Frailty and cognitive decline

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Frailty and D1X Xcognitive D2X Xdecline

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3X XDAIENE XD DE MORAIS FABRI´CIOD4X X, D5X XMARCOS HORTES N. CHAGASD6X X, and D7X XBRENO S. DINIZD8X X

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Frailty and cognitive impairment are among the 2D9X X most common geriatric syndromes. Their presence poses major risks to the elderly including greater disability, reduced quality of life, and higher morbi-mortality. Recent evidence suggest that frailty can be a risk factor for incident dementia. The opposite is also true since subjects with Alzheimer’s disease and other dementia also present with more severe frailty measures. The XX mechanisms for the association between frailty and cognitive impairment is not clear, but possibly involves abnormalities in biological processes related to aging. Here, we will review the current evidence of the association between frailty and cognitive impairment. We will also review the possible biological mechanistic links between the 2D10X X conditions. Finally, we will address potential therapeutic targets and interventions that can mitigate both conditions. X X (Translational Research 2020; &&:&&-&&)

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lthough a public health success, the aging of the population has been accompanied by many challenges, 2D1X X of the most common of which are frailty syndrome and cognitive decline.1,2 These conditions have a direct impact on health, increasing disability, reducing quality of life, and contributing to adverse outcomes.1,3 Therefore, understanding the association between frailty and cognitive decline can assist the planning of preventive and treatment strategies. Frailty is a clinical syndrome with different definitions. Depending on the region studied and the screening

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From the Department of Psychology, Federal University of S~ao Carlos, S~ao Carlos, S~ao Paulo, Brazil; Department of Gerontology, Federal University of S~ao Carlos, S~ao Carlos, S~ao Paulo, Brazil; Adult Neurodevelopment and Geriatric Psychiatry Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Platform for Peripheral Biomarkers Discovery, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Submitted for Publication December 6, 2019; received submitted January 16, 2020; accepted for publication January 18, 2020.

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Reprint requests: Breno S. Diniz, Centre for Addiction and Mental Health (CAMH), 250 College St, Toronto, ON M5T 1R8. E-mail address: [email protected].

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method employed, its prevalence ranges from 5% to 58%.4 The most widely known definition was proposed by Fried et al. (2001), who defined frailty syndrome as “a state of physiological vulnerability associated with the aging process, resulting in a reduction in homeostatic reserve and difficulty in responding adequately to stressful events.” Thus, the clinical manifestations of frailty syndrome are related to the impairment of important functional reserve systems that govern hormonal, immunological, inflammatory, and neurological processes.5 Although epidemiological and clinical studies have demonstrated a close relationship between frailty and cognitive decline,6-9 how these conditions are interrelated has not been fully clarified.10 In this review, we will summarize the evidence of the association between frailty syndrome and cognitive decline.

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CLINICAL RELATION D12X X D13X X BETWEEN D14X X FRAILTY D15X X SYNDROME, D16XCOGNITIVE X D17X X DECLINE, AND DEMENTIA D18X X

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The high prevalence and the severity of the associated adverse outcomes have led to the development of several screening methods for the assessment of frailty syndrome. The 2D19X X main theories about the frailty syndrome are based on the accumulation of deficits model11 and the phenotype-based model.5 The accumulation of deficits model considers frailty syndrome to be a multidimensional

