A new possible marker: can pennation angle defined by ultrasound predict the frailty?

BACKGROUND: Frailty indicates older people who are vulnerable to stressors. The relation between ultrasonographic parameters of muscle and frailty among older people has yet to be investigated. AIMS: The aim of the study is to investigate the relationship between frailty and the ultrasonographic measurements of the rectus femoris muscle (RFM). METHODS: This cross-sectional study included 301 participants who were ≥65 years. The FRAIL questionnaire assessed frailty. The thickness, cross-sectional area (CSA), fascicle length, pennation angle (PA), stiffness, and echogenicity of RFM were assessed by ultrasound. The accuracy of parameters in predicting the frailty was evaluated by ROC analysis. RESULTS: Of all 301 participants, 24.6% were frail. Pre-frail and frail participants had significantly lower thickness (p = 0.002), CSA (p = 0.009), and fascicle length (p = 0.043) of RFM compared to robust. PA was significantly lowest in frails (p < 0.001). The multivariate logistic regression analysis showed that PA values lower than 10.65 degrees were an independent predictor of frailty (OR = 0.83, 95% Cl: 0.70-0.97, p = 0.019). Results of ROC analysis demonstrated a satisfactory result between the PA and frailty (AUC = 0.692, p < 0.001). DISCUSSION: Thickness, CSA, and PA of RFM were found to be lower in frail subjects, which may indicate the changes in muscle structure in frailty. Among all parameters, lower PA values were independent predictors of frailty. These findings may indicate a novel ultrasound-based method in frailty, that is more objective and unrelated to the cross-sectional evaluation. CONCLUSIONS: Ultrasonographic measurements of RFM, especially the lower PA may predict frailty in older people. As an objective and quantitative method, PA may be used to define frailty with acceptable sensitivity.

Unlocking the protective potential of the angiotensin type 2 receptor (AT2R) in acute lung injury and age-related pulmonary dysfunction.

Despite its known importance in the cardiovascular system, the specific role and impact of the angiotensin type 2 receptor (AT2R) in lung physiology and pathophysiology remain largely elusive. In this study, we highlight the distinct and specialized lung-specific roles of AT2R, primarily localized to an alveolar fibroblast subpopulation, in contrast to the angiotensin type 1 receptor (AT1R), which is almost exclusively expressed in lung pericytes. Evidence from our research demonstrates that the disruption of AT2R (AT2R-/y), is associated with a surge in oxidative stress and impaired lung permeability, which were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, AT2R-/y mice show an increase in oxidative stress, premature enlargement of airspaces, as well as increased mortality when exposed to hyperoxia as compared to age-matched WT mice. Our investigation into Losartan, an AT1R blocker, suggests that its primary HALI lung-protective effects are channeled through AT2R, as its protective benefits are absent in AT2R-/y mice. Importantly, a non-peptide AT2R agonist, Compound 21 (C21), successfully reverses lung oxidative stress and TGFß activation in wild-type (WT) mice exposed to HALI. These findings suggest a possible paradigm shift in the therapeutic approach for lung injury and age-associated pulmonary dysfunction, from targeting AT1R with angiotensin receptor blockers (ARBs) towards boosting the protective function of AT2R.

Navigating and diagnosing cognitive frailty in research and clinical domains.

While physical frailty has been recognized as a clinical entity for some time, the concept of cognitive frailty (CF) is now gaining increasing attention in the geriatrics research community. CF refers to the co-occurrence of physical frailty and cognitive impairment in older adults, which has been suggested as a potential precursor to both dementia and adverse physical outcomes. However, this condition represents a challenge for researchers and clinicians, as there remains a lack of consensus regarding the definition and diagnostic criteria for CF, which has limited its utility. Here, using insights from both the physical frailty literature and cognitive science research, we describe emerging research on CF. We highlight areas of agreement as well as areas of confusion and remaining knowledge gaps, and provide our perspective on fine-tuning the current construct, aiming to stimulate further discussion in this developing field.

Decoding Angiotensin Receptors: TOMAHAQ-Based Detection and Quantification of Angiotensin Type-1 and Type-2 Receptors.

Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-ß load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.

Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline: Insights From an Inducible Humanized IL-6 Knock-In Mouse Model.

Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty.

Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment.

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT1R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT1R, AT2R, and AT4R. The AT1R promotes inflammation and mitochondrial reactive oxygen species generation. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer's dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70-90 years old, n = 30 in each group). We show that ARB use is associated with higher brain AT4R, lower oxidative stress, and amyloid-ß burden in NCI participants. In AD, ARB use was associated with lower brain AT1R but had no impact on inflammation, oxidative stress, or amyloid-ß burden. Our results may suggest a potential role for AT4R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice.

Chronic inflammation, oxidative stress, and dysregulation of the renin-angiotensin system are closely linked, and their crosstalk commonly contributes to age-related physical and cognitive decline. The primary dementia-protective benefits of Angiotensin II type 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is an independently regulated brain-specific renin-angiotensin system. Here, we examined the impact of 4 weeks of oral Losartan treatment on the brains of aged (100 weeks old) IL-10-/- mice, an animal model of chronic inflammation and frailty. Our data show that aged IL-10-/- mice have higher AT1R and Nitrotyrosine (oxidative stress marker) levels in their frontal cortex tissue but not in cerebellar or hippocampal tissue compared to age- and sex-matched wild type mice. Losartan treatment for 4 weeks is associated with lower AT1R protein level, Nitrotyrosine, and Tau protein in the frontal cortex of aged IL-10-/- mice. Our results highlight the impact of Losartan, an AT1R blocker commonly prescribed for treating high blood pressure, on the brain-specific angiotensin system and AT1R-linked downstream effects such as brain oxidative stress damage and Tau burden in a frailty mouse model.

Association between sarcopenia and erectile dysfunction in older males.

INTRODUCTION: In advanced age, both sarcopenia and erectile dysfunction (ED) occur with similar underlying causes through different mechanisms. In our study we investigated the association between sarcopenia and ED in older men. METHODS: A total of 193 male patients aged 60 years and older were included in the study. The presence of sarcopenia was investigated in accordance with EWGSOP2 diagnostic criteria. For evaluation of ED, we used the 5-question International Index of Erectile Dysfunction questionnaire with categories of no ED, mild-moderate ED, and moderate-severe ED. Total testosterone levels were measured. RESULTS: The median age of the patients was 71.9 (range 60-93 years). The prevalence of sarcopenia was 24.9%, and moderate-severe ED was 49.2%. Moderate-severe ED was more common in patients with sarcopenia than those without (70.8% vs 42.1%, p < 0.001). After adjustment for age and Charlson Comorbidity Index, the presence of sarcopenia was significantly associated with moderate-severe ED with odds ratio (OR) of 2.71 (95% Confidence Interval [CI] 1.29-5.73, p = 0.009). The components of sarcopenia were assessed separately in multivariate analysis. Muscle strength and muscle mass were significantly associated with moderate-severe ED with OR of 0.93 (95%CI 0.89-0.98) and 0.68 (95%CI 0.54-0.86), respectively, whereas gait speed was not associated with moderate-severe ED. CONCLUSION: The presence of sarcopenia in older men is associated with an increased risk of moderate-severe ED. In addition, decreased muscle strength and decreased muscle mass are associated with an increased risk of moderate-severe ED. Prospective studies are needed to reveal the causality between sarcopenia and ED.

Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer's Dementia.

Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using postmortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-ß and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-ß scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

The relationship between sarcopenia and central hemodynamics in older adults with falls: a cross-sectional study.

