Physical strategies to prevent disuse-induced functional decline in the elderly.

Disuse situations can have serious adverse health consequences in the elderly, including mainly functional impairment with subsequent increase in the risk of falls or morbimortality. The present review provides clinicians and care givers with detailed and practical information on the feasibility and effectiveness of physical strategies that are currently available to prevent or attenuate the functional decline that occurs secondarily to disuse situations in the elderly, notably in the hospital setting. In this context, active approaches such as resistance exercises and maximal voluntary contractions, which can be performed both isometrically and dynamically, are feasible during most immobilization situations including in hospitalized old people and represent powerful tools for the prevention of muscle atrophy. Aerobic exercise should also be prescribed whenever possible to reduce the loss of cardiovascular capacity associated with disuse periods. Other feasible strategies for patients who are unwilling or unable to perform volitional exercise comprise neuromuscular electrical stimulation, vibration, and blood flow restriction. However, they should ideally be applied synchronously with voluntary exercise to obtain synergistic benefits.

Associations of pre-existing co-morbidities with skeletal muscle mass and radiodensity in patients with non-metastatic colorectal cancer.

BACKGROUND AND AIM: Co-morbidities and computerized tomography-measured muscle abnormalities are both common in cancer patients and independently adversely influence clinical outcomes. Muscle abnormalities are also evident in other diseases, such as diabetes and obesity. This study examined for the first time the association between co-morbidities and muscle abnormalities in patients diagnosed with colorectal cancer (CRC). METHODS: This cross-sectional study included 3051 non-metastatic patients with Stages I-III CRC. Muscle abnormalities, measured at diagnosis, were defined as low skeletal muscle mass index (SMI) or low skeletal muscle radiodensity (SMD) quantified using computerized tomography images using optimal stratification. Co-morbidities included in the Charlson index were ascertained. χ2 tests were used to compare the prevalence of co-morbidities by the presence or absence of each muscle abnormality. Logistic regressions were performed to evaluate which co-morbidities predicted muscle abnormalities adjusting for age, sex, body mass index, weight change, cancer stage, cancer site, race/ethnicity, and smoking. RESULTS: Mean age was 63 years; 50% of patients were male. The prevalence of low SMI and low SMD were 43.1% and 30.2%, respectively. Co-morbidities examined were more prevalent in patients with low SMD than in those with normal SMD, and most remained independent predictors of low SMD after adjustment for covariates. Co-morbidities associated with higher odds of low SMD included myocardial infarction [odds ratio (OR) = 1.77, P = 0.023], congestive heart failure (OR = 3.27, P < 0.001), peripheral vascular disease (OR = 2.15, P = 0.002), diabetes with or without complications (OR = 1.61, P = 0.008; OR = 1.46, P = 0.003, respectively), and renal disease (OR = 2.21, P < 0.001). By contrast, only diabetes with complications was associated with lower odds of low SMI (OR = 0.64, P = 0.007). CONCLUSIONS: Prevalence of muscle abnormalities was high in patients with non-metastatic CRC. Pre-existing co-morbidities were associated with low SMD, suggestive of a potential shared mechanism between fat infiltration into muscle and each of these co-morbidities.

The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy.

This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 °C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60-week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers.

The effect of exercise hypertrophy and disuse atrophy on muscle contractile properties: a mechanomyographic analysis.

PURPOSE: To determine whether mechanomyographic (MMG) determined contractile properties of the biceps brachii change during exercise-induced hypertrophy and subsequent disuse atrophy. METHODS: Healthy subjects (mean ± SD, 23.7 ± 2.6 years, BMI 21.8 ± 2.4, n = 19) performed unilateral biceps curls (9 sets × 12 repetitions, 5 sessions per week) for 8 weeks (hypertrophic phase) before ceasing exercise (atrophic phase) for the following 8 weeks (non-dominant limb; treatment, dominant limb; control). MMG measures of muscle contractile properties (contraction time; T c, maximum displacement; D max, contraction velocity; V c), electromyographic (EMG) measures of muscle fatigue (median power frequency; MPF), strength measures (maximum voluntary contraction; MVC) and measures of muscle thickness (ultrasound) were obtained. RESULTS: Two-way repeated measures ANOVA showed significant differences (P < 0.05) between treatment and control limbs. During the hypertrophic phase treatment MVC initially declined (weeks 1-3), due to fatigue (decline in MPF), followed by improvement against control during weeks 6-8. Between weeks 5 and 8 treatment, muscle thickness was greater than control, reflecting gross hypertrophy. MMG variables Dmax (weeks 2, 7) and Vc (weeks 7, 8) declined. During the atrophic phase, MVC (weeks 9-12) and muscle thickness (weeks 9, 10) initially remained high before declining to control levels, reflecting gross atrophy. MMG variables D max (weeks 9, 14) and V c (weeks 9, 14, 15) also declined during the atrophic phase. No change in T c was found throughout the hypertrophic or atrophic phases. CONCLUSIONS: MMG detects changes in contractile properties during stages of exercise-induced hypertrophy and disuse atrophy suggesting its applicability as a clinical tool in musculoskeletal rehabilitation.

