ReviewFrailty and cognitive impairment—A review of the evidence and causal mechanisms
Introduction
One of the greatest achievements of public health in the twentieth century has been the almost doubling of life expectancy in the Western world (Oeppen and Vaupel, 2002). Yet this now ageing population brings new challenges as the prevalence of little-understood geriatric conditions increases. One of the biggest challenges facing modern healthcare is the economic and medical burden of caring for dependent older people limited by physical and mental impairments. Two of the most common and yet least understood of these are frailty and cognitive impairment.
Frailty is a reduction in the ability to respond to stressors and an increased vulnerability to adverse outcomes (Fried et al., 2001). Although the trajectory of decline varies widely, it is most commonly characterised by a progression of physiological decline leading to dependency and disability (Fried et al., 2001, Gill et al., 2010). Frailty can be preceded by, but also occurs in the absence of chronic disease (Rockwood et al., 2007b). The highest prevalence is found in the older population and advanced age is a major risk factor (Fried et al., 2001). Frailty has significant implications for the ability to maintain independent, high quality living and carries an increased risk of hospital visits, disability, institutionalisation and death (Heuberger, 2011). There is no consensus on how best to operationalise or define frailty but two types of definitions have emerged as the most commonly used constructs:
- 1)
The Cumulative Burden Index as proposed by Rockwood et al. (1994; Rockwood and Mitnitski, 2007b): frailty is defined as an accumulation of health conditions and deficits. The index of deficits is not limited to those included in the original model but can include any domains that fulfil the criteria laid out by Rockwood and colleagues.
- 2)
The Biological Syndrome Model as proposed by Fried et al. (2001): a person is deemed to be frail if they present with three or more of: poor grip strength, slow walking speed, low levels of physical activity, exhaustion and unintentional weight loss.
A number of variations on these models of frailty have emerged over the past decade but the underlying constructs remain broadly similar. The Fried and Rockwood models are moderately correlated with each other and are associated with the same adverse outcomes (Rockwood et al., 2007a).
Cognitive impairment is the decline of intellectual functions such as thinking, remembering, reasoning and planning. It is common among older people but the effects range from mild forms of forgetfulness to severe and debilitating dementia. Mild cognitive impairment (MCI) is a term used to define a state of cognitive decline that is not accompanied by any significant functional disability (Allegri et al., 2008, Petersen and Negash, 2008). It has a high rate of progression to all types of dementia in which severe cognitive impairment is accompanied by increasing physical decline, eventually leading to full physical dependency. The Medical Research Council Cognitive Function and Ageing Study, a 10 year population-based cohort study of individuals 65 and over in England and Wales, reported that dementia has a prevalence of around 10% in the population aged 65 and over, and a prevalence at death of one in three (Brayne et al., 2006). Up to one quarter of hospital beds in the UK are in use by people over 65 years old with dementia and the prevalence is around 50% among those in institutional care (Lakey, 2009, Matthews and Dening, 2002). Dementia has an enormous impact on the individual, their families, healthcare systems and wider society, with a direct cost of healthcare services associated with each person with dementia of $17,700 per year (Wimo et al., 2007).
Many pathological processes contribute to cognitive impairment, leading to several possible avenues for dementia prevention. A significant fraction of dementia in the population is attributable to neuropathology such as the neocortical neurotic plaques and tangles associated with Alzheimer's disease (19%) or cerebrovascular pathology (21%) but much remains unexplained (Brayne and Davis, 2012, Matthews et al., 2009). Age is consistently reported as the most important independent risk factor for cognitive impairment and dementia, and so it is likely that many of the age-associated processes that lead to frailty in older people are also responsible for brain ageing and consequent cognitive decline. The benefits of understanding the relationship between cognition and frailty are twofold: First, the frail are likely to be at high risk of cognitive impairment and vice versa. Second, understanding the link between frailty and cognition may lead to new interventions for the prevention and management of both conditions.