PURPOSE: Falls are an important cause of morbidity and mortality in geriatric patients. Sarcopenia and central blood pressure may be associated with falls. This study aimed to investigate the association between sarcopenia and blood pressure parameters in older patients with falls. METHODS: A comprehensive geriatric evaluation of 72 elderly patients was performed using established assessment tests. Peripheral and central hemodynamic measurements, including office DBP and SBP, daytime-night peripheral and central DBP and SBP, cardiac output, augmentation index, pulse wave velocity (PWV), pulse rate, and peripheral resistance and reflection, were measured with a 24-hour ambulatory blood pressure measuring device. RESULTS: Of 72 patients with a mean age of 77.51 ± 6.5 years, 12 (16.7%) were non-sarcopenic, 32 (44.4%) were probable, nine (12.5%) were confirmed, and 19 (26.4%) were severe sarcopenic. PWV, which is an indicator of arterial stiffness, was found to be significantly higher in the sarcopenic group. The other cardiac risk markers [daytime peripheral SBP, mean arterial pressure (night), pulse pressure (daytime), and peripheral resistance (daytime and night)] were significantly lower in the sarcopenic patients. PWV correlated with gait speed, Katz score, and hand grip strength (Spearman's rho: -0.337, -0.310, and -0.334; P < 0.001, 0.008, and 0.001, respectively). Age and hypertension were the most important factors increasing the risk of falls. CONCLUSION: Sarcopenia is associated with central and peripheral blood pressure changes in patients with falls. When sarcopenia is diagnosed in older people with falls, 24-hour ambulatory peripheral and central pressures should be evaluated for cardiac risk screening.

Attitudes of a geriatric population towards risks about COVID-19 pandemic: in the context of anxiety and depression.

BACKGROUND: A curfew for elderly people was announced in Turkey to protect the geriatric population during the COVID-19 pandemic. Although this may have the beneficial effect of preventing infection, psychological distress may also increase with prolongation of the pandemic. METHODS: Geriatric patients were interviewed by telephone due to the ongoing curfew. Demographical characteristics, comorbidities, personal risk perception of COVID-19, common concerns related to COVID-19, and experiences of delayed hospital admission due to the pandemic were recorded. The Hospital Anxiety and Depression Scale (HADS) was used to assess psychological distress, anxiety, and depression. RESULTS: Participants (n = 136; 82 females, 60.3%) had a mean age of 73.4 ± 5.9 years. The most common comorbidity was hypertension (75%). Approximately 80% of the participants reported a decrease in physical activity during the curfew period. The HADS scores indicated rates of anxiety as 25.7% and depression as 16.9%. Anxiety was significantly more common in females than males (P = 0.002). Sleep problems (P = 0.000), fatigue (P = 0.000), and hopelessness (P = 0.000) were more common in participants with depression and anxiety. Logistic regression analyses showed an association between a delay in hospital admission and the presence of depression (P = 0.0029, R2  = 0.146). Personal risk perception of COVID-19 was statistically significantly higher among patients with anxiety (P = 0.0027, R2  = 0.157). CONCLUSION: Decreased adaptation to external and internal factors among older individuals may facilitate unfavourable outcomes of the pandemic. These results indicate that the geriatric population was mentally and physically affected by the restrictions and isolation.

A new easily accessible and practical method for dynapenia screening: blink rate.

BACKGROUND: The methods used in the diagnosis and screening of sarcopenia are not available everywhere. There is a need for more practical tests that can be used especially in the first step. AIMS: We aimed to investigate the usability of blink rate as an alternative test for dynapenia screening. METHODS: A total of 355 patients ≥ 65 years of age (254 (71.50%) female and 101 (28.50%) male) who were admitted to geriatric outpatient clinic were included in this prospective cross-sectional study. RESULTS: Blink rate was positively correlated with grip strength and negatively correlated with SARC-F. Also, it was found that the blink rate was associated with dynapenia independent of other factors. The optimal cut-off value of 15 s blink rate to predict dynapenia was measured as ≤ 40.5, with 70.3% sensitivity and 43.3% specificity. CONCLUSION: Our study indicated the relationship between blink rate with dynapenia and grip strength. Especially in patients with limited mobilization and where it is not possible to reach the hand dynamometer to measure grip strength, the blink rate can be used as an alternative test to detect dynapenia.

Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.

The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer's disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

May zoledronic acid have negative effects on cognition and muscle performance?

BACKGROUND: We aimed to investigate the effects of zoledronic acid treatment on daily living activities, cognitive functions, depression, muscle strength, and performance. METHODS: The study was conducted retrospectively. Bone mineral densitometry (BMD) values, Katz activities of daily living (ADL), Lawton-Brody instrumental activities of daily living (IADL), mini mental state examination (MMSE), geriatric depression scale (GDS), mini nutritional assessment (MNA), grip strength, and gait speed scores before and 6 months after zoledronic acid administration were compared. RESULTS: A total of 115 patients were included in the study. There was a significant increase in lumbar total (p < .001), femoral neck (p = .002), and femur total (p = .001) BMD values after zoledronic acid treatment. Significant decrease was found in MMSE (p = .016) and gait speed scores (p = .008) after zoledronic acid treatment, but no significant difference was found in terms of Katz ADL, Lawton-Brody IADL, MNA, GDS, and grip strength (p > .05). CONCLUSION: Our study indicated that zoledronic acid did not affect daily living activities, depression, and muscle strength. Although we have concluded that cognitive and muscle performance may be adversely affected by zoledronic acid treatment.