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construct and includes items beyond the biological aspect, such as social support, nutrition, mood, and cognition.12,13 The phenotype-based model defines the frailty syndrome as a phenotype involving 5D20X X biological componentsD21X X unintentional weight loss (more than 4.5 kg or 5% of one’s body weight in the previous year), self-reported fatigue, muscle weakness, low level of physical activity, and slow gait.5 Regardless of the screening method and definition, the outcomes associated with frailty syndrome are the same D2X X the aggravation of diseases, cognitive decline, functional decline, hospitalization, and death.14 Some factors can exert an impact on the state of frailty in older adults, such as mental health and cognition.15 A growing body of evidence indicates that frail older adults are at higher risk of cognitive decline, which, in turn, increases the likelihood of becoming frail.2 This suggests that the coD23X Xoccurrence of these conditions can predict the incidence of dementia and that each condition exerts an influence on the other.16,17 A longitudinal study, including brain autopsy, found that individuals with Alzheimer’s disease were classified as frail shortly before death,18 raising the hypothesis that frailty may be a prodrome of dementia.8 Moreover, frail individuals with cognitive impairment have higher progression rates of all types of dementia.2 A study conducted with 761 older adults without cognitive impairment at baseline found that being frail was associated with a 60% greater risk of developing mild cognitive impairment, and this association was maintained even after controlling for depressive symptoms and cardiovascular disease.19 The occurrence of frailty was also associated with a faster decline in 4D24X X cognitive domains (semantic memory, working memory, perceptual speed, and visuospatial skill).19 Thus, determining the prevalence of frailty in individuals with dementia seems essential to the planning of strategies for maintaining cognitive and physical health during the aging process.20 Besides the association between frailty and dementia, some studies have also investigated the relationship between the components of the frailty phenotype and cognitive performance in specific domains. Yassuda et al. (2012) suggest that compromised motor skills may be related to cognitive impairment, with slow gait speed significantly associated with worse cognitive performance.21 Bunce et al. (2018) evaluated associations between specific cognitive domains and frailty syndrome over 12 years and found that individuals classified as frail at baseline exhibited deficits on tests that evaluated information processing speed and verbal fluency.22 Stern€ang et al. (2016) examined the association between grip strength and cognition in 708 individuals between 40 and 86 years of age at baseline over 20 years of follow-up.23 They found that the decline in muscle strength over time was associated

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with poorer performance on tests that evaluated memory, verbal skills, spatial skills, and processing speed.23 A study conducted in China found that older adults with cognitive impairment had low grip strength even after controlling for age, muscle mass, morbidities, and physical activity level.24 Other lines of evidence suggest that frail individuals exhibit deficits on tests that involve areas of executive control, especially the frontal cortex. Thus, abnormalities in frontal circuits may be related to both changes in motor skills and executive performance, raising the possibility of common mechanisms and pathological changes in both conditions.18,22,25,26 The growing body of scientific evidence on the association between frailty syndrome and cognitive impairment has led to the emergence of the term “D25X Xcognitive frailty,”D26X X which describes individuals with both characteristics but without a clinical diagnosis of dementia.27 Researchers in the health field highlight the importance of assessing both physical and cognitive function in older adults for the planning of timely interventions and state that the inclusion of cognitive measures in the assessment of frailty can improve the predictive validity of the phenotype regarding adverse health outcomes in this population.28,29 In contrast, other groups suggest that frailty syndrome and neurocognitive disorders should be treated as distinct conditions that interact in a bidirectional way. Bunce et al. (2018) found that although frail older adults performed poorly on cognitive tests, they did not exhibit significant changes in the cognitive variables evaluated over 12 years.22 Likewise, Avila-Funes et al. (2009) evaluated a large sample of older residents of 3D27X X French cities and found that the incidence of dementia was higher among those with cognitive impairment independently of the degree of frailty.28 Despite evidence of the close relationship between frailty syndrome and cognitive impairment, the mechanisms involved in this association have not yet been fully clarified. Sternberg et al. (2011) found that the cognitive domain was part of 50% of the definitions of frailty syndrome.4 Thus, the central aspect of this debate resides in the frailty construct, as some screening methods do not include the cognitive domain as a component of frailty syndrome. The association between these conditions may, therefore, depend on the concept of frailty employed.

