Michael Drey

The Fried Frailty Criteria as Inclusion Criteria for a Randomized Controlled Trial: Personal Experience and Literature Review

Background: Among current operational definitions of frailty, the criteria proposed by Fried and colleagues have attracted great scientific interest. However, these criteria have usually been applied in epidemiological and only rarely in interventional studies. Objective: The present paper aims at testing the applicability of the Fried frailty criteria in the context of the recruitment process of a randomized controlled trial in prefrail older persons, and it discusses the respective scientific literature. Methods: Recruitment was promoted by newspaper articles as well as by targeted mail to customers of a local health insurance company and to recently treated patients of a geriatric day clinic. Furthermore, presentations were given in assisted living facilities. Potential candidates were screened for prefrailty, i.e. to see whether they met 1 or 2 of the Fried criteria (weight loss, handgrip strength, gait speed, exhaustion, physical activity). Results: A total of 298 people were screened. Among them 181 were not frail, 116 were prefrail and 1 was diagnosed as frail. The most prevalent criterion was exhaustion (24% of those screened). The second most prevalent criterion was low handgrip strength (20%). Low gait speed (8%), low physical activity (2%) and weight loss (2%) had a lower prevalence. According to the Geriatric Depression Scale, 14% of those who met the criterion ‘exhaustion’ were depressed. With regard to the Minnesota Leisure Time Physical Activity Questionnaire, used for the evaluation of ‘physical activity’, only 3 activities among the 18 selected by Fried were applicable to our cohort. Conclusions: Under the study conditions, good applicability of the Fried criteria was observed. Nevertheless, further refinement may be expedient in several criteria, especially exhaustion and physical activity, to enhance clinical usefulness. It may be helpful to adapt the cutoffs when applying the criteria to a European population.

Prospective Validation of the Modified Mini Nutritional Assessment Short-Forms in the Community, Nursing Home, and Rehabilitation Setting

To validate the modified Mini Nutritional Assessment (MNA) short‐forms (MNA‐SFs) with respect to agreement with full MNA classification in the target populations of the MNA.

C-terminal Agrin Fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction

INTRODUCTION Sarcopenia is considered to be an enormous burden for both the individuals affected and for society at large. A multifactorial aetiology of this geriatric syndrome has been discussed. Amongst other pathomechanisms, the degeneration of the neuromuscular junction (NMJ) may be of major relevance. The intact balance between the pro-synaptic agent agrin and the anti-synaptic agent neurotrypsin ensures a structurally and functionally intact NMJ. Excessive cleavage of the native motoneuron-derived agrin by neurotrypsin into a C-terminal Agrin Fragment (CAF) leads to functional disintegration at the NMJ and may consecutively cause sarcopenia. The present study evaluates the hypothesis that CAF serum concentration is a potential marker for the loss of appendicular lean mass in older adults. It also explores how CAF concentration is influenced by vitamin D supplementation and physical exercise. METHOD Serum was taken from 69 (47 female) prefrail community-dwelling older adults participating in a training intervention study to measure the CAF concentration using the Western blot technique. All participants were supplemented orally with vitamin D3 before the training intervention period commenced. Appendicular lean mass (aLM) was evaluated by dual energy X-ray absorptiometry. Multiple linear regression models were used to identify factors significantly associated with CAF concentration. RESULTS Appendicular lean mass, age and sex were identified as significant explanatory factors for CAF concentration. Gait speed and hand grip strength were not associated with CAF concentration. Male participants showed a strong correlation (r=-0.524) between CAF serum concentration and aLM, whereas this was not the case (r=-0.219) in females. Vitamin D supplementation and physical exercise were significantly associated with a reduction in CAF concentration, especially in participants with initially high CAF concentrations. CONCLUSIONS C-terminal Agrin Fragment could be a potential marker for identifying sarcopenia in a subgroup of affected individuals in the future. The decline of muscle mass seems to be a CAF-associated process in males, whereas the situation in females may be more complex and multifactorial. CAF concentration is reduced by vitamin D supplementation and physical exercise and therefore suggests a potentially positive effect on NMJs. Further prospective studies of sarcopenic patients in addition to muscle biopsy and electromyographical investigations are planned to verify the external validity of the CAF concept.

Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients

Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74 years) detected CAF in the limited range of 2.76 ± 0.95 ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87 years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged-matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo.

Residual effects of muscle strength and muscle power training and detraining on physical function in community-dwelling prefrail older adults: a randomized controlled trial

BackgroundAlthough resistance exercise interventions have been shown to be beneficial in prefrail or frail older adults it remains unclear whether there are residual effects when the training is followed by a period of detraining. The aim of this study was to establish the sustainability of a muscle power or muscle strength training effect in prefrail older adults following training and detraining.Methods69 prefrail community-dwelling older adults, aged 65–94 years were randomly assigned into three groups: muscle strength training (ST), muscle power training (PT) or controls. The exercise interventions were performed for 60 minutes, twice a week over 12 weeks. Physical function (Short Physical Performance Battery=SPPB), muscle power (sit-to-stand transfer=STS), self-reported function (SF-LLFDI) and appendicular lean mass (aLM) were measured at baseline and at 12, 24 and 36 weeks after the start of the intervention.ResultsFor the SPPB, significant intervention effects were found at 12 weeks in both exercise groups (ST: p = 0.0047; PT: p = 0.0043). There were no statistically significant effects at 24 and 36 weeks. In the ST group, the SPPB declined continuously after stop of exercising whereas the PT group and controls remained unchanged. No effects were found for muscle power, SF-LLFDI and aLM.ConclusionsThe results showed that both intervention types are equally effective at 12 weeks but did not result in statistically significant residual effects when the training is followed by a period of detraining. The unchanged SPPB score at 24 and 36 weeks in the PT group indicates that muscle power training might be more beneficial than muscle strength training. However, more research is needed on the residual effects of both interventions. Taken the drop-out rates (PT: 33%, ST: 21%) into account, muscle power training should also be used more carefully in prefrail older adults.Trial registrationThis trial has been registered with clinicaltrials.gov (NCT00783159)

The Motor Unit Number Index (MUNIX) in sarcopenic patients

INTRODUCTION The cause of sarcopenia is still not fully understood. A multifactorial aetiology is discussed. Neurodegenerative aspects in the genesis of sarcopenia, such as loss of motoneurons, have not yet been explored to a sufficient extent. METHOD The Motor Unit Number Index (MUNIX) is a method for assessing the number and size (Motor Unit Size Index - MUSIX) of Motor Units (MUs) using the Compound Muscle Action Potential (CMAP) and the Surface electromyographic Interference Pattern (SIP). This method was used to study the hypothenar muscle in the right hand of 27 sarcopenic patients. RESULTS The mean MUNIX (111±51) of all investigated sarcopenic patients lies between the mean MUNIX of healthy persons and the mean MUNIX of ALS patients. 25% of sarcopenic patients exhibit pathologic values for both MUNIX (<80) and MUSIX (>100 μV). A strong correlation (r=0.75, p<0.001) between MUSIX and the reciprocal value of MUNIX was identified. CONCLUSION It was demonstrated for the first time by applying the MUNIX technique that loss of motoneurons plays a pathogenic role in the onset of sarcopenia. This was shown in 25% of sarcopenic participants who exhibited pathologic values for both MUNIX and MUSIX. Nerve sprouting seems to be an important mechanism of compensation for loss of motoneurons, reflected by the strong correlation between MUNIX and MUSIX. Use of MUNIX leads to the identification of a distinct subgroup of sarcopenic patients, which might have a major impact on future diagnostic and therapeutic concepts.

