Significant Functional Decline Research Articles

Novel nerve regeneration assessment method using adult zebrafish with crush spinal cord injury.

Zebrafish (Danio rerio), an alternative to rodents, are widely used in neurological, genetic, and toxicology research. The zebrafish larval spinal cord injury model has been used in neural mechanistic analyses owing to its high regenerative capacity and throughput; however, it also had several limitations in imitating rodents. Therefore, we investigated the use of adult zebrafish as an alternative model to rodents for evaluating nerve regeneration. Here, we established a novel spinal cord regeneration evaluation method, which was based on the maximum swimming speed of adult zebrafish in a custom-built hydrodynamic-based aquarium. The spinal cords of adult male zebrafish were crushed using forceps, and maximum swimming speed and histological spinal cord regeneration were evaluated. Spinal cord-injured zebrafish showed a significant decline in motor function, followed by recovery at 3weeks postoperatively, accompanied by histological regeneration. Spinal cord regeneration can be indirectly assessed by monitoring maximum swimming speed. They were also fed a diet containing fig extract, which can promote peripheral nerve regeneration; they were fed daily starting 1week before the operation. Maximum swimming speed was measured time-dependently until 3weeks postoperatively. Fig-consuming fish showed improved recovery of maximum swimming speed compared to the controls, which was consistent with the histological analysis. In summary, we established a spinal cord regeneration assessment system using adult zebrafish in a customized aquarium, which enables researchers to evaluate spinal cord regeneration in adult zebrafish similar to that of rodent experiments, contributing to faster and easier screening of neuroregenerative technology.

Long-term outcome of interstitial lung disease in patients with primary Sjögren's syndrome: a retrospective observational study.

Interstitial lung disease (ILD) is a potentially serious but underdiagnosed manifestation of primary Sjögren's syndrome (pSS). This observational study investigated the prevalence and clinical course of ILD in pSS, together with prognostic factors. A multicenter, retrospective longitudinal study was performed using findings from baseline and follow-up pulmonary function tests and chest computed tomography. Predisposing factors for the development of ILD and acute exacerbation (AE) were identified using a logistic regression model. The risk factors for a significant decline of pulmonary function were determined by the Cox proportional hazard model. A total of 1,306 patients with pSS were included in this study (female, 98%; mean age, 54 years). Among them, 79 patients with pSS were comorbid with ILD. ILD was more frequently found in male, older patients. Nonspecific interstitial pneumonia was the most prevalent imaging pattern in pSS-ILD (51%), followed by usual interstitial pneumonia (22%). At diagnosis with pSS-ILD, 54% of patients had restrictive pulmonary function, and 41% of patients initiated pharmacological treatment. During the median 4-year follow-up period, AE, a significant decline in pulmonary function, and death occurred in 19%, 29%, and 9% of patients with pSS-ILD, respectively. The neutrophil-to-lymphocyte ratio (NLR) increased 3 months prior to AE, and it was associated with AE. Older age at pSS-ILD diagnosis was a prognostic factor for a significant decline in pulmonary function. ILD accounted for 6% of the comorbidity of pSS. AE was associated with a significant decline in pulmonary function, and the NLR may predict AE.

Development of a multivariate model predictive of post-adrenalectomy renal function decline in patients with primary aldosteronism: a large-cohort single-center study.

To develop a multivariate liniear model for predicting long-term (> 3 months) post-adrenalectomy renal function decline in patients with primary aldosteronism (PA). The model aims to help identify patients who may experience a significant decline in renal function after surgery. We retrospectively analyzed the clinical data of 357 patients who were diagnosed with PA and underwent adrenalectomy between September 2012 and February 2023. LASSO and multivariate linear regression analyses were used to identify significant risk factors for model construction. The models were further internally validated using bootstrap method. Age (P < 0.001), plasma aldosterone concentration (PAC) measured in the upright-position (PACU, P = 0.066), PAC measured after saline infusion (PACafterNS, P = 0.010), preoperative blood adrenocorticotropic-hormone level (ACTH, P = 0.048), preoperative estimated glomerular filtration rate (eGFR, P < 0.001) and immediate postoperative eGFR (P < 0.001) were finally included in a multivariate model predictive of post-adrenalectomy renal function decline and the coefficients were adjusted by internal validation. The final model is: predicted postoperative long-term (> 3 months) eGFR decline =-70.010 + 0.416*age + 6.343*lg PACU+4.802*lg ACTH + 7.424*lg PACafterNS+0.637*preoperative eGFR-0.438*immediate postoperative eGFR. The predicted values are highly related to the observed values (adjusted R = 0.63). The linear model incorporating perioperative clinical variables can accurately predict long-term (> 3 months) post-adrenalectomy renal function decline.

Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice.

The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Current management of chronic kidney disease in type-2 diabetes-A tiered approach: An overview of the joint Association of British Clinical Diabetologists and UK Kidney association (ABCD-UKKA) guidelines.

