Aging results in a progressive loss of muscle mass and functional decline, which leads to an increase in the incidence and prevalence of chronic diseases [1, 2], which leads to situations of multimorbidity [3] and has an impact on functional autonomy [4]. The most severe expression is the condition of frailty, “a progressive decline in physiological systems that results in decreased reserves of intrinsic capacity, which confers extreme vulnerability to stressors and increases the risk of a range of adverse health outcomes”[5]. Frailty is associated with dependency, hospitalization, institutionalization, falls, poor quality of life, and mortality [6–10] and with increased healthcare costs [11, 12]. Standardized diagnostic criteria are lacking, but the two most accepted ones [13, 14] are based on the phenotype construct [4], in which frailty is diagnosed if three or more of the following criteria are present: unintentional weight loss, self-reported exhaustion, decreased grip strength, slow gait speed and low physical activity. Additionally, the "Cumulative Deficit Model - Frailty Index", includes cognitive, functional, emotional and nutritional status [15, 16].
The frailty phenotype described by Fried involves muscle dysfunction at its core [17]. Given that weakness, slowness and impairment of the muscular system are hallmarks of frailty, sarcopenia is likely to be a key physiopathological contributor. [13, 18]. Sarcopenia is a progressive skeletal muscle disease, whose prevalence increases with age. Sarcopenia is estimated to affect between 6% and 19% of the general population ≥ 60 years of age, differing according to the definition applied [19]. Currently most used definitions are from the European Working Group on Sarcopenia in Older People (EWGSOP-2)[20], the Definition and Outcomes Consortium (DOCS)[21], and the National Institute of Health Foundation (NIHF)[22]. According to EWGSOP-2, reduced muscle strength is the first criterion of probable sarcopenia, while reduced muscle mass and quality confirms the diagnosis. In addition, when low physical performance is detected sarcopenia is graded as severe [20]. The DOCS agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia [21]. NIHF defines sarcopenia as a loss of strength, diagnosed by low grip strength, together with low muscle mass [22].
To assess muscle mass and quality in clinical care, a semi-quantitative assessment is performed with two-dimensional images by Dual-energy X-ray absorptiometry (DXA) and with a body composition estimate with Bioelectrical impedance analysis (BIA)[20]. These techniques may however be confounded by other variables such as skeletal mass and large body mass index [23]. Radiological imaging allows full-scale three-dimensional mapping of muscle composition and microstructure. Magnetic resonance imaging (MRI) and computed tomography (CT) sequences have been proposed, which allow assessment of adipose fraction and fibrous microstructure, among others [24–26]. However, due to their high cost and potential patient complications, these methods are currently only applied in research or as a supplementary examination for a different primary indication [27].
Sarcopenia and frailty are related but distinct conditions related to aging. While sarcopenia is mainly based on the musculoskeletal system, frailty is a more multifactorial condition [28, 29]. Different studies have shown that the prevalence of sarcopenia among frail older adults is higher than the prevalence of frailty among those with sarcopenia. [28, 30–32]. The adverse outcomes associated with muscular decline can be prevented, delayed or even reversed by early detection and interventions including nutritional support and physical exercise programs [13, 18, 33]. However, there is a need for simple and reliable tools that allow the assessment of muscle quality and its impact on frailty [28, 34].
Ultrasound is a fast, non-invasive and affordable imaging modality which is rapidly emerging for musculoskeletal examination [35, 36]. Current clinical ultrasound images (B-mode) allow for assessment of muscle mass and morphology. Common features include measures of muscle thickness, pennation angle, cross-sectional area, echo intensity and fascicle length [37–39]. Despite ongoing efforts for standardization, these measurements are highly dependent on the expertise and skills of the operator and do not show definite results for early staging of muscle quality loss [37, 40]. Ultrasound morphometric measurements of sarcopenia in older adults have shown mild to moderate associations with frailty [41]. More recently, several quantitative ultrasound techniques have emerged based on the analysis of echogenicity, texture parameters, elastography and acoustic wave properties, with still limited translation to clinical practice [42–51]. Artificial intelligence is bringing new opportunities to objectivize musculoskeletal ultrasound, with recent works demonstrating automatic muscle segmentation and fiber angle detection and textural discrimination of muscle microstructures [52–55].
Biological biomarkers are valuable tools in the diagnosis and stratification of patients as well as in the understanding of the underlying pathophysiology of the disease. Oxidative stress, pro-inflammatory state and immune aging are relevant in the relationship between nonspecific biomarkers and specific biological systems and frailty and sarcopenia [56–59]. Recent studies have addressed the complex interrelationships among the different systems underlying frailty through multi-omics approaches [60]. For instance, the FRAILOMIC initiative used blood samples to describe a set of biological biomarkers, both protective and risk factors. In particular, oxidative stress, vitamin D, and cardiovascular system were associated with frailty [61]. Despite these advances, currently available biomarkers are individually poorly associated with the clinical outcomes of sarcopenia and frailty and their capability to detect changes after physical intervention is largely unknown.
Only a limited number of works have explored combinations of ultrasound and blood-based biomarkers. A study identified circulating biomarker changes corresponding to a short-term resistance exercise intervention in older adults, which were significantly related with ultrasound leg cross-sectional area [62]. Associations were identified between combined genetic and methylation scores and ultrasound-derived skeletal muscle morphometry in elderly women [63]. Another cross-sectional study related ultrasound characteristics of the quadriceps femoris in sarcopenic patients to blood and urinary biomarkers [64].
Overall, simple and objective screening tools to diagnose frailty and sarcopenia are lacking [28, 34]. B-mode image clinical standardization is necessary, but there is also a need for advances in ultrasound technology to create quantitative indicators for evaluating muscle quality [65, 66]. This study is designed to evaluate objective muscle quality assessment methods using quantitative analysis techniques based on the analysis of ultrasound raw data combined with blood-based biomarkers. In addition, this study will examine the capability of these biomarkers to detect muscle quality changes as a result of a physical exercise intervention program in frail elderly people.
Thus, the main objective of this study is to evaluate the feasibility of combinations of point-of-care quantitative ultrasound parameters with blood-based essays for assessment of muscle quality and frailty in older adults in both hospital setting and community care with respect to clinical evaluation.