Frailty syndrome and cognitive impairment in older adults: systematic review of the literature

Objective: to synthesize the knowledge about the association of frailty syndrome and cognitive impairment in older adults. Method: the Joanna Briggs Institute’s systematic review of etiology and risk factors was adopted. The search for the studies was conducted by two independent reviewers in the databases MEDLINE, Embase, CINAHL and LILACS and by manual search was performed by tow reviewers independently. The measures of association Odds Ratio and Relative Risk were used in the meta-analysis. The software R version 3.4.3 and the meta-analysis package Metafor 2.0 were used for figure analysis. Results: three studies identified the association of frailty syndrome and cognitive impairment through Odds Ratio values show that frail older adults are 1.4 times more likely to present cognitive impairment than non-frail older adults. Four studies analyzed the association through the measure of Relative Risk and found no statistical significance, and four studies used mean values. Conclusion: despite of the methodological differences of the studies and the lack of definition of an exact proportion in the cause and effect relationship, most studies indicate Frailty Syndrome as a trigger for Cognitive decline.

incidence is directly proportional to the increase in age and there is evidence of a biological substrate of frailty that may promote or accelerate cognitive decline (9) . This hypothesis reinforces the argument that frailty syndrome and cognitive decline share the same pathophysiological mechanisms.
Thus, frailty syndrome and cognitive impairment have been increasingly studied, because they are considered a public health issue, in the sense that their early detection has a direct impact on health outcomes (10) .
Given the importance of the topic, associated with an increased population aging and greater life expectancy, a systematic review was conducted to identify the relationship between frailty syndrome and cognitive impairment. The researchers started the discussion on the topic of physical frailty, however, in the nursing practice, cognitive impairment was also identified as a fragility of older adults in the development of their daily activities, impairing spatial function, temporality, calculations, sentence construction, self- Therefore, the objective of this study was to synthesize the knowledge about the association between frailty syndrome and cognitive impairment in older adults through a systematic review.
A preliminary study protocol was elaborated with the objective of finding a systematic approach to be employed in the review. This enabled a transparent process, methodological rigor and reduced the possibility of bias in the final report. The protocol elaborated guided a prior search in the main databases to find out if there were any proposed or conducted systematic review that answered the present guiding question (11) .
Other reviews found discussed the proposed theme, but not with the emphasis that guides this study: to identify the association between cognitive impairment and frailty syndrome in older adults. In this protocol, the objectives, criteria and methods were previously specified.

Method
This is a systematic review of etiology and risk factors with meta-analysis, based on the recommendations of The Joanna Briggs Institute (JBI). The model adopted aimed to analyze the association between certain factors and the development of a disease, condition or other health outcome, following a structured process, with a rigorous method, to ensure that the results achieved are reliable and meaningful. This review followed eight steps, namely: 1) title of the review; 2) objective and guiding question; 3) introduction (background); 4) inclusion criteria; 5) methods (search strategy, critical appraisal, selection of studies and synthesis of data); 6) results; 7) discussion; and 8) conclusion and recommendations (11) .
The first step of the review was choosing the title, which presented the main elements of the guiding question, aligned with the objectives and the inclusion criteria. Then, a protocol was structured so the whole process of this systematic review would be guided by the objectives and methods.
The objective and the guiding question were elaborated according to the PEO model, with P = Population (older adults); E = Exposure of interest (frailty syndrome) and O = Outcome (cognitive impairment (12) .
Based on this strategy, it was possible to construct the critical thinking about the topic and formulate the The quality assessment of studies was the necessary process of establishing internal validity, by verifying possible biases and the reliability of the evidence (15) .
In this study, the methodological quality assessment was performed by two independent reviewers, using the Methodological Index for Non-Randomized Studies (MINORS) (16) . This instrument contains eight items for non-comparative studies: 1) A clearly stated aim; 2) Inclusion of consecutive patients; 3) Prospective collection of data; 4) Endpoints appropriate to the aim of the study; 5) Unbiased assessment of the study endpoint; 6) Follow-up period appropriate to the aim of the study; 7) Loss to follow-up less than 5%; and 8) Prospective calculation of the study size. Each item was rated from 0 to 2, which means: the score 0 indicates that the information was not reported, 1 indicated that the information was inadequately reported, and 2 that the information was adequately reported (16) .
The data extraction occurred in two phases: in the first one, the data from the articles included in the study were extracted by the reviewer (researcher); in the second, another data extraction was carried out by a second reviewer. The data extracted referred to specific information related to the research question and the objective of the review, such as: author(s); year of publication; journal; language; country; title;

