cognitive frailty: a review of the mechanisms and challenges...cognitive frailty: a review of the...

Cognitive Frailty: A Review of the Mechanisms and Challenges

Grace Shu Hui Chiang MPH

Introduction

Population aging is a transforming demographic force. The proportion of older adults and life

expectancy is expected to increase with global population expansion and aging. This

demographic shift is accompanied by various challenges such as ensuring successful aging and

preventing illness, disability and dependency; and has implications for health care and social

costs.

The process of aging is a deterioration and decline of functional properties at the cellular,

tissue and organ level, this results in homeostatic dysregulation and increased vulnerability to

stressors(Holliday, 1995). The global failure in hemodynamics resultant from aging contributes

to frailty which has been postulated to be induced by reaching a threshold resultant from

multisystem dysregulation(Gruenewald, Seeman, Karlamangla, & Sarkisian, 2009; Walston et

al., 2006).

Frail elderly experience decline in reserve and function in one or more domains (physical,

cognitive and psychosocial)(R. Gobbens, Luijkx, Wijnen-Sponselee, & Schols, 2010; T.

Malmstrom & J. E. Morley, 2013). While physical frailty has been acknowledged to be an

important geriatric syndrome(Abate et al., 2007; R. J. Gobbens, van Assen, Luijkx,

Wijnen-Sponselee, & Schols, 2010; Sourdet, Rougé-Bugat, Vellas, & Forette, 2012), cognitive

frailty is still a novel concept. An international consensus group recently proposed the concept

of cognitive frailty as “an heterogenous clinical manifestation characterized by the simultaneous

presence of both physical frailty and cognitive impairment”, excluding concurrent dementia or

1 Cognitive Frailty: A Review of the Mechanisms and Challenges

other dementias.(Kelaiditi et al., 2013) However, in the clinical setting there is still much

uncertainty regarding the definition, validity, relevance and utilization of cognitive frailty(Cesari,

Andrieu, Rolland, Nourhashemi, & Vellas, 2013).

Frail elderly are at risk of poor outcomes such as increased risk of hospitalization,

dependency in activities of daily living, institutionalization, and death.(Coelho, Paul, Gobbens,

& Fernandes, 2015; L. P. Fried, Ferrucci, Darer, Williamson, & Anderson, 2004) Even lesser

degrees of frailty can affect one’s ability to work, live and socialize, and represent a major

obstacle to active ageing(Fry, 2014). Given the potential economic and social burden resultant

from the consequences of frailty, it is imperative to prevent the development or slow the

progression of frailty through targeting specific biological underpinnings. Hence, it is important

that the concept of cognitive frailty be better understood as it can aid in informing public health

policies for the implementation of early intervention and treatment programs.

This report aims to explore the definitional challenges, mechanisms, possible measurement

tools for screening cognitive frailty and the possible preventive measures that can be taken to

prevent the development or slow the progression of cognitive frailty.

Frailty: Definitional Issues

The importance of addressing the construct of cognitive frailty has been recognized. The

term cognitive frailty was first used in a cohort study of older adults on the performance on a

clock-drawing test and its associations with known and potential protective and risk factors for

Alzheimer’s disease in 2001(Paganini-Hill, Clark, Henderson, & Birge, 2001). This term was

subsequently proposed in a study reviewing pre-dementia syndrome vascular risk factors by


Panza et al in 2006(Panza et al., 2006). Since then, research has shown that both cognitive and

physical factors are predictors of mortality(Pilotto et al., 2012).

In 2013, an international consensus group proposed that cognitive frailty refers to a

heterogenous clinical syndrome in older adults without Alzheimer’s dementia and other

dementias, that is characterized by ongoing physical frailty and potentially reversible cognitive

impairment(Kelaiditi et al., 2013). This seems to suggest that cognitive frailty is parallel to

physical frailty, however the causal links between the two are unclear.

Moreover, to date despite the ongoing research into frailty there has been no definitive

consensus regarding the conceptualization or definition of frailty. There are currently two major

concepts of frailty:

● Deficit-driven frailty: agnostic as to number and type of deficits, the more related or

unrelated clinical deficits accumulate the more likely the patient is to be frail. This was

operationalized by Rockwood et al as the Frailty Index(FI)(Rockwood & Mitnitski, 2007;

Rockwood et al., 1999).