The place of cognitive impairment in a definition of frailty has been widely debated. Fried's model does not include cognitive function in its definition, while Rockwood's model allows poor cognition to be included as one of the possible deficits. Recent consensus papers have suggested that an operational definition of frailty should include components from the domains of nutrition, mobility, physical activity, strength, endurance, balance, cognition, senses, mood, coping, social relations and social support although researchers do not agree on diagnostic procedures to achieve this definition of frailty (Gobbens et al., 2010, Rodriguez-Manas et al., 2013). A recent review of frailty measures found that the most commonly included components in an operational definition of frailty were physical function, gait speed and cognition, with cognition being included in 50% of the definitions (Sternberg et al., 2011). On the other hand, statistical analyses on these proposed components of frailty suggest that, while physical activity, mobility, energy, strength and mood aggregate as one concept, cognition does not correlate strongly with this and therefore may not be part of the frailty syndrome (Sourial et al., 2010, Sourial et al., 2012). Furthermore, a recent study of Alzheimer's dementia (AD) patients found that 22% had no indications of frailty (Bilotta et al., 2012a, Bilotta et al., 2012b). It seems most useful therefore to treat frailty and cognitive impairment as related but distinct concepts which frequently co-occur.
A 2011 review described several studies illustrating a link between frailty in dementia and ‘pre-dementia’ cognitive states, highlighting the scarcity of information at that time on the magnitude of the association and mechanisms underlying the link (Panza et al., 2011). Interest in this field has rapidly developed over the course of two years. Many epidemiological studies from different countries have since explored this association and, of particularly relevance, many have disentangled the broad concepts of frailty and cognition into their specific components in order to better understand the relationship. Here we update the 2011 review to include these new studies on the relationship between frailty and cognitive impairment, the possible mechanisms behind this association, and its significance with respect to the possibility of future interventions to interrupt the progression of either frailty or cognitive decline.
Section snippets
Methods
We searched PubMed for papers published before May 2013 – we did not specify a lower date limit – using combinations of the following keywords: frail, frailty, cognition, dementia and Alzheimer's disease. One thousand three hundred and fourteen abstracts were reviewed for relevance including those already contained within the Panza et al., review. We did not apply strict inclusion or exclusion criteria but included all papers which examined cognition and an operationalised definition of frailty
Evidence for the relationship between frailty and cognition
The relationship between cognitive impairment and frailty has been demonstrated both cross-sectionally and longitudinally by a number of epidemiological and clinical studies. These are described in Table 1, Table 2.
Cross-sectional studies
Several cross-sectional studies have demonstrated higher rates of cognitive impairment in frail compared to pre-frail or robust older people. Data from the Three City Study suggests that 22% of frail participants had cognitive impairment (defined as being in the lowest quartile of
Mechanisms behind the link
Although there is now significant epidemiological evidence linking elements of frailty and cognitive decline, little work has directly explored mechanisms underlying this link. A number of papers outlined below have suggested mediators or possible pathways but there is a lack of experimental evidence to support these suggestions.
Interventions
Although evidence for interventions into frailty coupled with cognitive decline is limited, a small number of studies point to the cognitive benefits of physical activity. A 2010 review found that physical activity protected against both sarcopenia and cognitive decline in experimental training trials and in observational studies (Landi et al., 2010). Furthermore, a number of studies showed that aerobic exercise training could reduce levels of both CRP and IL-6 in middle-aged or older persons
Conclusions
Brain health is strongly linked to physical health, and physical function is, to a large extent, cognitively mediated. It should therefore be no surprise that physical frailty and poor cognitive function are related. Fried's definition of frailty is composed of five parts and each of these, individually, has previously been found to be associated with cognitive decline. It is thus not surprising that combining these elements together will create a measure that predicts cognitive decline.
Funding
This work was supported by Irish Life, the Department for Health and Children, a Health Research Board grant (HRA_PHS/2011/26) and The Atlantic Philanthropies. No funding body had any say in how this study was conducted or in how the manuscript was written.
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