Validation of the Italian version of the SBMA Functional Rating Scale as outcome measure.

The Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) is an established rating instrument used to assess the functional status of patients with Spinal and Bulbar Muscular Atrophy (SBMA). Our aim was to validate an Italian version of the scale. We administered the SBMAFRS to sixty SBMA patients during routine follow-up of clinical evaluations. To estimate the test stability, the scale was re-administered to a subset of 39 randomly selected patients after 8 weeks. The patients underwent clinical evaluation including 6-min walk. Psychometric analysis included reliability assessment and factorial analysis. To evaluate convergent validity, correlations between SBMAFRS items and muscular force assessed by manual testing, ALSFRS total score and subscales scores, and forced vital capacity, were performed. Internal consistency as measured by Cronbach's alpha (total scale 0.85) was high. Test-retest reliability assessed by Spearman's rho was also high. Principal component analysis with varimax rotation yielded a four-factor solution accounting for approximately 79 % of the variance. The scale total score and subscales score were strongly correlated with respective items and subscores of the ALSFRS, with respiratory function and with the 6-min walk test. In conclusion, we performed an Italian validation of the only existing disease-specific Functional Rating Scale for SBMA patients. This scale will be a useful tool not only in the clinical practice but also as an outcome measure in upcoming clinical trials.

The clinical application of preimplantation genetic diagnosis for the patient affected by congenital contractural arachnodactyly and spinal and bulbar muscular atrophy.

PURPOSE: To investigate the usefulness of preimplantation genetic diagnosis (PGD) for the patient affected by congenital contractural arachnodactyly (CCA) and spinal and bulbar muscular atrophy (SBMA). METHODS: Multiple displacement amplification (MDA) was performed for whole genome amplification (WGA) of biopsied trophectoderm (TE) cells. Direct mutation detection by sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used for CCA diagnosis. Direct sequencing of the PCR products and sex determination by amplification of sex-determining region Y (SRY) gene were used for SBMA diagnosis. After PGD, the unaffected blastocyst (B4) was transferred in the following frozen embryo transfer (FET). RESULTS: In this PGD cycle, sixteen MII oocytes were inseminated by ICSI with testicular spermatozoa. Four blastocysts (B4, B5, B10, B13) were utilized for TE cell biopsy on day 5 after ICSI. After PGD, B4 was unaffected by CCA and SBMA. B5 was affected by CCA and carried SBMA. B10 was unaffected by CCA and carried SBMA. B13 was affected by CCA and unaffected by SBMA. B4 was the only unaffected blastocyst and transferred into the uterus for the subsequent FET cycle. The accuracy of PGD was confirmed by amniocentesis at 21 weeks of gestation. A healthy boy weighing 2850 g was born by cesarean section at the 38th week of gestation. CONCLUSIONS: PGD is a valid screening tool for patienst affected of CCA and SBMA to prevent transmission of these genetic diseases from parents to children.

Molecular diagnosis of spinal and bulbar muscular atrophy in Slovakia.

OBJECTIVES: Molecular-genetic analysis is a determining step in setting the diagnosis of spinal and bulbar muscular atrophy (SBMA). We present the first nation-wide study and experience with this disease and its diagnosis in Slovakia. The study is enriched by comparison of genetic findings from Slovak patients to patients from other countries. METHODS: Molecular-genetic analysis was performed for patients suspected of SBMA. Data of patients with confirmed diagnosis were statistically evaluated. In addition, the detection rate and the prevalence of the disease for Slovakia were estimated. RESULTS: In 40 patients with confirmed diagnosis of SBMA, average values were observed at 44.7 CAG repeats and 52.5 years at the time of molecular-genetic diagnosis. The detection rate represents approximately 23% and an estimated prevalence is of 1 : 41,700. CONCLUSION: Concerning the population of Slovakia with 5,420,000 inhabitants, we document a relatively large cohort of SBMA patients. This is obvious when comparing similar studies from other countries, while this is the only study representing the Central Europe. Our findings prove that molecular-genetic analyses for the detection of this neuromuscular disorder show high efficiency. This fact underlines the necessity of such testing and may serve as a guide for clinicians from other countries in setting the right diagnosis for these patients (Tab. 1, Fig. 2, Ref. 29).

