CI]) = 1.19 (0.77 - 1.62); however, heterogeneity was considerably high I 2 = 95%. Aerobic (B = 8.881) and resistance exercise (B = 4.464) was significantly associated with better results in global cognitive functions when compared to active control. A higher number of female participants cin intervention groups had a statistically significant effect on the global cognitive function (B = 0.229). onclusions: Physical exercise was associated with cognitive function improvement in older people with cognitive impairments. Aerobic exercise was more strongly associated than resistance exercise to combat cognitive decline. Keywords: Physical activity, Dementia, Aging, Meta-analysis, Aerobic exercise, Cognitive function


Background
The number of older adults with dementia is on the rise due to global population ageing.
Current estimates suggest that more than 131.5 million people will be affected by dementia by the year 2050 [1]. Dementia is generally characterized by a progressive decline in cognitive and physical functions, often leading to a loss of independence and in some cases, institutionalization [2]. Thus, dementia impacts not only the daily lives of individuals diagnosed with the condition but also their families and broader society.
During the past two decades, epidemiological research has highlighted the link between modifiable lifestyle factors and cognitive function. For example, current evidence has demonstrated that a physically active lifestyle may help to delay the onset of cognitive decline and slow down disease progression [3], and physically active individuals have been shown to have a smaller risk of developing dementia or mild cognitive impairment than those who do not take part in any regular physical activity [4]. Moreover, results from several prospective studies have shown that exercise and physical fitness seem to have a positive effect on brain health [5,6]. In particular, it has been demonstrated that regular physical activity in mid-life is associated with a lower risk of dementia in later life [7], as well as that one of the most effective protections against neurodegenerative or vascular dementia is to be sufficiently physically active from mid-life [3]. In addition, it is now well known that exercise interventions increase the functional performance and activities of daily living in patients with cognitive impairments [8,9,10,11,12]. A positive effect of physical exercise on global cognition in individuals with mild cognitive impairments was partly confirmed [13,14,15,16,17,18]. Nevertheless, the effects of exercise on global cognitive function in people taking into account the level of cognitive impairment has still not been clearly elucidated. Likewise, the effects of aerobic and resistance exercise require further investigations too. 4 Therefore, the main aims of this study were to generally analyze the effects of exercise on cognitive functions in older adults divided according to cognitive impairment severity, taking into consideration the effects of resistance exercise and aerobic exercise separately. Additionally, we aimed to investigate the association between selected factors including the passive or active control, cognitive impairment severity, age, sex, frequency of exercise per week, and length of interventions on global cognitive function. We hypothesized that there exists a difference between aerobic and resistance exercise in terms of the effect on cognitive functions and that the effect might vary across different levels of cognitive impairment. We also hypothesized that different activity programs in control groups might influence the results. For example, a social program without physical activities may be beneficial for older adults with cognitive impairment. We also assumed that social or education activities in control groups might be more helpful against the cognitive decline rather than inactivity in passive control groups.

Methods
This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [19]. A compiled PRISMA checklist is included in Table 1. Following global cognitive function tests were considered appropriate: Cambridge Cognitive Examination (CAMCOG) [20], the Mini-Mental State Examination (MMSE) [21], the Rapid Evaluation of Cognitive Function (ERFC) [22], the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) [23], and the Montreal Cognitive Assessment (MoCA) [24]. Table 1 Checklist of items to include when reporting a systematic review or meta-analysis    Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, metaregression [see Item 16]

Inclusion criteria for this study
This meta-analysis assessed the effects of physical exercise programs on people with cognitive impairment. The following inclusion criteria were applied: only data from randomized trials (RCT) were used, and the participants had to be diagnosed with a cognitive impairment according to one of the standardized tools with a closed scale (as mentioned above) -all written in the English language. Concerning the exercise programs, only exercise activities that required increased energy output without taking frequency or intensity into account were included. All intervention groups from studies with a combination of physical exercise and cognitive training were excluded. However, their control groups were included if they met our search criteria.

Search strategy
The analysis was conducted by identifying relevant papers referenced in the Web of Science, Scopus, and PubMed. Search terms used in all databases are presented in 8 Table 2.  Data extraction and quality assessment All potential papers were first downloaded into EndNote. Then, our three reviewing authors (LS, AT, and MS) deleted all the duplicates and scanned the titles and abstracts of the papers in order to identify studies that had the potential to meet the eligibility criteria. Full texts were subsequently assessed for eligibility. Any disagreements among the reviewers (KD, and IH) were resolved through discussions. We used the Physiotherapy Evidence Database (PEDro) scale to assess the methodological quality of the included studies [25]. We collected the following data for both the exercise groups and control groups separately: baselines and after intervention means with 95% confidence interval (CI) and/or standard deviation (SD); and if described, also the mean of post-pre intervention score with SD or 95% CI were collected. Additionally, for factors or covariates for general linear models, we collected information about the type of exercise or control group activities, age of participants, sex of participants, length of interventions, and 9 frequency of exercise.

Cognitive impairment
We divided the participants into three categories according to the level of their cognitive impairment: mild, mild to moderate, and moderate to severe impairment. In the classification, we used a 95% CI of the baseline mean in the standardized 100 points scale. Mild cognitive impairment = the lower 95% CI > 65.0 points, mild to moderate cognitive impairment = the lower 95% CI > 57 to points, and moderate to severe impairment = the upper 95% CI < 60 points. This division was in concordance with the standard diagnostic of cognitive impairment according to MMSE [26]. We could say with 95% certainty that in the mild impairment group there were not participants with less than 20.1 points, in the mild to moderate impairment group there were not participants with less than 17.1 points and in the moderate to severe impairment group, there were not any participants with higher than 18 points.

