Novel genetic loci associated with osteoarthritis in multi-ancestry analyses in the Million Veteran Program and UK Biobank.

Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.

Selective serotonin reuptake inhibitors-associated apathy syndrome: A cross sectional study.

Selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with loss of motivation, anergy, and lack of curiosity often referred collectively as apathy. However, this association has not been systematically assessed using a specific rating scale for measuring apathy syndrome. Our objective was to study the association between SSRI use and apathy syndrome.We conducted a retrospective chart review of 125 patients enrolled in an outpatient psychiatry clinic. The prevalence of apathy syndrome and its clinical significance (based on standardized assessment) were compared between patients treated and not treated with SSRIs. Apathy was assessed using the Apathy Evaluation Scale-clinician version with a score ranging 18-72 with higher score for worse apathy. A score of greater than 30 is considered clinically significant apathy.Among 119 patients, the mean apathy scores were significantly higher in those treated with SSRIs compared to those not treated with SSRIs (42.5 ±â€Š9.2 vs 31.3 ±â€Š6, P < .0001). The SSRI group also had a significantly higher percentage of patients with clinically significant apathy (92% vs 61%, P < .0001). Use of all SSRIs was associated with the presence of apathy. Apathy was seen in all mental health diagnostic categories with highest Apathy evaluation scale-clinician version scores in those with dementia.SSRI use may be associated with higher rates of apathy syndrome. Clinicians should specifically inquire about iatrogenic apathy syndrome when evaluating patients on an SSRI if there is suspicion of loss of motivation. Limitations of this study included retrospective nature of this study, and that majority of the sample was males. Prospective studies are needed to elucidate information regarding the prevalence, etiology, and treatment response for SSRI-associated apathy syndrome.

Neuromodulation for Apathy in Alzheimer's Disease: A Double-Blind, Randomized, Sham-Controlled Pilot Study.

BACKGROUND: Apathy, a profound loss of motivation, initiation, and goal directed cognition, is a common comorbidity of Alzheimer's disease (AD). The presence of apathy is associated with rapid progression of AD, long-term impairment, disability, and higher mortality. Pharmacological treatments of apathy are limited. OBJECTIVE: The primary objective was to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) for apathy in AD. METHODS: A randomized, double-blind, parallel-arm, sham-controlled pilot study was conducted in subjects with AD and apathy (N = 20). Subjects were randomized to rTMS or sham treatment (5 days/week) for four weeks. Primary outcome, apathy evaluation scale-clinician version (AES-C), and secondary outcome measures, modified-Mini Mental State Examination (3MS), instrumental activities of daily living (IADL), and clinical global impression (CGI), were assessed at baseline and four weeks. Follow-up visits were conducted at 8 and 12 weeks to test the durability of effects of intervention. RESULTS: Mean age was 77.3 (±7.2) years, 80% were Caucasians and 10% were females. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment (-10.1 (-15.9 to -4.3); t (16) â€Š= -3.69; p = 0.002) at 4 weeks. There was also significantly greater improvement in 3MS (6.9 (1.7 to 12.0); t (15) â€Š= 2.85; p = 0.012), IADL (3.4 (1.0 to 5.9); χ21 = 7.72; p = 0.006), CGI-S (1.4 (0.5 to 2.3), t (16) â€Š= 3.29; p = 0.005), and CGI-I (-2.56 (-3.5 to -1.6), t (17) â€Š= -5.72; p < 0.001) for rTMS compared to the sham at 4 weeks. The effects of rTMS were durable at 12 weeks. CONCLUSION: rTMS may be safely used in subjects with AD and may improve apathy, function, and some aspects of cognition.

Home-Based Physical Activity and Diet Intervention to Improve Physical Function in Advanced Liver Disease: A Randomized Pilot Trial.