● Syndromic or phenotypic frailty: Fried et al operationalized frailty as a biologic

syndrome wherein declines in specific physiological systems are hypothesized to be part

of the etiology of frailty(Linda P Fried et al., 2001).

Given that the operational definition of frailty is still uncertain, it is even more difficult to

establish a precise operational definition for cognitive frailty. In the past, cognitive frailty has

been used to refer to cognitive impairment related to advanced age or cognitive

disturbances/pre-dementia occurring simultaneously with other comorbidities(Chouliara,


Kearney, Stott, Molassiotis, & Miller, 2004). Therefore, a number of challenges will need to be

addressed before a definition for cognitive frailty can be developed.

Cognitive Frailty and Cognitive Reserve

Some difficulty exists in delineating the difference between cognitive frailty and

cognitive reserve.

Brain reserve can be divided into structural reserve and functional reserve i.e “cognitive

reserve”. The concept of cognitive reserve refers to one’s capacity to withstand cognitive

decline(Stern, 2002). Individuals with high cognitive reserve process cognitive tasks better, this

serves as a buffer and enables them to cope better than others with brain pathology.(Stern, 2009)

Prior cognitive abilities and educational attainment are important influences of cognitive reserve

as they can lead to a more efficacious neural network system or “a wider repertoire of conscious

and preconscious cognitive strategies”(Sachdev & Valenzuela, 2009; Stern, 2002, 2009; Stern,

Albert, Tang, & Tsai, 1999).

Cognitive frailty, on the other hand, has been characterized by Kelaidit et al as a reduction in

cognitive reserve(Kelaiditi et al., 2013). As such, cognitive frailty can be seen as the opposite of

cognitive reserve.

Link between frailty and cognition

Frailty is a multidimensional syndrome, it is the decline in reserve and function in one or

more domains (physical, cognitive and psychosocial)(R. Gobbens et al., 2010; T. Malmstrom &

J. E. Morley, 2013). Hence, cognition is an important mediator in the development and

progression of frailty.


Age is a common risk factor for the development of both cognitive impairment and frailty.

Additionally, mechanisms such chronic inflammation, nutrition, presence of vascular diseases,

depression and endocrinological disorders have been found to be implicated in both frailty and

cognitive impairment(Arts et al., 2016; Baylis et al., 2013; Bonnefoy et al., 2015; Fairfield &

Fletcher, 2002; Hyde et al., 2010; S. X. Leng et al., 2004; Semba et al., 2006; Shah, 2013).

Cognitive impairment has a synergistic effect on physical frailty. Multiple cross-sectional

and longitudinal studies have been done demonstrating this relationship between frailty and

cognition. Both cognitive impairment and incident dementia have been found to be more

prevalent in frail individuals compared to those who are pre-frail or robust(Auyeung, Lee, Kwok,

& Woo, 2011; Ávila-Funes et al., 2009; Feng et al., 2017; Jürschik et al., 2012; Macuco et al.,

2012; Mitnitski, Fallah, Rockwood, & Rockwood, 2011). Both physical frailty and cognitive

impairment act in a cycle of decline leading to further physical and cognitive decline and

decreased quality of life(Feng et al., 2017; Eun Sook Han, Yunhwan Lee, & Jinhee Kim, 2014;

M Houles et al., 2012; Nishiguchi et al., 2015; Deirdre A Robertson, George M Savva, & Rose

Anne Kenny, 2013; Wu et al., 2015).

Mechanisms: Parallels between Physical Frailty and Cognitive Frailty

Both physical frailty and cognitive frailty can co-exist in an individual(E. S. Han, Y. Lee,

& J. Kim, 2014; T. Malmstrom & J. E. Morley, 2013; Shimada et al., 2013; Witham & Sayer,

2015; Woods, Cohen, & Pahor, 2013). There are shared factors causing both physical frailty and

cognitive frailty. Factors leading to physical frailty may cause cognitive frailty, likewise, factors

causing cognitive impairment can lead to physical disability(Clegg, Young, Iliffe, Rikkert, &

Rockwood, 2013; J. Morley, 2015; Morley, 2011, 2014). These risk factors include


leukoaraiosis(Group, 2011; Ogama, Sakurai, Shimizu, & Toba, 2014), accumulation of

neurotoxic b-amyloid in the brain(Buchman, Schneider, Leurgans, & Bennett, 2008), nigral

neuronal loss(Buchman et al., 2014), cardiovascular diseases such as diabetes(Formiga et al.,