Effects of Strength Training versus Power Training on Physical Performance in Prefrail Community-Dwelling Older Adults

Background: It has been unclear which training mode is most effective and feasible for improving physical performance in the risk group of prefrail community-dwelling older adults. Objective: The purpose of the present study was to compare the effects of strength training (ST) versus power training (PT) on functional performance in prefrail older adults. This study was registered at clinicaltrials.gov as NCT00783159. Methods: 69 community-dwelling older adults (>65 years) who were prefrail according to the definition of Fried were included in a 12-week exercise program. The participants were randomized into an ST group, a PT group and a control group. All participants were supplemented with vitamin D3 orally before entering the intervention period. The primary outcome was the global score on the Short Physical Performance Battery (SPPB). Secondary outcomes were muscle power, appendicular lean mass (aLM) measured by dual energy X-ray absorptiometry and self-reported functional deficits (Short Form of the Late-Life Function and Disability Instrument, SF-LLFDI). Results: Regarding changes in the SPPB score during the intervention, significant heterogeneity between the groups was observed (p = 0.023). In pair-wise comparisons, participants in both training groups significantly (PT: p = 0.012, ST: 0.009) increased their SPPB score (PT: Δmean = 0.8, ST: Δmean = 1.0) compared to the control group, with no statistical difference among training groups (p = 0.301). No statistical differences were found in changes in aLM (p = 0.769), muscle power (p = 0.308) and SF-LLFDI (p = 0.623) between the groups. Muscle power significantly increased (p = 0.017) under vitamin D3 intake. Conclusions: In prefrail community-dwelling adults, PT is not superior to ST, although both training modes resulted in significant improvements in physical performance. With regard to dropout rates, ST appears to be advantageous compared to PT. The high prevalence of vitamin D3 deficiency and the slight improvement of physical performance under vitamin D3 supplementation among study participants underline the relevance of this approach in physical exercise interventions.

Nutrition, frailty, and sarcopenia

Frailty and sarcopenia are important concepts in the quest to prevent physical dependence, as geriatrics are shifting towards identifications of early stages of disability. Definitions of both sarcopenia and frailty are still developing, and both concepts clearly overlap in their physical aspects. Malnutrition (both undernutrition and obesity) plays a key role in the pathogenesis of frailty and sarcopenia. The quality of the diet along the lifespan has a close relation with the incidence of both entities, and nutritional interventions may be able to reduce the incidence or revert either of them. This brief review explores the role of energy and protein intake and other key nutrients on muscle function. Nutrition may be a key element of multimodal interventions for frailty and sarcopenia. The results of the “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) trial will offer key insights on the effect of such interventions in frail, sarcopenic older individuals.

Sarcopenia – pathophysiology and clinical relevance

ZusammenfassungDie Ursachen der Sarkopenie sind multidimensional. Der Verlust an schnell kontrahierenden Muskelfasern übersteigt den Verlust an langsam kontrahierenden Muskelfasern und endet in einem klinisch relevanten Verlust an Muskelpower. Auf der subzellulären Ebene führen altersabhängige Veränderungen der Mitochondrien zu einer Reduktion der muskulären Performance. Durch einen Rückgang der Anzahl der motorischen Einheiten der Muskulatur entsteht eine Muskelfaseratrophie mit konsekutivem Rückgang der Muskelkraft. Erniedrigte Spiel an anabolen Hormonen und ein überwiegen von proinflammatorischen Zytokinen sind verantwortlich für Veränderungen der Körperzusammensetzung. Ein geringes Maß an körperlicher Aktivität, Vitamin-D-Mangel und geringe Proteinzufuhr sind stark mit einem Muskelverlust assoziiert. Sarkopenie verursacht bei den Betroffenen einen Verlust an Unabhängigkeit, gesteigerten Bedarf an medizinischer Versorgung und erhöhte Kosten für das Gesundheitswesen.SummaryThe causes of sarcopenia are multidimensional. The loss of fast-twitch muscle fibres exceeds the loss of slow-twitch muscle fibres and ends as a clinical relevant loss of muscle power. On a sub-cellular level, age associated changes in the mitochondria lead to functional decline of the muscle. The reduction of motor units causes muscle fibre atrophy and loss of muscle strength. Low levels of anabolic hormones and the imbalance of pro- and anti-inflammatory cytokines are responsible for changes in body composition of older adults. Reduced levels of physical activity, vitamin D and protein are highly associated with muscle loss. Sarcopenia causes loss of independence and high medical and nursing needs resulting in great economic healthcare burden.

Relation between muscle mass, motor units and type of training in master athletes

The aim of this study was to measure the number of motor units and muscle mass in power‐trained and endurance‐trained master athletes compared with community‐dwelling older adults.