INTRODUCTION: A decline in physical function is highly prevalent and a poor prognostic factor in cirrhosis. We assessed the benefits of a home-based physical activity program (HB-PAP) in patients with cirrhosis with a randomized pilot trial. METHODS: All participants received a personal activity tracker to monitor daily activities and were given 12 g/day of an essential amino acid supplement. The HB-PAP intervention consisted of biweekly counseling sessions to increase physical activity for 12 weeks. Six-minute walk test (6MWT) and cardiopulmonary exercise testing (CPET) assessed changes in aerobic fitness. Different anthropometric measuring tools were used for skeletal muscle and adiposity assessment. RESULTS: Seventeen patients (60% male; 29% nonalcoholic steatohepatitis/cryptogenic, 29% hepatitis C, 24% alcohol, 18% other) were randomized, 9 to HB-PAP group. There were no significant differences in MELD-sodium between HB-PAP and controls at baseline or after the 12-week intervention. By the end of study, there was a significant between-group difference in daily step count favoring the active group (2627 [992-4262], p = 0.001), with less sedentary patients in the active group (33-17% vs. 25-43%, p = 0.003). The 6MWT improved in the HB-PAP group (423 ± 26 m vs. 482 ± 35 m), while the controls had a nonsignificant drop (418 ± 26 m vs. 327 ± 74 m) with a significant between-group difference. CPET did not change. Other than an improvement in psoas muscle index, there were no differences in anthropometry, or in quality of life. CONCLUSIONS: HB-PAP maintained physical performance and improved aerobic fitness according to 6MWT but not CPET, supporting the use of personal activity trackers to monitor/guide home-based prehabilitation programs in cirrhosis.

A guide for using NIH Image J for single slice cross-sectional area and composition analysis of the thigh from computed tomography.

Reports using computed tomography (CT) to estimate thigh skeletal muscle cross-sectional area and mean muscle attenuation are often difficult to evaluate due to inconsistent methods of quantification and/or poorly described analysis methods. This CT tutorial provides step-by-step instructions in using free, NIH Image J software to quantify both muscle size and composition in the mid-thigh, which was validated against a robust commercially available software, SliceOmatic. CT scans of the mid-thigh were analyzed from 101 healthy individuals aged 65 and older. Mean cross-sectional area and mean attenuation values are presented across seven defined Hounsfield unit (HU) ranges along with the percent contribution of each region to the total mid-thigh area. Inter-software correlation coefficients ranged from R2 = 0.92-0.99 for all specific area comparisons measured using the Image J method compared to SliceOmatic. We recommend reporting individual HU ranges for all areas measured. Although HU range 0-100 includes the majority of skeletal muscle area, HU range -29 to 150 appears to be the most inclusive for quantifying total thigh muscle. Reporting all HU ranges is necessary to determine the relative contribution of each, as they may be differentially affected by age, obesity, disease, and exercise. This standardized operating procedure will facilitate consistency among investigators reporting computed tomography characteristics of the thigh on single slice images. Trial Registration: ClinicalTrials.gov NCT02308228.

Tutorial for using SliceOmatic to calculate thigh area and composition from computed tomography images from older adults.

OBJECTIVE: Area of muscle, fat, and bone is often measured in thigh CT scans when tissue composition is a key outcome. SliceOmatic software is commonly referenced for such analysis but published methods may be insufficient for new users. Thus, a quick start guide to calculating thigh composition using SliceOmatic has been developed. METHODS: CT images of the thigh were collected from older (69 ± 4 yrs, N = 24) adults before and after 12-weeks of resistance training. SliceOmatic was used to segment images into seven density regions encompassing fat, muscle, and bone from -190 to +2000 Hounsfield Units [HU]. The relative contributions to thigh area and the effects of tissue density overlap for skin and marrow with muscle and fat were determined. RESULTS: The largest contributors to the thigh were normal fat (-190 to -30 HU, 29.1 ± 7.4%) and muscle (35 to 100 HU, 48.9 ± 8.2%) while the smallest were high density (101 to 150 HU, 0.79 ± 0.50%) and very high density muscle (151 to 200 HU, 0.07 ± 0.02%). Training significantly (P<0.05) increased area for muscle in the very low (-29 to -1 HU, 5.5 ± 7.9%), low (0 to 34 HU, 9.6 ± 16.8%), normal (35 to 100 HU, 4.2 ± 7.9%), and high (100 to 150 HU, 70.9 ± 80.6%) density ranges for muscle. Normal fat, very high density muscle and bone did not change (P>0.05). Contributions to area were altered by ~1% or less and the results of training were not affected by accounting for skin and marrow. CONCLUSIONS: When using SliceOmatic to calculate thigh composition, accounting for skin and marrow may not be necessary. We recommend defining muscle as -29 to +200 HU but that smaller ranges (e.g. low density muscle, 0 to 34 HU) can easily be examined for relationships with the health condition and intervention of interest. TRIAL REGISTRATION: Clinicaltrials.gov NCT02261961.