2014; Francesco Landi, Onder, & Bernabei, 2013; Leenders et al., 2013; Verny et al., 2015),

hypertension and hyperlipidemia(D. A. Robertson, G. M. Savva, & R. A. Kenny, 2013);

nutritional deficiencies such as hypovitaminosis D and inadequate nutrition(Annweiler et al.,

2011; M Houles et al., 2012; Kelaiditi et al., 2013; D. A. Robertson et al., 2013); inflammatory

processes(Michaud et al., 2013; D. A. Robertson et al., 2013); endocrinological pathologies such

as insulin resistance and low testosterone(D. A. Robertson et al., 2013); depression(M. Houles et

al., 2012; D. A. Robertson et al., 2013); behavioral and lifestyle factors (low physical

activity)(Norton, Matthews, Barnes, Yaffe, & Brayne, 2014; N. A. Singh et al., 2012).

Leukoaraiosis

Leukoaraiosis is the increase in white matter hyperintensities in the brain on MRI, there

is a disconnect between different regions from the brain from resultant vascular disease,

oxidative damage to brain tissue and disruption to the blood brain barrier(Group, 2011; J. E.

Morley, 2015). This mechanism has been shown to link cognition to physical frailty(Group,

2011). There is a correlation between leukoaraiosis and decreased executive function, increased

incidence of physical frailty, depression, balance disorders and falls(Group, 2011; Hui, Morley,

Mikolajczak, & Lee, 2015; Ogama et al., 2014). Diabetes mellitus and cardiovascular conditions

such as atrial fibrillation and heart failure in particular have been associated with an increased

risk of developing leukoaraiosis and subsequent cognitive frailty(Ampadu & Morley, 2015;

Conti, Frei, & Noble, 2013; Formiga et al., 2014; Hui et al., 2015; Verny et al., 2015).


Alzheimer’s Disease Pathology

Studies have found that there is an inter-relationship between physical frailty and the

pathology of Alzheimer’s dementia in older adults with and without dementia, longitudinal

studies have found that age-related brain pathology such as macroinfarcts, nigral neuronal loss

and Alzehimer’s disease pathology were significantly associated with an increased rate of

decline in both cognition and physical frailty, which suggests that there might be a common

pathological basis to explain the pathophysiology of physical frailty and cognitive

decline(Buchman et al., 2008; Buchman et al., 2014; Gray et al., 2013).

The accumulation of neurotoxic B-amyloid in the brain causes acceleration of tau

deposition, this results in neurodegeneration, neuronal loss and local synaptic dysfunction which

in turn leads to a direct neurotoxic effect which has been associated with decreased gait speed

due to a dysregulation of motor and sensorimotor circuits(Gómez-Isla et al., 1997; Josephs et al.,

2008).

Nigral neuronal loss is reduced in neurodegenerative conditions such as Alzheimer’s

disease and Parkinson disease, as the substantia nigra contributes to brain reserve capacity, it is

not surprising that a study has found that nigral neuronal loss is correlated with an increased rate

of decline of physical frailty(Buchman, Yu, Wilson, Schneider, & Bennett, 2013).

It is important to note that the correlation between Alzheimer’s disease pathology and

increased frailty did not vary with dementia status, this association remained significant

irrespective of dementia diagnosis(Buchman et al., 2013; Schneider et al., 2006).

Cardiovascular Risk Factors and Disease


Cardiovascular disease has been found to be associated with both frailty(Chaves et al.,

2005; Fugate Woods et al., 2005; Newman et al., 2001) and cognitive impairment(Ampadu &

Morley, 2015; Formiga et al., 2014; Hui et al., 2015). Cardiovascular disease is independently

associated with both baseline and incident frailty at 3 years(Chaves et al., 2005; Fugate Woods et

al., 2005; Newman et al., 2001). This might be due to an increased risk of sarcopenia, an

age-related decline in skeletal muscle mass and muscle function, which is intrinsically related to

the development of frailty(Chaves et al., 2005; Fugate Woods et al., 2005; Newman et al., 2001).

Additionally, a relationship might exist between sarcopenia and cognitive decline, wherein the

prognosis of neurodegenerative diseases are worsened by sarcopenia(Nourhashémi et al., 2002).

Cardiovascular disease is associated with the development of cognitive decline and dementia as

it is an underlying risk factor for stroke and cerebrovascular disease(Jack, 2010; Newman et al.,

2001).