Exercise interventions
Walking, stretching, toning, kinesiotherapeutic exercise, music-based dance therapy, ergometer cycling, as well as generally specified "aerobic exercise" were classed as aerobic exercise. When the intervention program included high-intensity functional exercise, strengthening exercise with own body weight, or exercise with dumbbells, we classed it as resistance exercise. According to the activities that they had prescribed, we divided the control groups into two categories -active and passive control groups. All the control groups with activities that could have potentially been beneficial for cognitive functions (for example, attention-control educational programs, social visits, or recreational activities such as card playing or home craftwork) were categorized as the active control groups. Control groups asked to maintain their usual activities were categorized as the passive control groups. We also analysed information about the length of intervention, the duration of exercise per week, and female ratios.

Data analysis
The sample size and mean post-pre intervention score with standard deviation (SD) from intervention as well as control groups were used to calculate the standardized mean differences (SMD). The random effect models were used for all the analyses [27]. To assess the heterogeneity I 2 was considered. A rough guide to the interpretation of I 2 is as follows: 0 to 40% might not be important, 30-60% may represent moderate heterogeneity, 50-90% may represent considerable heterogeneity, and 75-100% represents substantial heterogeneity [28]. Additionally, we standardized all the mean of the baseline score and post-pre intervention score from all the groups separately onto the 100 points scale. Then  which corresponded to 20.1 (95% CI 18.7-24.5) points of the MMSE classed as a mild to moderate cognitive impairment according to the standard interpretation of MMSE [26].
In the generalized linear models, when we used the active control groups as a reference category, its change on the aerobic exercise group caused an increase in the post-pre intervention score estimate by more than 8 times (B = 8.881) and the change on resistance group by 4 times (B = 4.464) both significantly. When comparing passive groups to active groups there was found a negative trend for the passive controls, nevertheless, not significant. Cognitive impairment level, as well as age and length of intervention, were not significantly associated with the post-pre intervention score. The result of the generalized linear model of intervention and control groups together is presented in Table 6.   Table 7. Table 7 was not provided with this version of the manuscript.

Discussion
It is well-established that cognitive functions decline gradually over time as part of the natural ageing process [55]. The overall results of this meta-analysis indicate that physical exercise and specifically aerobic exercise may have the power to mitigate cognitive decline process even in people with cognitive impairment.
According to our results, aerobic exercise had 2x higher impact on cognitive functions than resistant exercise when compared to active controls, and 4x when compared only the intervention groups. Previous studies partly confirmed a positive effect of physical exercise on executive functions [14,15], and global cognition [16,17,18] in individuals with mild cognitive impairments. However, we found that aerobic exercise also had a statistically significant positive effect in moderate to severe cognitively impaired people.
Probably the positive effect of aerobic exercise on brain health seems to lie in the proposed mechanisms behind aerobic exercise such as neovascularization, synaptogenesis and angiogenesis, hippocampal high-affinity choline uptake and upregulation of muscarinic receptor density, increasing of mitochondrial volume in Purkinje cells, inhibition of the apoptotic biochemical cascades, identified primarily through animal research [56,57,58,59].
Moreover, a higher number of female participants in intervention groups had a positive effect on global cognitive function. This result could be explained by both different cognitive responses to exercise between men and women as well as by the different ratios in elderly females suffering dementia. As described by Baker et al. (2010), aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor in women but not in men [60]. They also found that peak oxygen consumption was associated with improved executive function in women. It turns out that gender differences in cognitive functions can be related to the metabolic effects of physical activity. However, there are several other reasons that sex may influence trial results. For instance, women have a higher lifetime risk of dementia [61], 20 greater vulnerability to certain risk factors such as sex specific chromosomes, APOE ε4, sex differences in hormone levels etc. [62], and they demonstrate higher differential associations between biomarkers and cognitive impairment than men [63]. Moreover, there was a higher percentage of female participants in the intervention studies (19 of 24 intervention studies had a majority of female participants). One reason for this fact could be higher life expectancy in females [64] although the gender gap has been narrowing in Europe recently [65]. Another explanation could be greater adherence to health-related exercise programs in older women [66].
Studies included in this meta-analysis varied in terms of length of interventions. In fifteen studies, the duration of interventions was less than half a year, and in another nine, the duration of the interventions was for more than half a year. According to our analysis, it seems that the length of the intervention was associated with cognitive decline, which was probably caused by the natural ageing process. Surprisingly the frequency of exercise per week did not play any significant role in global cognition.
It should be noted that several limitations are involved in this study. There was considerable heterogeneity in all the analyses. Unfortunately, it could not be controlled for by the sensitivity analysis otherwise more than half of the studies would have to be excluded. In fact, heterogeneity is a common problem when conducting meta-analyses on this topic [14,18], so the standard approach is not always the best. Nevertheless, using general linear models involved some limitations too. For example, we used only individual standardized post-pre mean difference and not the total amplitude such as 95% CI, therefore, the statistical significance of individual studies could not be drawn. Moreover, it was almost impossible to create a category with similar cognitive impairment because it varied considerably among the studies. The same is true for exercise interventions because the interventions included many different activities with different durations and 21 intensities.

Conclusion
Despite the numerous above-mentioned limitations this study has shown that physical exercise and especially aerobic exercise may have the power to influence cognitive functions in people with cognitive impairment. Such findings could have practical implications such as to recommend physical activity as a nonpharmacologic treatment to combat the progression of cognitive decline in patients with cognitive impairment. Future research based on longitudinal epidemiological studies is needed to confirm such findings further.

Availability of supporting data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This research was supported by the Alzheimer Endowment Fund -AVAST, the project Q41, the AZV research project NV18-09-00587 of the Ministry of Health and project SVV 260466.
The funding agencies played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.   Effects meta-analysis of physical activities on cognitive function in people divided according to their cognitive impairment severity