Spinal and bulbar muscular atrophy and Charcot-Marie-Tooth type 1A: Co-existence of two rare neuromuscular genetic diseases in the same patient.

Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling.

A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study.

We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects.

Spinal and bulbar muscular atrophy: pathogenesis and clinical management.

Spinal and bulbar muscular atrophy, or Kennedy's disease, is an X-linked motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. The disease is characterised by weakness, atrophy and fasciculations in the limb and bulbar muscles. Affected males may have signs of androgen insensitivity, such as gynaecomastia and reduced fertility. Neurophysiological studies are typically consistent with diffuse denervation atrophy, and serum creatine kinase is usually elevated 2-5 times above normal. Progression of the disease is slow, and the focus of spinal and bulbar muscular atrophy (SBMA) management is to prevent complications.

Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions.

Trinucleotide repeat disorders are a heterogeneous group of diseases caused by the expansion, beyond a pathogenic threshold, of unstable DNA tracts in different genes. Sequence interruptions in the repeats have been described in the majority of these disorders and may influence disease phenotype and heritability. Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a CAG trinucleotide expansion in the androgen receptor (AR) gene. Diagnostic testing and previous research have relied on fragment analysis polymerase chain reaction to determine the AR CAG repeat size, and have therefore not been able to assess the presence of interruptions. We here report a sequencing study of the AR CAG repeat in a cohort of SBMA patients and control subjects in the United Kingdom. We found no repeat interruptions to be present, and we describe differences between sequencing and traditional sizing methods.

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy.

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work.

Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods.

BACKGROUND: We report on a unique complication of cerebellar ataxia and motor neuron disease named Asidan/SCA36 with a high frequency of tongue atrophy. We aimed to elucidate dysphagia in amyotrophic lateral sclerosis (ALS) and spinal, bulbar muscular atrophy (SBMA), and Asidan/SCA36 patients with new methods. METHODS: Patients diagnosed with ALS (n=20), SBMA (n=6), and Asidan (n=12) were included. A videofluoroscopic swallow study (VFS), an assessment of maximal tongue pressure (MTP), and impedance pharyngography (IPG) were applied. RESULTS: The frequencies of VFS abnormalities were 70%, 50%, and 33% in ALS, SBMA, and Asidan/SCA36, respectively. Compared with control subjects (31.6 ± 6.3 kPa, mean ± SD), MTP was significantly decreased in ALS patients and SBMA patients, but was relatively preserved in Asidan patients. ALS patients performed more swallowing actions (Ns) detected by IPG than did control subjects, but SBMA and Asidan/SCA36 patients performed similar Ns to control subjects. CONCLUSIONS: VFS showed a higher frequency of swallowing abnormalities in ALS patients. MTP and IPG measurements showed the most severe involvement in ALS patients and a relatively preserved swallowing function in SBMA and Asidan/SCA36 patients.

Rapidly progressive frontotemporal dementia and bulbar amyotrophic lateral sclerosis in Portuguese patients with C9orf72 mutation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) form a spectrum of clinically, pathologically, and genetically overlapping disorders, as confirmed by the recent report that it can be caused by a hexanucleotide repeat expansion in C9orf72. One hundred and fourteen Portuguese cases diagnosed as probable or possible familial FTLD, as part of the EOD consortium study, and nine further Portuguese cases with familial ALS were tested for the presence of this mutation. Results showed that six Portuguese patients from unrelated families had the mutation, five (4.4%) patients from the FTLD group and one (11.1%) from the ALS sample. Of these, three patients had FTLD and rapidly progressive bulbar ALS. Electromyography confirmed diffuse loss of motor units with marked bulbar involvement. In conclusion, the cases now reported showed a very rapid progression, suggesting bulbar ALS could be particularly common and aggressive in patients with the C9orf72 hexanucleotide repeat expansion, in the Portuguese population.

Cross-sectional and longitudinal analysis of an oxidative stress biomarker for spinal and bulbar muscular atrophy.

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. The aim of this study was to verify whether urinary 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, is a biomarker for SBMA. METHODS: We measured the levels of urinary 8-OHdG in 33 genetically confirmed SBMA patients and 32 age-matched controls over a 24-month period at 6-month intervals. RESULTS: Urinary 8-OHdG levels in SBMA patients were significantly elevated compared with those of controls and correlated well with motor function scores. During the follow-up period, urinary 8-OHdG levels increased and correlated with motor function at each time-point. In addition, urinary 8-OHdG levels at baseline were correlated with changes in the 6-minute walk test during 24 months. CONCLUSIONS: Urinary 8-OHdG is a biomarker for SBMA, reflecting the severity and possibly predicting the deterioration of motor function.