Results
Of  In the eleven studies included, the researchers analyzed the association between frailty syndrome and cognitive impairment in older adults, with a total sample of 12,656 non-frail participants with no and 2,340 were selected to read titles and abstracts.
Among these, 2,266 studies were excluded because they did not meet the inclusion criteria and, after evaluation of the studies, 74 studies were selected for reading in full. After this step, 63 studies were excluded, resulting in 11 articles included in this study (Figure 2). www.eerp.usp.br/rlae It was also verified that two studies (22)(23) used the Hazard Ratio (HR) as a measure of association between the study variables. In the evaluation of cognitive impairment of the studies analyzed, the Kaplan-Meier Survival Analysis (23) showed that in the domain of executive functioning it was related to frailty, with 3.3 (95% CI: 1.4 to 7,6). On the other hand, other authors (22) who used Logistic Regression found no association between variables.
Four studies used mean as a measure of association between the variables frailty and cognitive impairment (24) , and adopted Multiple Linear Regression (10,21) and Poisson Regression (18) .
Regarding the values of the studies that used OR as measure of association, we observed that two studies (19,27) results did not cross the vertical line, which means there is association. The data from study did not present statistical significance (26) (Figure 4).
In the meta-analysis, the diamond is on the right side of the vertical line, meaning that the frail older person is 1.24 times more likely to have cognitive decline in comparison to the non-frail individual (statistically significant, with p<0.005).

Discussion
Aging is a gradual process characterized by individual and diverse trajectories. In a biological perspective, it is characterized by physical, cognitive and social alterations that lead to increased susceptibility to adverse health events (29) .
Aging is a process characterized by progressive, time-dependent, and heterogeneous decline in physiological function. It is orchestrated by a plethora of molecular mechanisms that change body homeostasis (30) , causing different geriatric syndromes, which, in turn, have a negative effect on quality of life and lead to an increase in disabilities and in the use of medical resources (31) .
Frailty syndrome is a new pathophysiological concept that has gained relevance, especially because it can be applied in clinical practice and is considered an important prognostic criteria for difficult therapeutic decisions (28) . This can be explained by the genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin signaling pathway, the growth factor, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems involved in the aging process (32) .
The accumulation of molecular and cellular damage in the aging process can cause hormonal and inflammatory dysregulation that leads to frailty and cognitive decline (33) . group that defined the new concept of "cognitive frailty".
This new construct extends the definition of physical frailty by including the cognitive issue (34) .
Cognitive frailty is defined as a "heterogeneous clinical manifestation in older adults characterized by the simultaneous presence of both physical frailty and cognitive impairment". In order to define such a condition, it is also necessary to exclude Alzheimer's disease or other dementias (35) .
Among the studies included in the review, only one presented the definition of cognitive frailty as theoretical framework (22) . However, despite not applying the concept of cognitive frailty, other authors used its criteria (physical frailty, cognitive decline and absence of dementia) to evaluate the association between physical frailty and cognitive decline even though the construct of cognitive frailty has not been used as referential.
This decline is caused by white matter hyperintensities in the brain, related to small vessel injuries, breakdown of the blood-brain barrier and oxidative damage in brain tissue, which decreases the connections between different regions of the brain that can be seen in magnetic resonance imaging (6,36) .
Longitudinal studies on the temporal association between cognition and frailty found that the frailty domains are associated with lower performance in the cognitive domains, that frailty increases the risk of cognitive decline and dementia, and that there's higher risk of mortality throughout follow-up of participants over time (39) . Decline in cognitive function is a process that occurs in the course of the aging process and is subject to multiple alterations that can lead the older person to develop some type of dementia (40) .

This data is confirmed by a study conducted in
China with 19,943 participants over 65 years of age in a 12-year follow-up. The results showed greater cognitive decline among older adults living in rural area than among those living in urban area. This difference was associated with lower level of education, limited access to health services and decreased physical activity (41) .
The identification of the risk of cognitive decline related to physical causes becomes very relevant due to its potential for reversibility.
The results related to the association between frailty and cognitive decline were significant in a study with 2,737 older adults without cognitive impairment living in a community. Frailty was measured by the following aspects: reduction of skeletal muscle mass, grip strength and chair-stand test, weight loss, reduced walking speed and step length. The results indicated that for all men, all measures of frailty were associated with a decrease in the MMSE score over four years (24) .
Physical frailty and cognitive deficit are closely associated, and one component may affect the other and initiate a cycle of adverse events, such as functional disability, altered quality of life, dementia and death (38) .
The results of this systematic review showed a prevalence of the association between frailty and cognitive decline, especially when frailty was identified as a physical syndrome. Only one study (26) did not find this association, since it presented OR=1.04; 95%CI Alzheimer's or other neurodegenerative disease (42)(43) .
In this review, the meta-analysis for RR did not  (44) .
The relevance of the studies depends on their methodological quality, and the evaluation of this issue is considered important to guarantee the rigor of the systematic review. The methodological quality assessment or critical evaluation is the process of establishing internal validity, by verifying possible biases and the reliability of the evidence (15) . Most of the studies included in the present review show that the meta-analysis provides evidence on the association between these two variables: frailty and cognitive decline. Therefore, health professional must evaluate