The relationship between all-cause mortality sarcopenia and sarcopenic obesity among hospitalized older people.

BACKGROUND AND AIM: Sarcopenia and sarcopenic obesity (SO) are associated with adverse health outcomes in older people. Data on sarcopenia- and SO-related mortality are insufficient for hospitalized older people. The aim of this study was to evaluate the relationship between sarcopenia, SO and mortality among hospitalized older people. METHODS: Two-centered prospective observational study was conducted among 350 hospitalized older people in geriatric units of two university hospitals. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People. Obesity was defined according to fat mass percentage. Medical history, cognitive status, nutritional status and functionality and laboratory tests were assessed. All-cause mortality rate was recorded at 2 years. RESULTS: The prevalence of SO was 21.1%. The prevalence of sarcopenia was 11.4%. Both sarcopenia (log rank p < 0.001) and SO (log rank p < 0.001) were associated with all-cause mortality at 2 years. There was no difference between sarcopenia and SO for mortality. SO (HR 5.23, p < 0.001), sarcopenia (HR 9.26, p < 0.001), male gender (HR 2.25, p = 0.035), Lawton IADL (HR 0.77, p = 0.02), heart failure (HR 3.25, p = 0.02) and chronic obstructive lung disease (HR 5.16, p = 0.01) were independently related to all-cause mortality. DISCUSSION AND CONCLUSIONS: Both sarcopenia and SO showed an independent relationship for 2-year all-cause mortality after hospital discharge. These results suggest that preventive and treatment options should be taken to decrease mortality associated with these conditions among hospitalized older people.

Hepatopulmonary Syndrome and Liver Transplantation: A Recent Review of the Literature.

A severe and common pulmonary vascular complication of liver disease is hepatopulmonary syndrome (HPS). It is a triad of liver dysfunction and/or portal hypertension, intrapulmonary vascular dilatations, and increased alveolar-arterial oxygen gradient. Prevalence varies according to various study groups from 4%-47%. While the most common presenting symptom of HPS is dyspnea, it is usually asymptomatic, and thus all liver transplant candidates should be screened for its presence. Pulse oximetry is a useful screening method, but arterial blood gas examination is the gold standard. If there is an abnormal P (A-a)O2 gradient, microbubble transthoracic echocardiography should be done for diagnosis. Outcome is unpredictable, and there is currently no effective medical therapy. The only effective therapy is considered to be liver transplantation. Complete resolution of HPS after liver transplantation is seen within a year in most HPS patients.

Portopulmonary Hypertension and Liver Transplant: Recent Review of the Literature.

Portopulmonary hypertension is one of the main pulmonary conditions affecting patients with liver disease and/or portal hypertension. Other conditions include hepatopulmonary syndrome and hepatic hydrothorax. Portopulmonary hypertension is caused by pulmonary vasoconstriction and increased pulmonary vascular resistance. It develops as a result of portal hypertension with or without liver disease and is associated with a higher morbidity and mortality. However, portopulmonary hypertension is usually asymptomatic; the most common symptoms are dyspnea, fatigue, and peripheral edema. All liver transplant candidates should be screened for potential portopulmonary hypertension because its coexistence can affect survival rates after transplant. All patients with cirrhosis who present with dyspnea should also be screened. Transthoracic echocardiography is a noninvasive, useful method for screening, but right heart-sided catheterization remains the criterion standard for diagnosis. Portopulmonary hypertension carries a poor prognosis without liver transplant, and its severe form is considered to be a contraindication for liver transplant. Treating patients with pulmonary arterial hypertension-specific therapies before liver transplant for moderate and severe portopulmonary hypertension appears to be beneficial.