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FRAILTY AND COGNITIVE DECLINE: D28X X D29X X MECHANISTIC D30XLINKS X

Although there is emerging literature linking physical frailty to cognitive decline and dementia, the possible

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mechanisms linking both conditions have not been fully explored. Both conditions are complex and multifactorial. Most probably, the pathophysiologic mechanisms for both conditions considerably overlap and develop a positive feedback loop leading to more frailty and cognitive decline. Recent evidence indicates that the mechanisms involved in the onset of frailty syndrome are also those that promote neurodegeneration, including chronic inflammation30 and oxidative stress.31 Other clinical comorbidities can increase the risk of both frailty and dementia, such as heart failure, peripheral vascular disease, diabetes, and hypertension.32 It is, therefore, likely that frailty and dementia share common risk factors and biological mechanisms. In this section, we will review how abnormalities in different biological processes can be mechanistic links Q4 between frailty and cognitive decline. X X Inflammation. Mild, chronic proDinflammatory 31X X activation is a feature of the normal aging process, and is often referred to as “inflammaging.”D32X33 X As we age, the levels of proDinflammatory 3X X cytokines (eD34X XgD35X X, IL-6, TNF-a) increase and are not counterbalanced by anti-inflammatory activity. Though it is considered a physiological process, the chronic proDinflammatory 36X X state is linked to age-related diseases and adverse health outcomes in the elderly.34 Previous studies have linked changes in inflammatory markers with frailty syndrome. One of the earliest studies to examine the association between frailty and inflammatory markers included a small sample of subjects (11 frail and 19 nonD37X Xfrail) and showed that the serum IL-6 levels were significantly higher in the former group.35 This early finding was further confirmed in different studies including specific clinical populations (eD38X XgD39X X, patients with cancer, HIV+ individuals) and in the general elderly population and evaluating other inflammatory biomarkers (eD40X XgD41X X, TNFa receptors, IL-8, and CRP).36-40 Besides the cross-sectional evidence, longitudinal cohort studies also provide strong evidence of the association between inflammation and frailty. Puts et al.41 Q5 showed that increased levels of CRP, X X a marker of innate inflammatory activity, was associated with a higher risk of frailty incidence (odds ratioD42X X 1.69, 95% confidence intervalD43X X 1.09 D4X X2.63) after 3D45X X years in the Longitudinal Aging Study AmsterdamD46X X. The association between inflammatory markers and higher incidence of frailty in nonD47X Xfrail elderly were further confirmed in an independent cohort study that showed a similar magnitude of association between high CRP levels and incidence of frailty in nonD48X Xfrail older adults.42 There is abundant data linking inflammatory changes to Alzheimer’s disease (AD). Animal and cellular studies have shown that inflammation modulates the amyloid protein precursor processing and increases the production of amyloid-b42 peptide, a hallmark of the pathogenesis of

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AD.43 PostD49X Xmortem studies have demonstrated the presence of activated microglia surrounding neuritic plaques and the increased expression of proDinflammatory 50X X markers in AD brains.44 Clinical studies have shown that patients with AD have higher levels of circulating proD51X Xinflammatory cytokines (eD52X XgD53X X, IL-6, IL-1b, TNF-a receptors).45,46 Higher levels of proD54X Xinflammatory have been linked to the faster progression from mild cognitive impairment, a high-risk state for clinical dementia.47 It is worth noting that the inflammatory changes observed in individuals with frailty and dementia are of similar direction and magnitude. This raises the hypothesis that proDinflammatory 5X X activation can be a robust mechanistic link between both conditions. Few studies evaluated the association between inflammation, frailty, and AD. Tai et al.D48 56X X showed that in patients with MCI and AD, higher levels of TNF-a were significantly associated with physical frailty. They also showed that high proD57X Xinflammatory state was associated with significantly higher odds of frailty worsening over 1 year of followup. In another study, Namioka et al.D49 58X X also showed that individuals with AD and classified as frail or preD59X Xfrail had significantly higher levels of the proDinflammatory 60X X marker IL-6. Despite this evidence, no study so far has directly addressed if inflammatory changes in frailty can lead to higher risk of dementia in the elderly. Mitochondrial dysfunction and oxidative stress. Mitochondrial dysfunction is an important hallmark of aging and has been implicated in the pathophysiology of different age-related diseases.50 One of the negative consequences of mitochondrial dysfunction is the increased generation of reactive oxygen species (ROS) that, when not counterbalanced by antioxidant defenses, lead to DNA and other macromolecular damage. Mitochondrial dysfunction has been significantly associated with sarcopenia, a key feature of physical frailty.51,52 In a study including older adults classified as frail, preD61X Xfrail, and nonD62X Xfrail, those in the frail/preD63X Xfrail groups had higher levels of 8-oxo-DNA, a marker of oxidative stress damage, compared to the nonD64X Xfrail group.53 Additional clinical and population-based studies also demonstrated that ROS, protein carbonylation, and lipid peroxidation markers were increased in frail compared to nonDfrail 65X X older adults, independent of potential confounding factors.54-56 A recent meta-analysis also showed a reduction in antioxidant defenses in frail older adults adding evidence for a significant imbalance between oxidative stress and antioxidant defenses.57 Mitochondrial dysfunction and oxidative stress imbalance are also a common feature of ADD6X X. There is a large amount of evidence from animal models indicating that mitochondrial dysfunction is related to increased production of amyloid-b and synaptic failure in the brain.58,59 Greater amyloid-b burden can promote increased levels

