Association of Low Muscle Mass With Cognitive Function During a 3-Year Follow-up Among Adults Aged 65 to 86 Years in the Canadian Longitudinal Study on Aging

Key Points Question Is low muscle mass associated with declines in different cognitive domains over 3 years? Findings In cohort study that included 8279 older adults, the presence of low muscle mass was significantly and independently associated with faster subsequent executive function decline over 3 years. Meaning These findings suggest the potential for clinical screening of older adults to identify those with low muscle mass to assist in risk detection of cognitive impairment development.


Introduction
Dementia is increasingly prevalent with age and negatively affects the quality of life of both patients and families. 1 Unfortunately, the pathological changes responsible for dementia appear to be irreversible by the time of diagnosis. Treatments are few, very limited in efficacy, and target symptoms. 2 Therefore, identifying modifiable biomarkers that may estimate the risk for subsequent cognitive decline is critical. Such measurable biomarkers could identify high-risk patients appropriate for further testing of potential disease-modifying therapies.
Depending on definitions, sarcopenia prevalence ranges from 10% to 40% in communitydwelling older adults. 3,4 Sarcopenia, originally characterized by age-related low skeletal muscle mass also includes low muscle strength and physical performance, 5 but a consensus definition has not been reached. [6][7][8] The pathogenetic mechanisms proposed for accelerated cognitive decline are similarly implicated in sarcopenia-lack of anabolic hormones, vascular diseases, chronic inflammation, insulin resistance, neuronal dysfunction-suggesting both may be linked. 9 Sarcopenia may be prodromal to the onset of cognitive impairment 10 and may represent a sensitive marker of cognitive decline. However, the sarcopenia construct, including 3 related but distinct components, precludes identifying independent associations of each with cognition, which could be important to guide future mechanistic investigations. Physical and cognitive functions are dually related, and as such, are part of the frailty 11 and the motoric cognitive risk syndromes. 12 Lower handgrip strength has recently been associated with higher incident dementia risk and mortality in the UK Biobank. 13 However, little attention has been brought to muscle mass. Beyond its role in body strength and function, muscle is an endocrine organ releasing several myokines involved in brain functions. 14,15 To date, few cross-sectional studies have explored the relationship between muscle mass or the combination of low muscle mass and strength with cognitive impairment. Conclusions were not uniform with some showing an association between the 2 conditions [16][17][18] and others not. [19][20][21][22] To our knowledge, no studies have explored the relationship between muscle mass, independently of strength, and subsequent cognitive decline. To address this gap, we examined the associations between low appendicular lean soft tissue mass (ALM, proxy for skeletal muscle mass) and 3-year decline in 3 cognitive domains-memory, executive functions, and psychomotor speed-in free-living older adults of the Canadian Longitudinal Study on Aging. Given the multiple possible links between muscle and cognition, we hypothesized that low muscle mass would be associated with decline in all 3 cognitive domains studied.

Study Population
The design and methods of the nationally representative Canadian Longitudinal Study on Aging (CLSA) have been described. 23 Between 2011 and 2015, the comprehensive cohort enrolled 30 097 free-living male and female participants aged 45 to 85 years across 11 cities in 7 provinces.
Participants were able to speak French or English, were free of cognitive impairment that precluded and 4003 female participants) (Figure 1). Analyses were conducted from April 24 to August 12, 2020. The CLSA study was approved by the research site ethics boards and all participants of the comprehensive cohort provided informed written consent. 24 The present study was approved by the research ethics board of the McGill University Health Centre. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Neuropsychological Assessment
Thorough neuropsychological testing was performed by a trained staff member at baseline and after 3 years. 25,26 The battery consisted of 10 standard English and French cognitive tests, assessing 3 distinct cognitive domains: memory, executive functions, and psychomotor speed, selected for relevance to diseases of aging and psychometric properties. Memory was assessed using the 15-word Rey auditory-verbal-learning test (RAVLT). Results of the first trial (immediate recall) and second trial (5-minute delayed recall) were used. Executive functions were evaluated using 4 tests: the mentalalternation test (MAT), high interference (color names in incongruent colors/colored dots) of the Stroop test, the animal-fluency test (AFT), and the controlled-oral-word-association test for the letters F, A, and S (COWAT). For the present analysis, the sum of words across the 3 letters was calculated to provide a single total COWAT result. Psychomotor speed was assessed using computeradministered choice reaction times. The mean response time was used for analyses. The RAVLT, MAT, and AFT were administered in home and the COWAT, CRT and Stroop during the interviews at a CLSA data collection site.

