Sarcopenia: Technological Advances in Measurement and Rehabilitation

Sarcopenia is an important recently defined disease affecting people aged ≥ 65 years all over the world. Improving the assessment of loss of muscle mass is becoming mandatory. In this regard, various new technologies have been advanced. Although the gold standard is represented by magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS), computed tomography (CT) or dual-energy X-ray absorptiometry (DXA), followed by biological impedance analysis (BIA) compared with DXA, there are numerous correlations between sarcopenia and health domain of everyday life that must be investigated and addressed, trying to obtain the best possible outcome in the older population. In this review, we focused on all types of new technologies assessing loss of muscle mass, frailty, inde-pendence, walking, capacity to get dressed, and loss of balance or sleepiness in older people and that could improve the diagnosis of sarcopenia or the rehabilitation of sarcopenic patients to prevent possible accidents. Different technologies have been proposed to investigate the factors promoting the loss of muscle mass and weakness. Despite the standard EWGSOP 2019 guidelines defining a specific methodology for the diagnosis of sarcopenia, not all domains and devices were included, and new frontiers of prevention have been explored.


Introduction
Sarcopenia was defined by the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) and recognized as a disease in 2016 [1][2][3]. In 2019, the European Working Group on Sarcopenia in Older People (EWGSOP) published important recommendations for the diagnosis of Sarcopenia for Caucasian People [4]. These recommendations are currently used as guidelines for the assessment of sarcopenia.
The first guidelines for the diagnosis of sarcopenia were written on the occasion of the first EWGSOP Congress in 2010 [5]. They also included some criteria for the diagnosis of pre-sarcopenia (loss of muscle mass and its variability).
The functional and anatomical areas to investigate for diagnosis, defined in both the first and second EWGSOP Congress [4], are muscle strength (hereinafter referred to as MS); muscle quality (hereinafter referred to as MQ ), and physical performance (hereinafter referred to as PP). Nowadays, in accordance with the second EWGSOP guidelines, MS is evaluated through the assessment of grip strength (subsequently referred to as handgrip strength or HGS). The dynamometer is an inexpensive and efficient tool, but it investigates only the strength exerted by the upper limbs and has several limitations [6]. The recommended tests for MQ are magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS); computed tomography (CT); dual-energy X-ray absorptiometry (DXA) [4], including the alternative use of the biological impedance analysis (BIA) [7]. Regarding PP, the suggested gold standards are the short physical performance battery (SPPB) combined with the time-up and go test (TUG), or, as an alternative, the gait speed test (GS) [4].
However, the problem is that DXA, MRI, and BIA are not always available in hospitals and at the surgeries of general practitioners, and are fairly expensive.
Therefore, the aim of this review is to suggest some new and less expensive tools and technologies that may substitute the three tests mentioned above and that are able to maintain a reliable level of diagnostic accuracy. Moreover, we would like to extend the MS parameters not only to the upper limbs but also to the lower limbs and to the assessment of balance and spatial coordination. The use of these accurate and cheaper tools would favor the diagnosis of sarcopenia and, consequently, the prevention of loss of muscle mass, in a higher number of patients. Alternative tools for the evaluation of MS and PP as well as some rehabilitation tools for the prevention of bad outcomes in pre-sarcopenic and sarcopenic patients will also be proposed.