Immunohistochemical Identification of Human Skeletal Muscle Macrophages.

Macrophages have well-characterized roles in skeletal muscle repair and regeneration. Relatively little is known regarding the role of resident macrophages in skeletal muscle homeostasis, extracellular matrix remodeling, growth, metabolism and adaptation to various stimuli including exercise and training. Despite speculation into macrophage contributions during these processes, studies characterizing macrophages in non-injured muscle are limited and methods used to identify macrophages vary. A standardized method for the identification of human resident skeletal muscle macrophages will aide in the characterization of these immune cells and allow for the comparison of results across studies. Here, we present an immunohistochemistry (IHC) protocol, validated by flow cytometry, to distinctly identify resident human skeletal muscle macrophage populations. We show that CD11b and CD206 double IHC effectively identifies macrophages in human skeletal muscle. Furthermore, the majority of macrophages in non-injured human skeletal muscle show a 'mixed' M1/M2 phenotype, expressing CD11b, CD14, CD68, CD86 and CD206. A relatively small population of CD11b+/CD206- macrophages are present in resting skeletal muscle. Changes in the relative abundance of this population may reflect important changes in the skeletal muscle environment. CD11b and CD206 IHC in muscle also reveals distinct morphological features of macrophages that may be related to the functional status of these cells.

Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study.

Apathy is a common and disabling behavioral concomitant of many neurodegenerative conditions. The presence of apathy with Mild Cognitive Impairment (MCI) is linked with heightened rates of conversion to Alzheimer's disease. Improving apathy may slow the neurodegenerative process. The objective was to establish the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving apathy in older adults with MCI. An 8-week, double-blind, randomized, sham-controlled cross-over study was conducted in nine subjects (66 ± 9 years) with apathy and MCI. Subjects were randomized to rTMS or sham treatment (5 days/week) for 2 weeks following which they underwent a 4-week treatment-free period. Subjects then crossed-over to receive the other treatment for 2 weeks. The primary (apathy (AES-C)) and secondary (cognition (3MS & MMSE), executive function (TMT-A & TMT-B), and clinical global impression (CGI)) outcomes were assessed at baseline, 2, 6, and 8 weeks. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment at 2 weeks. There was significantly greater improvement in 3MS, MMSE, TMT-A, and CGI-I with rTMS compared to the sham treatment. This study establishes that rTMS is efficacious in improving apathy in subjects with MCI.

Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer's Disease: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: Apathy is a common behavioral problem in Alzheimer's disease. Apathy has profound consequences, such as functional impairment, higher service utilization, higher caregiver burden, and increased mortality. The authors' objective was to study the effects of methylphenidate on apathy in Alzheimer's disease. METHOD: A 12-week, prospective, double-blind, randomized, placebo-controlled trial (methylphenidate versus placebo) was conducted in community-dwelling veterans (N=60) with mild Alzheimer's disease. The primary outcome for apathy (Apathy Evaluation Scale-Clinician) and secondary outcomes for cognition (Mini-Mental State Examination, Modified Mini-Mental State Examination), functional status (activities of daily living, instrumental activities of daily living), improvement and severity (Clinical Global Impressions Scale [CGI]), caregiver burden (Zarit Burden Scale), and depression (Cornell Scale for Depression in Dementia) were measured at baseline and at 4, 8, and 12 weeks. RESULTS: Participants were all men (77 years old, SD=8). After adjusting for baseline, the methylphenidate group had significantly greater improvement in apathy than the placebo group at 4 weeks, 8 weeks, and 12 weeks. At 12 weeks, there was also greater improvement in cognition, functional status, caregiver burden, CGI scores, and depression in the methylphenidate group compared with the placebo group. CONCLUSIONS: Methylphenidate improved apathy in a group of community-dwelling veterans with mild Alzheimer's disease. Methylphenidate also improved cognition, functional status, caregiver burden, CGI scores, and depression.

Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study.