Endocrine System Alterations– Hormonal Changes

Reduced testosterone and other androgen hormones have been associated with the

development of cognitive impairment and frailty(Maggio et al., 2012; Muller, Grobbee, Thijssen,

van den Beld, & van der Schouw, 2003). Low testosterone and insulin resistance are both

thought to be common factors or mediators in the causal pathway of both cognitive decline and

frailty.

Sarcopenia which is integral in the development of frailty can result from endocrine

system alterations such as low testosterone(Kurita et al., 2014; Morley, 2013; Muller et al.,

2003). In older males, the best hormonal indicator of cognitive status is bioavailable testosterone,

males with cognitive impairment had lower testosterone levels(Morley et al., 1997).


Testosterone promotes synaptic plasticity in the hippocampus and regulates the accumulation of

B-amyloid, it is through this mechanism that testosterone is postulated to be protective against

cognitive decline(Maggio et al., 2012).

Age-related decline in insulin sensitivity or insulin resistance is associated with an

increased risk of both frailty and cognitive impairment even after adjusting for

confounders(Abbatecola, Ferrucci, Marfella, & Paolisso, 2007). Insulin resistance causes

increased catabolism and sarcopenia(Abbatecola et al., 2007).

Inflammation

Another factor in the pathogenesis of both frailty(Collerton et al., 2012; Hubbard &

Woodhouse, 2010; S. Leng, Chaves, Koenig, & Walston, 2002; Michaud et al., 2013) and

cognitive decline(Aktas, Ullrich, Infante-Duarte, Nitsch, & Zipp, 2007; Baune et al., 2008;

Jefferson et al., 2007; Yaffe et al., 2003) is chronic inflammation. Inflammatory cytokines such

as interleukin (IL)-6 and tumor necrosis factor-a are associated with increased frailty and

functional impairment(Michaud et al., 2013). Likewise, inflammatory markers such as IL-8, IL-6

and C-reactive protein(CRP) have been prospectively linked to cognitive impairment in older

adults. Increased amyloid precursor peptide can result from oxidative damage from the brain

which causes increased inflammatory cytokines(Morley, Armbrecht, Farr, & Kumar, 2012;

Mulero, Zafrilla, & Martinez-Cacha, 2011), these cytokines can also cross the blood brain barrier

to accelerate the development of cognitive impairment(Banks, Farr, La Scola, & Morley, 2001).

Nutrition

Inadequate nutrition is an important determinant in the development of frailty and

cognitive decline(Bonnefoy et al., 2015; Cruz-Jentoft, Kiesswetter, Drey, & Sieber, 2017) both


through a direct and indirect casual pathway through its association with other risk factors of

frailty such as increased risk of chronic diseases(Fairfield & Fletcher, 2002), decreased bone

density(Rizzoli, 2010), decreased immunity(High, 1999), sarcopenia and functional

decline.(Milaneschi, Tanaka, & Ferrucci, 2010; Robinson, Cooper, & Aihie Sayer, 2012)

Sarcopenia which can result from malnutrition, is an integral factor in the development of both

frailty and cognitive impairment through an oxidative stress mechanism(Mulero et al., 2011;

Nourhashémi et al., 2002).

Cognitive decline and fatigue which are both components and risk factors of frailty

interact within a cycle of decline associated with aging and inadequate nutrition which further

hastens the development of frailty(D. A. Robertson et al., 2013; Theou, Jones, Overend, Kloseck,

& Vandervoort, 2008). Inadequate homocysteine-related vitamins and antioxidant nutrients

increase the risk of cognitive decline and fatigue, this results in a bidirectional relationship

wherein fatigue and cognitive decline further worsens malnutrition and hence

frailty(Gillette-Guyonnet, Van Kan, Andrieu, & Barberger-Gateau, 2007; Topinková, 2008).

Studies have found that an adherence to Mediterranean diet, high in antioxidants is linked

to both a decreased incidence of frailty and improved cognition(Leon-Munoz, Guallar-Castillon,

Lopez-Garcia, & Rodriguez-Artalejo, 2014; Ngandu et al., 2015; Shah, 2013; B. Singh et al.,

2014).

Physical Activity


Positive associations have been reported between frailty, cognitive impairment and lack

of physical activity(Fugate Woods et al., 2005; Norton et al., 2014; Ottenbacher et al., 2009;

Woo, Goggins, Sham, & Ho, 2005). There is a strong correlation between physical activity and

sarcopenia, a component of frailty and cognitive impairment; increased levels of physical

activity has been shown to reverse sarcopenia and cognitive impairment(Evans, 1996; Ngandu et

al., 2015).