Methodology
This is a review of five randomized control trials (RCT), three cohort studies (CS), 13 cross-sectional studies (CSS), two systematic reviews (SR), two systematic reviews & meta-analyses (SR&M), one quasi-experimental study (Q-ES), one design and validation study (DVS), one exploratory study (ES), four randomized control studies (RCS), and four articles on new integrated technologies, some of which not yet tested on humans. The research was carried out between April 2021 and July 2021. The following libraries were searched: PubMed, Cochrane Library, Google Scholar, and Scopus.
A total of 6069 records were obtained. Of these, 5931 were discarded: 1833 were duplicates and 4098 were eliminated because of the type of population or because they focused on populations affected by cancer, or having post-operative outcomes or head and neck cancer with post-surgical outcomes affecting the tongue, or because they were studies based the use of ultrasound, MRI, CT, and DXA. Also, we excluded papers dealing with the rehabilitation of sarcopenia after a hip fracture or other similar events.
The eligibility criteria were: (1) community-dwelling older adults; (2) older adult volunteers: out-patient or hospitalized patients; (3) frail subjects according to the frailty criteria defined by Fried et al. [8]. About age, some of the studies focused on patients aged ≥50 years (middle-aged), others on patients aged ≥65 years (older), and others on patients aged 19 to an older age. Studies that did not include older adults were excluded.
Works referring to the Asian Working Group for Sarcopenia guidelines were also excluded.
Moreover, of the remaining 138 articles, 102 were discarded because they were duplicates or because they were not pertinent to the aim of the research.
The studies analyzed for this review were 36: 32 dealing with tested technologies whose results were compared with the parameters established in the EWGSOP guidelines, and four studies presenting new and not tested technologies. The article search was carried out by using the following word strings and the PubMed's Boolean operators: "phase angle and sarcopenia"; "rehabilitation and sarcopenia"; "sarcopenia and measurement"; "actigraphy and sarcopenia"; "jumping mechanography"; "sarcopenia and wearable devices"; "sarcopenia robotic measurements". The search was restricted to the 2015-2021 period, including extremes.
To assess the quality of the paper, the Newcastle-Ottawa quality assessment scale was used [9].  [15].

Diagnosis and rehabilitation of sarcopenia
In 2018, the American Academy of Sleep Medicine recommended using the actigraphy test for the diagnosis of sleep disorders [16]. Subsequently, on the basis of the ascertained association between frailty domains and functional limitations [8,12,17], Pana et al. investigated the relationship between sleep quality and MS among community-dwelling middle-aged and older adults [12]. The existence of a correlation between sleep disorders and sarcopenia can be expected but, until now, research in this field has been fragmented and no studies have been carried out investigating a possible direct correlation between sleep disorders and sarcopenia. For example, a study [18] has been published on the correlation between peak oxygen consumption and muscle loss. Physiological data were obtained through a feature of the actigraphy test called Actihear [19] which, however, focused on muscular functionality and not on sleep quality.
Accelerometer has been proposed in wearable devices to assess different parameters of physical activity following the "The Physical Activity Guidelines for Americans" (PAG, 2nd edition) [13], as shown in Table 1. However, in two studies in which the accelerometry was used, the accelerometry threshold did not prove to be indicative [10,11]. Viecelli et al. [20] tried to obtain other parameters using displacement sensors. The purpose was to detect the contraction phase mapping to implement mechanobiological descriptors of MQ and MS. However, this study had a few limitations due to a low clinical relevance, a small sample of patients, and an undefined population [20].
Lastly, a very recent article [14] aimed at identifying and elaborating parameters from gait signals produced by the sensors in order to develop a screening and classification method for sarcopenia. In the study were used specific parameters that they interpreted through an artificial intelligence (AI) model called SHAP (Shapley Additive Explanations). The features obtained through the inertial signals were not exhaustive; for this reason, further data and greater cohorts, respectively, with additional clinical evaluations should be collected and studied [14].