BACKGROUND/OBJECTIVE: Balance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD. METHODS: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention). RESULTS: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p < 0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p = 0.445). CONCLUSION: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.

Efficacy of Wii-Fit on Static and Dynamic Balance in Community Dwelling Older Veterans: A Randomized Controlled Pilot Trial.

Background/Objectives. Balance problems are well-established modifiable risk factors for falls, which are common in older adults. The objective of this study was to establish the efficacy of a Wii-Fit interactive video-game-led physical exercise program to improve balance in older Veterans. Methods. A prospective randomized controlled parallel-group trial was conducted at Veterans Affairs Medical Center. Thirty community dwelling Veterans aged 68 (±6.7) years were randomized to either the exercise or control groups. The exercise group performed Wii-Fit program while the control group performed a computer-based cognitive program for 45 minutes, three days per week for 8-weeks. The primary (Berg Balance Scale (BBS)) and secondary outcomes (fear of falling, physical activity enjoyment, and quality of life) were measured at baseline, 4 weeks, and 8 weeks. Results. Of 30 randomized subjects, 27 completed all aspects of the study protocol. There were no study-related adverse events. Intent-to-treat analysis showed a significantly greater improvement in BBS in the exercise group (6.0; 95% CI, 5.1-6.9) compared to the control group (0.5; 95% CI, -0.3-1.3) at 8 weeks (average intergroup difference (95% CI), 5.5 (4.3-6.7), p < 0.001) after adjusting for baseline. Conclusion. This study establishes that the Wii-Fit exercise program is efficacious in improving balance in community dwelling older Veterans. This trial is registered with ClinicalTrials.gov Identifier NCT02190045.

Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans.

Protein aggregation increases with age in normal tissues, and with pathology and age in Alzheimer's hippocampus and mouse cardiac muscle. We now ask whether human skeletal muscle accumulates aggregates with age. Detergent-insoluble protein aggregates were isolated from vastus lateralis biopsies from 5 young (23­27 years of age) and 5 older (64-80 years) adults. Aggregates, quantified after gel electrophoresis, contain 2.1-fold more protein (P<0.0001) when isolated from older subjects relative to young. Of 515 proteins identified by liquid chromatography coupled to tandem mass spectrometry, 56 (11%) were significantly more abundant in older muscle, while 21 (4%) were depleted with age (each P<0.05). Orthologs to seven of these proteins were then targeted in C. elegans by RNA interference. Six of the seven knockdown treatments decreased protein aggregation (range 6-45%, P<0.01 to <0.0001) and increased muscle mass (range 1.5- to 1.85-fold, P<0.01 to <0.0001) in aged nematodes, and rescued mobility (range 1.4 to 1.65-fold, P≤0.0005 each) in a nematode amyloidopathy model. We conclude that specific aggregate proteins, discovered as differentially abundant in aging human muscle, have orthologs that contribute functionally to aggregation and age-associated muscle loss in nematodes, and thus can be considered potential drug targets for sarcopenia in humans.

Immune Function and Muscle Adaptations to Resistance exercise in Older Adults: Study Protocol for a Randomized Controlled Trial of a Nutritional Supplement.

BACKGROUND: Immune function may influence the ability of older adults to maintain or improve muscle mass, strength, and function during aging. Thus, nutritional supplementation that supports the immune system could complement resistance exercise as an intervention for age-associated muscle loss. The current study will determine the relationship between immune function and exercise training outcomes for older adults who consume a nutritional supplement or placebo during resistance training and post-training follow-up. The supplement was chosen due to evidence suggesting its ingredients [arginine (Arg), glutamine (Gln), and ß-hydroxy ß-methylbutyrate (HMB)] can improve immune function, promote muscle growth, and counteract muscle loss. METHODS/DESIGN: Veterans (age 60 to 80 yrs, N = 50) of the United States military will participate in a randomized double-blind placebo-controlled trial of consumption of a nutritional supplement or placebo during completion of three study objectives: 1) determine if 2 weeks of supplementation improve immune function measured as the response to vaccination and systemic and cellular responses to acute resistance exercise; 2) determine if supplementation during 36 sessions of resistance training boosts gains in muscle size, strength, and function; and 3) determine if continued supplementation for 26 weeks post-training promotes retention of training-induced gains in muscle size, strength, and function. Analyses of the results for these objectives will determine the relationship between immune function and the training outcomes. Participants will undergo nine blood draws and five muscle (vastus lateralis) biopsies so that the effects of the supplement on immune function and the systemic and cellular responses to exercise can be measured. DISCUSSION: Exercise has known effects on immune function. However, the study will attempt to modulate immune function using a nutritional supplement and determine the effects on training outcomes. The study will also examine post-training benefit retention, an important issue for older adults, usually omitted from exercise studies. The study will potentially advance our understanding of the mechanisms of muscle gain and loss in older adults, but more importantly, a nutritional intervention will be evaluated as a complement to exercise for supporting muscle health during aging. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02261961, registration date 10 June 2014, recruitment active.