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of oxidative stress markers what, in turn, lead to worsening of mitochondrial dysfunction creating a positive feedback loop.60 Clinical studies have demonstrated that older adults with ADD67X X have higher levels of oxidative stress markers and higher levels of these markers are related to synaptic dysfunction and cognitive decline. Despite the evidence that both frailty and ADD68X X are associated with oxidative stress, there is little empirical evidence of the impact of both conditions on oxidative stress markers. Namioka et al.D69X49 X showed in a small clinical study that older adults with both AD and frailty presented with the highest levels of oxidative stress markers (eD70X XgD,71X X blood ROS, urinary 8-oxo-DHdG, and 8isoprostane levels). These findings suggested that both conditions have a synergistic effect on increasing oxidative stress and related adverse effects in older adults. Epigenetic changes. Epigenetic changes, including increased DNA methylation of CpG islands, are one the main biological hallmarks of aging.50 Recently, there is a major focus on determining the epigenetic aging in different cohorts and medical conditions.50 One of the ideas behind this goal is that if the calculated epigenetic aging is higher than the chronological, there is evidence for an accelerated aging process in the individual or that is associated with the condition of interest. Recent studies evaluated the DNA methylation in frail vsD72X X nonD73X Xfrail populations. In a community-based study in Germany, including individuals between 50 andD74X X 75 years old, frailty was associated with epigenetic accelerated aging measured by the difference between predicted methylation age minus chronological age.61 Another large, community-based cohort study, including individuals born in 1936 and at the age of 70 when blood was collected for epigenetic analysis (the Lothian Birth Cohort 1936) also evaluated the association between frailty and epigenetic clock.62 They evaluated the epigenetic age based on 2 distinct methods (Horvarth63 and Hannun64). They showed that frailty was associated significantly higher risk of accelerated epigenetic aging (iD75X Xe,D76X X 6% increase in frailty risk per additional year of extrinsic accelerated epigenetic age). In a study examining the association between frailty and DNA methylation in older adults with 85 years and older, they showed higher methylation levels in specific genes (EPHA10, HAND2, HOXD4, TUSC3, and TWIST2), but not in the genomewide methylation levels.65 Overall, these studies suggest that frailty is associated with accelerated epigenetic aging. However, these results should be interpreted with caution since they are restricted to mostly Caucasian populations and were derived from cross-sectional studies. Epigenetic changes also contribute to AD pathology.66 Early studies showed an increased global DNA methylation in the blood and brain of individuals with AD compared to health controls.66-68 More recently, studies have