Electromyography
In Table 2, an interesting new technology capable of evaluating variations in muscle activity is shown: the EMG.
It was demonstrated [17] that some electrophysiological sarcopenic variables were associated with the frailty phenotype [8,17], but frailty in older men was Frailty and Sarcopenia -Recent Evidence and New Perspectives associated with lower CMAP and MUP, which however were not related to age and BMI.
On the basis of the data obtained by Habenicht et al. [21] in their study on back extension, a diagnostic algorithm for assessing the first signs of muscle weakness related to back extension may be developed [21]. Subsequently, Gennaro et al. [23], in their ES, defined "corticomuscular coherence" (CMC), obtained during locomotion by simultaneously measuring EEG and EMG, and suggested it as a new feature for the diagnosis of sarcopenia [23], reporting that it has a high sensitivity and specificity.
Marshall et al. [22] compared BW-RET with MN-RET and EB-RET in a group of healthy younger adults and a group of older adults: BW-RET proved less effective  than MN-RET and EB-RET. The EMG parameters were defined by studying a population composed of young adults, healthy and at-risk older adults [24] (as shown in Table 2). In the article, they concluded that it was not clear if EMG loss correlates with MS or mere loss of muscle mass [24].

Jumping mechanography
The association between the jumping mechanography (JM) and sarcopenia starts with Buehring et al. [30,31], who gave "operational definitions of the variables available through muscle mechanography" with the aim to propose muscle mechanography as a tool for what we defined as MQ parameter [31], supporting the reproducibility of JM in older people [25,30].
To assess muscle function and, at the same time, the MQ and PP parameters, JM can be considered an interesting new tool. It was first described by Dietzel [25][26][27]; in all of these studies, JM was performed by Leonardo Mechanograph® (Table 3). JM measures the peak of muscle power by a vertical jump, as this practice is considered safe and useful to assess not only MQ and PP parameters but also different geriatric outcomes clearly important in primary prevention. In all previous studies, participants were tested in accordance with the first EWGSOP guidelines [25,26] and showed a better correlation between ADL and JM performance. Such correlation gives useful indications for the prevention of falls and fractures. In another work [27], the feasibility and acceptability of JM were evaluated: JM was considered comfortable and the comfort was related to one's own JM performance.
Also, in the work by Alvero-Cruz et al. [29], sarcopenia was diagnosed according to the first EWGSOP guidelines. They did not use JM but studied highly trained track and field athletes to explain the age-related decline in vertical jumping performance, obtaining data from the Redcap, Leonardo, and BIA data merging [29].
Of interest, in 2020 a complete and well-designed RCT was carried out [28]. It consisted of an intervention program based on physical exercises to evaluate outcomes in anthropometrics, body composition, muscle function, mobility measures, JM, and dietary habits. It showed that the program could be feasible in a population of older adults and that JM detected differences in MS and MQ using the chair-rise test rather than the TUG test [28].
All the above-mentioned studies were carried out on the basis of the first EWGSOP guidelines. However, it is now necessary to perform studies comparing results with the second EWGSOP guidelines. Wiegmann et al. have been the first to define a diagnostic algorithm on the basis of the second EWGSOP guidelines [32].

Sarcopenia and BIA's phase angle
The BIA's phase angle (PhA) was mentioned for the first time in a work by Heymsfield et al. [7]. Biological impedance analysis (BIA) was considered a useful tool for sarcopenic patients who were unable to perform a handgrip test or to walk [4,35,36]. Nowadays, BIA is used to confirm the diagnosis of sarcopenia ( Table 4).
According to a study carried out in Mexico [33] on active older women, there seems to be no correlation between PhA and sarcopenia parameters, but PhA seems to be associated, with a doubtful biological meaning, with speed walking [33] (or PP). In a recent paper [34], they analyzed sarcopenia on the basis of the parameters defined by the second EWGSOP guidelines, and physical frailty, according to the parameters defined by Fried et al. [8], both adjusted to the Mexican population.
Studies on more homogeneous populations may clarify the usefulness of BIA's PhA.