Critical view on diagnosing muscle wasting by single-frequency bio-electrical impedance in COPD.

BACKGROUND: Assessment of muscle wasting in COPD is relevant as it is independently associated with metabolic and functional consequences and even survival. Muscle wasting can be approached by assessing fat free mass (FFM), but it is already demonstrated that FFM measured by bio-electrical impedance analysis (BIA) underestimates FFM measured by dual energy X-ray absorptiometry (FFM(DExA)) in a relatively small COPD group. OBJECTIVE: To evaluated critical points for defining muscle wasting in a large cohort of moderate to severe COPD patients and with DEXA scan as reference. DESIGN: FFM by BIA was compared with FFM(DExA) in 1087 COPD patients (641 male symbol, FEV1: 44.8+/-17.5%pred). In a subgroup (n=422), FFM(DExA) was predicted by multivariate analysis and a new formula to calculate FFM by BIA was developed. The new formula was compared with FFM(DExA) in the remaining subgroup (n=665). Muscle wasting was defined according to the cut-offs of Schols et al. (FFM index (FFMI)<16 kg/m(2) for men, 15 kg/m(2) for women), Vestbo et al. (FFMI<17.1 kg/m(2) for men, 14.6 kg/m(2) for women), and Coin et al. (FFMI<17.8 kg/m(2) for men, 14.6 kg/m(2) for women). RESULTS: There was an underestimation of FFM by BIA when compared to FFM(DExA) by the Bland Altman. Comparing the new formula with FFM(DExA), the mean underestimation almost disappeared but the variation remained. The proportion of muscle wasting was largely dependent on the used cut-offs, especially in men. CONCLUSION: The results of the present study emphasize the importance to accurately bare in mind the technique and cut-offs to establish muscle wasting before implementing it in the clinical practice.

Maximal and sustained isokinetic lower-limb muscle strength in hospitalized older people.

Maximal strength decreases with aging whereas sustained strength is less affected. Strength decline may be worsened by hospitalization. The aim of this study was to estimate the maximal and sustained isokinetic muscle strength of lower limbs in hospitalized elderly subjects. We evaluated 43 hospitalized elderly subjects (86 +/- 5 years), 28 elderly community-dwelling control subjects (75.4 +/- 6.2 years), and 25 young subjects (28.2 +/- 3.7 years). Among hospitalized subjects, 30 underwent isokinetic evaluation at clinical stability (T0) and again 1 month later (T1). Maximal peak torque (MPT) of the plantarflexors was measured at 30 degrees and 60 degrees /s, and knee flexors and extensors at 90 degrees /s. Evolution of the MPT and the endurance coefficient (EC) on 20 repetitions of plantarflexion at 60 degrees /s were calculated. MPT of plantarflexors and knee flexors and extensors had improved at T1 compared with T0, in hospitalized subjects. MPT evolution and EC values during the sustained strength test revealed no decrease in strength over time in hospitalized subjects at T0 and at T1 compared with community-dwelling control subjects and young subjects. In hospitalized subjects, the absence of an initial phase of fast decrease in muscle strength, which is observed in young subjects during the sustained strength test, could explain this result. It could be related to the modifications of muscle-fiber composition described in elderly subjects and enhanced by hospitalization.

Whipple's disease with muscle impairment.

A 67-year-old man presented with myalgia, muscle atrophy, and a history of seronegative polyarthritis. Blood tests showed inflammation but no hematologic or immunologic abnormalities. Muscle biopsy revealed no vasculitis or myositis but Tropheryma whipplei was detected by polymerase chain reaction in muscle, blood, and duodenum specimens; this was confirmed by immunohistochemistry. Ceftriaxone led to clinical improvement. Although rare, Whipple's disease should be considered in the differential diagnosis of diffuse myopathy.

Neuromuscular disorders in critical illness.

Neuromuscular disorders in the background of critical illness are under diagnosed. Standardized screening for weakness in the intensive care unit (ICU) setting is uncommon and persistent weakness as a sequel of critical illness is usually not recognized by physicians in the ICU for whom survival from acute illness is the primary outcome. The spectrum of illness ranges from isolated nerve entrapment with focal pain or weakness, to disuse muscle atrophy with mild weakness, and to severe myopathy or neuropathy with associated severe, prolonged weakness. This update focuses on neuromuscular disorders occurring in the critical care set up associated with diffuse and severe weakness.