Molecular changes in bone marrow, tumor and serum after conductive ablation of murine 4T1 breast carcinoma.

Thermal ablation of solid tumors using conductive interstitial thermal therapy (CITT) produces coagulative necrosis in the center of ablation. Local changes in homeostasis for surviving tumor and systemic changes in circulation and distant organs must be understood and monitored in order to prevent tumor re-growth and metastasis. The purpose of this study was to use a mouse carcinoma model to evaluate molecular changes in the bone marrow and surviving tumor after CITT treatment by quantification of transcripts associated with cancer progression and hyperthermia, serum cytokines, stress proteins and the marrow/tumor cross-talk regulator stromal-derived factor 1. Analysis of 27 genes and 22 proteins with quantitative PCR, ELISA, immunoblotting and multiplex antibody assays revealed that the gene and protein expression in tissue and serum was significantly different between ablated and control mice. The transcripts of four genes (Cxcl12, Sele, Fgf2, Lifr) were significantly higher in the bone marrow of treated mice. Tumors surviving ablation showed significantly lower levels of the Lifr and Sele transcripts. Similarly, the majority of transcripts measured in tumors decreased with treatment. Surviving tumors also contained lower levels of SDF-1α and HIF-1α proteins whereas HSP27 and HSP70 were higher. Of 16 serum chemokines, IFNγ and GM-CSF levels were lower with treatment. These results indicate that CITT ablation causes molecular changes which may slow cancer cell proliferation. However, inhibition of HSP27 may be necessary to control aggressiveness of surviving cancer stem cells. The changes in bone marrow are suggestive of possible increased recruitment of circulatory cancer cells. Therefore, the possibility of heightened bone metastasis after thermal ablation needs to be further investigated and inhibition strategies developed, if warranted.

Nutrient intake, peripheral edema, and weight change in elderly recuperative care patients.

BACKGROUND: It is unclear whether serial measures of body weight are valid indicators of nutritional status in older patients recovering from illness. Objectives. Investigate the relative influence of nutrient intake and changes in peripheral edema on weight change. METHODS: A prospective cohort study of 404 older men (mean age = 78.7±7.5 years) admitted to a transitional care unit of a Department of Veterans Affairs nursing home. Body weight and several indicators of lower extremity edema were measured at both unit admission and discharge. Complete nutrient intake assessments were performed daily. RESULTS: Over a median length of stay of 23 days (interquartile range: 15-41 days), 216 (53%) participants gained or lost more than or equal to 2.5% of their body weight. Two hundred eighty-two (70%) participants had recognizable lower extremity pitting edema at admission and/or discharge. The amount of weight change was strongly and positively correlated with multiple indicators of both nutrient intake and the change in the amount of peripheral edema. By multivariable analysis, the strongest predictor of weight change was maximal calf circumference change (partial R (2) = .35, p < .0001), followed by average daily energy intake (partial R (2) = .14, p < .0001), and the interaction of energy intake by time (partial R (2) = .02, p < .0001). CONCLUSIONS: Many older patients either gain or lose a significant amount of weight after admission to a transitional care unit. Because of the apparent high prevalence of co-occurring changes in total body water, the weight changes do not necessarily represent changes in nutritional status. Although repeat calf circumference measurements may provide some indication as to how much of the weight change is due to changes in body water, there is currently no viable alternative to monitoring the nutrient intake of older recuperative care patients in order to ensure that their nutrient needs are being met.