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also shown an increase in the DNA methylation in the CpG islands, with corresponding changes in gene expression, in the promoter region of genes that have been associated with higher risk of AD (eD7X XgD78X X, ABCA7, BIN1, and APOE).69,70 Although epigenetic changes can play an important role in the physiopathology and development of frailty and AD, there is no study in the literature that provide an evidence that epigenetic changes can be possible mechanisms linking these conditions. Hypothalamic-pituitary-adrenalD79X X axis dysfunction. Aging is associated with a gradual dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, with increased basal adrenocorticotropic hormoneD80X X and cortisol secretion, decreased glucocorticoidD81X X negative feedback, and flattening of diurnal pattern of cortisol release.71 Previous studies have linked HPA axis dysfunction with frailty and ADD82X X. Studies including institutionalized and community-dwelling older adults showed that frailty was associated with elevated morning cortisol levels,72,73 blunted diurnal cortisol fluctuation,74,75 and higher cortisol:DHEA-S ratio.76 Importantly, HPA axis dysfunction was a strong predictor of incident frailty, increasing the risk of frailty by 76% over 10 years of follow-up.72 HPA axis dysregulation have been recently shown to increase the risk of progression to AD in cognitively healthy older adults or with mild cognitive impairment, specially in those with higher brain amyloid-b burden, indicating a potential role of cortisol and other HPA hormones in the pathophysiology of AD.77,78

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THERAPEUTIC OPPORTUNITIES D83X X

The observation that frailty and cognitive decline are linked brings up the possibility that they can be a common therapeutic target for intervention. There is no clinical trial that specifically addressed if interventions focused on frailty can improve cognitive decline among patients with dementia, and vice-versa. Unfortunately, there is evidence that some of the current treatments available for dementia can be detrimental when it comes to frailty. For example, the cholinesterase inhibitors, drugs commonly used for the symptomatic treatment of AD, can cause loss of weight and sarcopenia, exacerbating frailty symptoms in this population. NonD84X Xpharmacological interventions are the main strategies to improve frailty, or components of this syndrome (eD85X XgD86X X, sarcopenia). Nutritional approaches and physical exercise have shown to significantly improve frailty measures in older adults under different conditions.79,80 Interestingly, recent studies examined the impact of a multifactorial nonD87X X pharmacological intervention program, including diet and physical activity, on frail subjects and showed a significant improvement in cognitive performance, including episodic

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memory and executive function domains.81,82 Nonetheless, these studies were in general of low methodological quality and they should be replicated in larger randomized, controlled trials. Although these studies did not evaluate possible biological mediators of the association between exercise and diet on cognitive performance among frail older adults, both interventions can have potent antiinflammatory, antiD8X Xoxidative stress effect, and significantly improve mitochondrial function that can be beneficial to both frailty and cognitive disorders.

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FUTURE DIRECTIONS D89X X

Frailty and dementia are among the most disabling and costly conditions in the elderly. The expected growth in the elderly population makes them major public health concerns. Age-related changes in different biological processes, like increased proD90X Xinflammatory status, mitochondrial dysfunction, epigenetic changes, and HPA axis dysfunction have been implicated in the pathogenesis of frailty and AD. Within this perspective, both conditions can be viewed as markers of accelerated aging process and the consequence of intrinsic and extrinsic perturbations in the biology of aging in a single individual. Nonetheless, not all aged adults develop frailty or dementia, nor these conditions have a direct causal relationship. Studies aiming at evaluating the mechanisms of these disorders should address which are the overlapping pathophysiologic mechanisms between aging, frailty, and dementia and aging; and which are unique to each of these conditions. A better understanding of the shared and unique mechanisms that leads to frailty and AD can inform the development or repurpose of therapeutic interventions for these conditions. Although there are no pharmacological interventions that can prevent or modify their natural history, nonD91Xpharmacological X interventions show great potential for treatment, but most importantly to prevent them. It is urgent that new and ongoing clinical trials, testing pharmacological and nonD92X Xpharmacological interventions, include measures of both frailty and cognition in different elderly populations. Results from these studies can provide additional evidence about which interventions are best for specific patient groups, allowing clinicians, and other health professionals to tailor their intervention to the needs of a particular individual.

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ACKNOWLEDGMENTSD93X X

All authors have read the journal’s policy on conflicts of interest. The authors do not have conflicts of interest related to this manuscript. All authors have read the journal’s authorship agreement.

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