New technologies tested
Magstim 200 system: Magnetic nerve stimulation was tested on older sarcopenic people [37]. The study reports several limitations in the execution and screening of sarcopenic patients whose functions were not highly compromised. Despite this and the fact that it is an expensive technique, this methodology is still considered acceptable and feasible. More tests on sarcopenic patients with highly impaired functionality would be needed ( Table 5).
Software HTSMavor: In South America, accessibility to DXA is very difficult. With the purpose to facilitate the assessment of sarcopenia, a screening algorithm for the diagnosis of sarcopenia, following the second EWGSOP guidelines, was developed. The results are very promising, but software accuracy should be implemented [38].   Bioelectrical impedance analysis to estimate the lean muscle volume: Serial bioelectrical impedance analysis (S BIA ) was compared with magnetic resonance imaging (MRI) [39]. As a strong agreement between IV BIA and IV MRI was found, a specific conductivity constant ( ) was computed in order to assess the reliability of S BIA as a possible alternative to MRI. Despite the study limitations, the technique appears to be very promising.

Rehabilitation in sarcopenia
Sarcopenic patients are not usually followed in the daily routine, therefore it would be advisable to develop rehabilitation programs to keep the progression of the disease under control. Rehabilitation programs usually contain enhanced physical exercises and dietary increased amounts of protein intake [40]. In the absence of these rehabilitation programs, physicians give advice on physical exercises and dietary habits to patients. However, these recommendations are rarely observed by the patients [41].
In the following part of this manuscript, we talk about new proposals on rehabilitation. Such proposals include new or old technologies that could be used in planned therapies for pre-sarcopenic and sarcopenic patients.

Virtual reality and laser therapy
Thousands of articles on rehabilitation protocols that use virtual reality in different research fields have been produced [44,45], but there are still few studies applying virtual reality to sarcopenia. The patients on whom the usability was tested were older patients with varied pathologies. The results were promising; therefore, it is hoped that it will be applicable to sarcopenic patients ( Table 6).
In the work by Chen et al. [43], the virtual reality-based progressive resistance training was tested on patients residing in a nursing home, over a period of 12 weeks. The outcomes were different, but the training determined an improvement especially of the upper limb strength, in other words, MS and MQ but not PP. An increase of ASMM was present but was not statistically significant [43]. Further studies are required.

