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Muscle Function & Cognitive Decline; Sarcopenia is associated with incident Alzheimer's dementia, mild cognitive impairment, and cognitive decline
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Download the PDF here
05 May 2021 - Journal of the American Geriatrics Society
from Jules: this is an example of an area of research in HIV & aging that has received little or no attention: what is the affect of HIV on muscle function ???
"In summary, in a large cohort of initially nondemented community-dwelling older adults we found an association of sarcopenia with late-life cognitive impairment. Adults with more severe baseline sarcopenia had an increased risk of incident AD, incident MCI, and a faster rate of cognitive decline. Our findings also suggest that the muscle function component of sarcopenia is the main driver of these associations. Further research is needed to identify which features of muscle structure and additional muscle function metrics can improve the specificity of sarcopenia for use as a clinical biomarker to identify adults at risk for late-life cognitive impairment......This study of 1175 well-characterized community dwelling older adults without dementia provides evidence that baseline sarcopenia is associated with incident AD dementia, incident MCI and the rate of cognitive decline. Analyses of the components used to construct sarcopenia suggest that muscle function, as measured by grip strength or gait speed rather than muscle mass is the primary driver of these associations. These longitudinal findings suggest that sarcopenia in older age is related to a wider range of adverse health outcomes including not only mortality and disability, but also late-life cognitive impairment. Our results provide additional support for the growing recognition that muscle function rather than muscle mass is the primary driver of the reported associations of sarcopenia with varied adverse health outcomes in older adults.......Our results that muscle mass does not predict late-life cognitive impairment, highlight that further work is needed to identify which features of muscle structure can be added to muscle function to improve the specificity of sarcopenia for identifying adults at risk for late-life cognitive impairment. For example, further studies of muscle morphology, including muscle fiber types and size, and fiber groupings may add to predictions of incident cognitive impairment. Many vital morphologic features of muscle are influenced by CNS structures distributed in regions extending from the brain to spinal motor neurons.29 While lean muscle mass may not be the salient feature of muscle structure driving cognitive impairment, few studies have systematically investigated muscle morphology in large numbers of well-characterized older adults and none have linked morphologic changes in muscle with degeneration of nerve, spinal cord, and brain in the same older individuals. While muscle can be obtained in living older adults, the influences of muscle and CNS degeneration can only be studied together in well-characterized older individuals at the time of death."
Abstract
Objective
We examined whether sarcopenia is associated with the occurrence of late-life cognitive impairment.
Methods
Nondemented older adults (N = 1175) underwent annual testing with 17 cognitive tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength. Cox proportional hazard models were employed to examine associations of sarcopenia with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI). Linear mixed-effect models determined the association of sarcopenia with cognitive decline. All models controlled for age, sex, education, race, and height squared.
Results
Average follow-up was 5.6 years. More severe sarcopenia at baseline was associated with a higher risk of incident AD (hazard ratio [HR], 1.50 [95% confidence interval 1.20–1.86]; p < 0.001) and of MCI (1.21 [1.01–1.45]; 0.04) and a faster rate of cognitive decline (estimate = −0.013; p = 0.01). Analyses of the individual components of sarcopenia showed that muscle function was associated with incident AD, incident MCI, and cognitive decline with and without a term for lean muscle mass in the model. In contrast, lean muscle mass was not associated with incident cognitive impairment or cognitive decline when a term for muscle function was included in the model.
Conclusions
Poor muscle function, but not reduced lean muscle mass, drives the association of sarcopenia with late-life cognitive impairment. Further work is needed to identify features of muscle structure, which may increase the specificity of sarcopenia for identifying older adults at risk for late-life cognitive impairment.
INTRODUCTION
Sarcopenia is a common aging phenotype defined as loss of muscle structure and its function.1-3 While cross-sectional studies suggest an association of sarcopenia with cognition, there is little data on the association of sarcopenia with incident cognitive impairments and cognitive decline. Motor function is a complex volitional behavior and its impairment precedes and predicts cognitive decline, incident mild cognitive impairment (MCI), and Alzheimer's dementia (AD) in many older adults.4-6 Considerable data suggest that shared neural substrate underlies motor and cognitive resources underlying volitional motor control, suggesting a common etiopathogenesis. For example, both motor and cognitive decline are related to many of the same AD and other related brain pathologies7 as well as cortical proteins,8 which drive late-life decline.
Higher body mass index (BMI), which encompasses muscle mass, is related to faster cognitive decline and incident AD.9, 10 Changes in BMI in older adults is also related to the same ADRD brain pathologies underlying cognitive decline11 and recent reports suggest that muscle proteins may reach the central nervous system (CNS) via systemic circulation to affect cognition.12 These studies support the biological plausibility for prior observational studies linking both elements of sarcopenia, that is, muscle structure and function with late-life cognitive impairment.
Recently, emerging technologies, such as bioimpedance, have made it easier to obtain measures of muscle mass outside of the laboratory setting permitting a reassessment of the independent role of lean muscle mass metrics as part of the construct of sarcopenia in predicting adverse health outcomes such as mortality and disability.1, 3 We are unaware of prior studies which have examined whether lean muscle mass is independently associated with incident AD, incident MCI, and cognitive decline when controlling for muscle function.
In this study we combine measures of grip strength with measures of lean muscle mass to assess the association of sarcopenia with incident AD, MCI, and cognitive decline in a sample of approximately 1200 community-dwelling older adults participating in the Rush Memory and Aging Project (MAP).13 In further analyses, we examined each of the components used to assess sarcopenia to test the hypothesis that lean muscle mass is independently associated with incident MCI and AD as well as the rate of cognitive decline when controlling for muscle function.