Depression

Psychological well-being and the positive psychology movement in adulthood and later

age have been associated with successful aging and decreased allostatic load(Bowling & Dieppe,

2005; Rowe & Kahn, 1987). Greater levels of frailty are associated with higher levels of

allostatic load which is an index of multisystem physiological dysregulation.(Gruenewald et al.,

2009) Depressive symptoms strongly influence the psychosocial and psychobiological

component of frailty and is significantly associated with the incidence of frailty and cognitive

impairment(Arts et al., 2016; Fugate Woods et al., 2005). There is a bidirectional relationship

between mood, frailty and cognitive impairment(Fitten, 2015). Individuals with depression are

less motivated(Smith, 2013), have lower expectations of aging and place less importance on

seeking healthcare(Sarkisian, Hays, & Mangione, 2002), are less socially engaged and

active(Glass, De Leon, Bassuk, & Berkman, 2006), and have poor self-care and

self-management abilities(Bayliss, Steiner, Fernald, Crane, & Main, 2003; Cramm & Nieboer,

2012).


Depression also shares several biological characteristics with frailty and cognitive

impairment such as loss of weight, fatigue, decreased physical activity and sarcopenia.

Ultimately, the biological and psychological effects of depression can negatively affect the

individuals’ life space, this constriction in life space can hasten deconditioning and worsen the

decline in physiological reserves and increased allostatic load which can lead to frailty(Q.-L.

Xue, Fried, Glass, Laffan, & Chaves, 2007; Q. L. Xue, 2011). Consequently, these biological

characteristics are common mediators in the pathway for both frailty and cognitive impairment.

Screening Measures for Cognitive Frailty

Effective screening and diagnostic tools for the characterization and prediction of frailty

and cognitive status will need to be developed before effective interventions for cognitive frailty

can be designed. The international consensus group has suggested that biomarkers

(inflammatory markers, B-amyloid protein, anemia, serum albumin, cholesterol, vitamin D

status), clinical markers (Mini-Mental State Examination, Executive tests, Alzheimer’s disease

Assessment Scale-cognitive subscale, gait speed, hand grip strength, Geriatric depression scale)

and imaging techniques (dual energy X-ray absorptiometry, cerebral computed tomography,

cerebral magnetic resonance imaging, functional magnetic resonance imaging) be utilized to

achieve this(Kelaiditi et al., 2013).

Other quick screening measures for cognitive frailty that have been suggested for use in

the community setting include the FRAIL(Woo et al., 2015), SARC-F(T. K. Malmstrom & J. E.

Morley, 2013; Woo, Leung, & Morley, 2014), MiniCog(Borson, Scanlan, Brush, Vitaliano, &


Dokmak, 2000), Rapid Cognitive Screen(Tariq, Tumosa, Chibnall, Perry, & Morley, 2006) and

“the 5 words” screen(Dubois et al., 2002).

Preventive Interventions

Primary prevention of frailty should be targeted at older adults to prevent the

development of cognitive frailty. Such measures include promoting healthy lifestyle behaviors

such as increased physical activity, a Mediterranean diet, cognitive stimulation, smoking

cessation, having a healthy mental state, being social engaged and prevention of cardiovascular

risk factors and diseases(Desai, Grossberg, & Chibnall, 2010; Sternberg, Wershof Schwartz,

Karunananthan, Bergman, & Mark Clarfield, 2011).

Secondary prevention measures are instituted in older adults with potential cognitive

frailty. Multidomain interventions which include targeting the physical, cognitive, psychological

and nutrition aspects of frailty have been found to be potentially effective in delaying the

progression of cognitive frailty(Ngandu et al., 2015; D. A. Robertson et al., 2013). Physical

activity in particular has been found to be protective against sarcopenia and cognitive

impairment(F. Landi et al., 2010; Langlois et al., 2013).

Summary

The global aging population heralds an increase in age-related illnesses such as frailty

and cognitive decline which pose a serious challenge to the healthcare, economic and social

systems. As such, a better understanding of the relationship between frailty and cognitive

impairment will be needed to move forward if we are to effectively manage and prevent these

conditions. Further research will need to be done before cognitive frailty can be definitively

operationalized and be considered a geriatric syndrome.


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