Electrostimulation included whole-body vibration
It is well-known, from previous studies, that electrostimulation can favor the increase of muscle fibers thus improving MS, MQ, and PP and today confirmed in different works [55]. In 2016, Wittman et al. [46] and then Klemmer et al. [47][48][49] evaluated the parameters linked to sarcopenia and the WB-EMS effects, according to sex: the FORMOsA trial was conducted on women and the FranSO trial was conducted on men ( Table 7).
The FORMOsA study concluded that the WB-EMS did not improve MS or PP nor decrease the fat mass, compared to the conventional physical activity [46], but it improved muscle mass. For this reason, it is advisable to use it in cases where the patient is unable to perform conventional resistance training [46,47]. The FranSO study, on the other hand, showed that in men WB-EMS succeeded in increasing muscle mass and lowering fat mass (in sarcopenic obesity), confirming its use in the case of older people unable to move or unmotivated [48,49].
To understand the effects of EMS intervention, Nishikawa et al. [50] made three measurements over a period of 12 weeks; then the results were compared with SEMG. Although their conclusions were closely related to a short group of individuals with the locomotive syndrome, the results suggested that EMS was able to increase MS and MQ. However, further studies would have to be performed [50] to obtain more conclusive results.
In the article by Jandova et al. [51], the EMS activity was completed in lumbar multifidus (LM) and vastus lateralis (VL). The results suggested an increase in muscle mass and mobility.
On the other hand, vibration therapy (VT) was considered a close relative of EMS and showed the potential to improve MS and PP in sarcopenic older adults [52].
Initially, whole-body vibration was tested both on Asiatic and European middleaged and older postmenopausal women [56]. Patients were enrolled if the diagnosis of sarcopenia was assessed by skeletal mass index. Later, other studies tried to determine the optimal rate of frequency per time [57]; there were some discrepancies due to the type of population and the criteria used to establish the diagnosis of sarcopenia, the point of stimulation, the type of exercises, and the measurements [52,56]. It was compared [53] RT, WBV, and EMS and concluded that the combined use of the three techniques had the capability to improve MS and functional performance. However, more studies would be necessary to obtain more evidence that the combined use of EMS, RT, and WBV is effective in improving MS [53]. In the same year, Wu et al. [52] published a systematic review and meta-analysis showing the efficacy of WBV in improving sarcopenia and important results demonstrating an increase in MS, MQ, and PP after treatment.
Finally, Yamazaki et al. evaluated proprioception in pre-sarcopenia in a group of 64 patients [54]. However, a limitation of the study was the absence of the diagnosis of sarcopenia. Nevertheless, the results suggested that the proprioception could be linked to the decline of lower leg skeletal muscle spindles in older adults with lower muscle mass.   Addante et al. [58] proposed new wearable devices incorporating the Arduino software to gain HGS, GS, and EMG data at the same time. Data acquisition was possible through the activation of a mobile application linked to the REST server, which was connected with the PostgreSQL database stored on a web application.
Concurrently, McGrath et al. [6] proposed a new dynamometer. It integrates the basic functionalities of any dynamometer with those of an accelerometer allowing a doubling of the features measured, obtaining a complete evaluation of the muscular capacities, integrating the parameters of MS, MQ, and PP, but only of the upper limbs.
Given the intimate connection between cerebral activity and muscles driving the whole gait cycle, Gennaro et al. [59] proposed a mobile wireless recording device of brain activity combined with several other body behavioral variables [60]. Through statistical methods based on blind source separation, they managed to segregate non-cerebral/artefactual sources from cerebral sources of activity: this system is called "mobile brain/body imaging" (MoBI) [59]. The obtained data were founded on coupled EEG-EMG analysis, in an interval from 0 to 1 named "corticomuscular coherence" (CMC) [59].
Friedrich et al. [60] introduced the MyoRobot technology (a full description is available on the biomechatronic platform [61]) designed for assessing the pathophysiologic mechanisms of muscle biomechanics. Nowadays, the technology is still being tested.

Discussion and conclusions
Sarcopenia is a disease that cannot be underestimated, given the impact it has on out-patient or hospitalized patients: complications, length of hospitalization, mortality, and possible problems that may occur in everyday life. In order to define target strategies or personalized therapies against sarcopenia, the diagnosis in older sarcopenic patients should be achieved through qualitative and quantitative measurements of muscle loss. Such measurements could be facilitated by the use, during hospitalization, of wearable devices capable of providing important data in a very short period of time.
In order to assess the reliability of the novel technologies proposed, a comparison on homogeneous populations should be made between the parameters obtained by using the second EWGSOP guidelines instructions and the parameters acquired through the technologies applied. Thereafter, it will be possible to define a diagnostic algorithm that would be able: • To distinguish pre-sarcopenia from sarcopenia and severe sarcopenia, as defined by the first EWGSOP guidelines; • On the basis of the MQ, MS, and PP parameters defined by the second EWGSOP guidelines, to build pre-sarcopenia cut-offs through the use of lowcost, safe, and useful technologies to assess pre-sarcopenia.
In conclusion, the proposed technologies are: (a) accelerometer and actigraph technology in wearable inertial sensors ( Table 1), focused on sleep quality and loss of muscle strength, and physical activity in older adults related to PP assessment; (b) EMG for diagnostic purposes ( Table 2); (c) JM (Table 3), (d) a short overview about the correlation between the PhA and muscle loss ( Table 4); (e) a new frontier of virtual reality ( Table 6) designed for rehabilitation programs for sarcopenic patients; (f) EMS and WBV ( Devices promoting active aging could be used to design rehabilitation and prevention programs in severe sarcopenic and pre-sarcopenic patients, respectively. It would be desirable that these devices were available in hospitals, occupational medicine physicians' offices, or at general practitioner's surgeries.