Anthropometry
Anthropometric assessments by trained health assessors included body weight measured wearing light clothing without shoes (140-10 Healthweight Digital Physician Scale; kg), standing height with heels, buttocks, and shoulder blades touching the stadiometer (Seca 213; cm). All were measured to the nearest 0.1 unit and the mean of 2 measurements for weight and height was used.

Discussion
This large longitudinal cohort study with detailed cognitive assessments found that community-     activity that was no longer significant, but low muscle mass remained associated with executive function decline.

JAMA Network Open | Geriatrics
To our knowledge, the present study is the first to identify an association between low muscle mass and subsequent cognitive decline, independently of strength typically combined in the sarcopenia construct and thought to drive the association. 17,31 Indeed, recent evidence from the UK Biobank cohort supports that low handgrip strength estimates increased dementia risk and mortality. 13 Cross-sectional associations between sarcopenia and cognitive impairment are accumulating 32,33 and support a positive link between conditions. Two recent meta-analyses found   Greater muscle mass may lead to and result from physical activity and cardiorespiratory fitness, hence more blood flow to the brain, 40 shown to favor executive functioning particularly. 41 Our statistical models accounted for baseline physical activity level, thus the independent association of low ALM suggests that components specific to skeletal muscle as an endocrine organ may play a protective role in maintaining cognitive executive functions. Indeed, the induction of muscle contraction through exercising may stimulate the release of myokines IL-6 (pleiotropic), IL-8, IL-15, and Brain-Derived Neurotrophic Factor (BDNF) with anti-inflammatory effects 14 and may partly explain the potential protective effect of preserving muscle mass for brain health. Additional to the hormonal theory, insulin resistance, oxidative stress, and low-grade chronic elevation of pro-inflammatory markers may be involved in both pathogeneses of sarcopenia and dementia. 9,42 Whether low muscle mass is an early marker or a causal factor of executive cognitive decline, and elucidation of mechanisms linking muscle mass to cognitive functions remain to be determined.
Numerous strengths pertain to this study, lending confidence in the observed results. These include data collected in a large and modern cohort of older adults and sample weights applied in all analyses allowing generalizability to the Canadian population. Also, 7 objective, valid, and reliable (potentially excluding the modified version of the RAVLT) cognitive tests were used, more than in most studies. 26 Lastly, lean soft tissue mass was evaluated using precise and accurate DXA, the reference method for estimating muscle mass 43 and study population-specific empirical low ALM cut points were applied. 3 The current study design is a limitation as it prevents causal inference.
However, our results were consistent before and after statistical adjustment for many key confounding factors, rendering alternative explanations for the observed associations less likely plausible. Finally, models were not adjusted for apolipoprotein E (APOE4) as it was not measured at the time of our analyses.

Limitations
This study has some limitations. Surprisingly, mean scores of both immediate and delayed memory tests increased over 3 years in sarcopenic and non-sarcopenic individuals, whereas memory loss is typically expected with aging. 44 Although the RAVLT test is sensitive in cognitive impairment detection, 45 our findings may be due to a retest effect or time-saving modifications brought to the RAVLT test in the CLSA (1 trial vs 5 in the original version and 5-minute vs 30-minute delay) 46 potentially impairing reliability. The increase in the immediate recall was nonetheless significantly blunted in individuals with sarcopenia vs those without, suggesting a deficit in the memory domain.
The overall improvement during follow-up in both memory scores may have obscured identification of such deficits and their association with sarcopenia. Also, the number of tests to assess each domain differed with more executive functions tests available, which may have introduced bias. It remains possible that the memory and psychomotor speed domains are affected upon further repeated measures and this can be addressed as future follow-up data become available in CLSA.

Conclusions
This cohort study found that the presence of low muscle mass measured by DXA was significantly and independently associated with faster subsequent executive function decline over 3 years among adults aged at least 65 years. Importantly, DXA is widely available and measures of lean mass could be routinely incorporated into the image analyses. Clinical screening of older adults to identify those with low muscle mass may provide insight regarding their risk of developing cognitive impairment and thereby guide the testing and application of preventative or therapeutic interventions.