DISCUSSION
This study of 1175 well-characterized community dwelling older adults without dementia provides evidence that baseline sarcopenia is associated with incident AD dementia, incident MCI and the rate of cognitive decline. Analyses of the components used to construct sarcopenia suggest that muscle function, as measured by grip strength or gait speed rather than muscle mass is the primary driver of these associations. These longitudinal findings suggest that sarcopenia in older age is related to a wider range of adverse health outcomes including not only mortality and disability, but also late-life cognitive impairment. Our results provide additional support for the growing recognition that muscle function rather than muscle mass is the primary driver of the reported associations of sarcopenia with varied adverse health outcomes in older adults.
Aging adults show changes in body composition and habitus with loss of lean muscle mass. Thus, early definitions of sarcopenia focused primarily on reduced muscle mass or bulk as the primary driver of the associations of sarcopenia with adverse health outcomes in old age.26 There has been increasing questions about the role of muscle mass as part of the definition of sarcopenia.2 The recently published consensus position by the Sarcopenia Definition and Outcomes Consortium concluded that muscle function, and not lean muscle mass, drives the association of sarcopenia with risk of mortality and incident disabilities.1, 3, 27 The current study lends further support to this conclusion by providing evidence that the association of sarcopenia with incident cognitive impairment in older adults is also driven primarily by muscle function and not muscle mass.
These reports emphasize previous findings in our cohort, that metrics of grip strength and gait speed are robust, but nonspecific predictors of adverse health outcomes in old adults.5, 6, 13 In other words, while grip strength and gait speed show significant associations with diverse adverse health outcomes in older adults, these metrics cannot identify individuals at risk for specific outcomes. Thus, by measuring grip strength and gait speed alone, it is not possible to identify an individual at risk for incident cognitive impairment rather than other adverse health outcomes such as disability or mortality. Our novel longitudinal findings have important clinical implications in that they broaden the spectrum of adverse health outcomes associated with sarcopenia to include incident AD, incident MCI, and cognitive decline. These findings also underscore the need to identify more granular metrics for both components of sarcopenia. Understanding the underlying varied biological mechanisms linking body composition measures and muscle function with distinct adverse health outcomes is crucial for development of more accurate risk stratification and targeted interventions. Recent studies in this cohort have employed wearable sensors to capture a wider range of gait and balance metrics which may complement conventional gait speed metrics. These studies suggest that collecting a wider range of muscle function metrics with wearable sensors may improve prediction models for specific adverse health outcomes such as incident AD and MCI.28
Our results that muscle mass does not predict late-life cognitive impairment, highlight that further work is needed to identify which features of muscle structure can be added to muscle function to improve the specificity of sarcopenia for identifying adults at risk for late-life cognitive impairment. For example, further studies of muscle morphology, including muscle fiber types and size, and fiber groupings may add to predictions of incident cognitive impairment. Many vital morphologic features of muscle are influenced by CNS structures distributed in regions extending from the brain to spinal motor neurons.29 While lean muscle mass may not be the salient feature of muscle structure driving cognitive impairment, few studies have systematically investigated muscle morphology in large numbers of well-characterized older adults and none have linked morphologic changes in muscle with degeneration of nerve, spinal cord, and brain in the same older individuals. While muscle can be obtained in living older adults, the influences of muscle and CNS degeneration can only be studied together in well-characterized older individuals at the time of death.
The basis for the associations of sarcopenia and cognitive impairment is unknown. Muscle secretes hormone-like proteins may reach cognitive brain regions via systemic circulation rather than via CNS connection to affect cognition.30, 31 Myokines, secreted by muscle, contribute to the regulation of hippocampal function32; moreover, myostatin, a potent myokine that modulates muscle atrophy, when blocked, leads to increase in muscle mass and grip strength and improved memory and learning in a transgenic model of AD.12These recent studies highlight the need for further studies to identify which markers of muscle structure highlight these muscle links with cognition, which if added to muscle function metrics, may improve the specificity of sarcopenia for identifying adults at risk for incident cognitive impairment.
This study has several limitations. The clinical data analyzed were derived from a select cohort who agreed to autopsy at death and may differ in important ways from older persons in the general population such as education, socio-economic status, and lifestyle. It will be important to replicate these findings in more diverse cohorts. The adults in this study were very old and our results may not reflect the associations that might be observed in mid-life or younger older adults. Mild cognitive impairment is intermediate between an individual with NCI and one with dementia. Our complementary analyses showing the associations of sarcopenia with cognitive decline, the principal manifestation of AD, lends confidence that the association of sarcopenia with incident MCI was not likely to have been affected by diagnostic misclassification. While the use of electrical bioimpendence measures has expanded, these measures may be more variable than traditional measures of muscle mass, that is, dual-energy X-ray absorptiometry (DXA), particularly in very old adults,33, 34 underscoring the importance of replicating our findings with more traditional measures of muscle mass35 and advancing the investigation of muscle morphology. Our results remained robust after adjusting for cardiovascular risk factors and diseases, but other factors such as cancer may have affected muscle mass and function. Confidence in the findings from this study is enhanced by several factors. Participants were examined annually for up to 13 years with structured validated clinical measures of muscle mass, muscle and cognitive function in a large number of males and females.
In summary, in a large cohort of initially nondemented community-dwelling older adults we found an association of sarcopenia with late-life cognitive impairment. Adults with more severe baseline sarcopenia had an increased risk of incident AD, incident MCI, and a faster rate of cognitive decline. Our findings also suggest that the muscle function component of sarcopenia is the main driver of these associations. Further research is needed to identify which features of muscle structure and additional muscle function metrics can improve the specificity of sarcopenia for use as a clinical biomarker to identify adults at risk for late-life cognitive impairment.
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