A growing and significant number of people with diabetes develop chronic kidney disease (CKD). Diabetes-related CKD is a leading cause of end-stage kidney disease (ESKD) and people with diabetes and CKD have high morbidity and mortality, predominantly related to cardiovascular disease (CVD). Despite advances in care over the recent decades, most people with CKD and type 2 diabetes are likely to die of CVD before developing ESKD. Hyperglycaemia and hypertension are modifiable risk factors to prevent onset and progression of CKD and related CVD. People with type 2 diabetes often have dyslipidaemia and CKD per se is an independent risk factor for CVD, therefore people with CKD and type 2 diabetes require intensive lipid lowering to reduce burden of CVD. Recent clinical trials of people with type 2 diabetes and CKD have demonstrated a reduction in composite kidney end point events (significant decline in kidney function, need for kidney replacement therapy and kidney death) with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonist finerenone and glucagon-like peptide 1 receptor agonists. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have previously undertaken a narrative review and critical appraisal of the available evidence to inform clinical practice guidelines for the management of hyperglycaemia, hyperlipidaemia and hypertension in adults with type 2 diabetes and CKD. This 2024 abbreviatedupdated guidance summarises the recommendations and the implications for clinical practice for healthcare professionals who treat people with diabetes and CKD in primary, community and secondary care settings.

Cardiac Fatigue in Male Athletes with Exercise-Induced Pulmonary Impairments After a Very Long-Distance Triathlon.

Prolonged strenuous exercise can transiently decrease cardiac function. Other studies have identified three major exercise-induced pulmonary changes: bronchoconstriction, dynamic hyperinflation and pulmonary oedema with reduced alveolar-capillary membrane diffusing capacity. This study investigated whether athletes with one of these pulmonary dysfunctions following a very long-distance triathlon exhibit similar cardiac alterations as those without dysfunctions. Sixty trained male triathletes (age 39 ± 9years) underwent baseline and post-race assessments, including echocardiography (with standard, 2D-strain and myocardial work assessments), spirometry and double-diffusion technique to evaluate alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO). Cardiac function in athletes with exercise-induced bronchoconstriction (> 10% decrease FEV1), dynamic hyperinflation (> 10% decrease inspiratory capacity) or impaired diffusion capacity (> 20% decrease DMCO/alveolar volume) were compared with those without these dysfunctions. The race lasted 14h 20min ± 1h 26min. Both systolic and diastolic cardiac functions declined post-race. Post-race, 18% of athletes had bronchoconstriction, 58% dynamic hyperinflation and 40% impaired diffusing capacity. Right and left ventricular standard and 2D-strain parameters were similar before the race in all subgroups and changed similarly post-race, except E/E', which decreased in the bronchoconstriction subgroup and increased in those with diffusion impairment. Global constructive work decreased by ~ 19% post-race (2302 ± 226 versus 1869 ± 328mmHg%, P < 0.001), more pronounced in athletes with diffusion impairment compared with others (- 26 ± 13 versus - 15 ± 9%, P = 0.001) and positively correlated with DMCO/alveolar volume reduction. After a very long-distance triathlon, bronchoconstriction and hyperinflation were not associated with significant cardiac changes, whereas impaired alveolar-capillary membrane diffusing capacity was associated with a more significant decline in myocardial function. These findings highlight the complex relationship between pulmonary gas exchange abnormalities and cardiac fatigue following prolonged strenuous exercise.

Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline.

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.

6411 Ozempic - Oh no! Acute Renal Failure Associated with Initiation of Semaglutide

Abstract Disclosure: K. Barney: None. D. Tahir: None. A. Pannu: None. R. Saeed: None. Background: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist which has been proven to reduce weight in those with obesity and improve glycemic control in patients with type II diabetes mellitus. The effect of semaglutide on kidney function has not been well established. The phase 3b SUSTAIN trials revealed that when compared with other GLP-1 agonists, semaglutide exhibited more frequent acute kidney injuries [1-3]. The SUSTAIN 6 trial reported two instances of acute renal failure (ARF) in patients with chronic kidney disease, and one case of ARF in a patient with normal kidney function who was treated with semaglutide [3]. Despite these reports, the SUSTAIN 1-9 trials report no significant decline in kidney function associated with semaglutide [3-6]. Case: We present the case of a 58-year-old male with a past medical history of human immunodeficiency virus (HIV), type II diabetes mellitus, and hypertension who presented to the hospital with ARF after initiation of Ozempic (semaglutide) two months prior to presentation. On admission, vitals were stable and physical examination was benign. His pertinent labs were blood urea nitrogen (BUN) 55 mg/dL, creatinine 5.94 mg/dL (baseline 1.2 mg/dL), and urinalysis with 2+ protein. To determine the cause of his renal failure, urine sodium and creatinine were obtained to calculate his fractional excretion of sodium, which was found to be consistent with intrinsic renal disease. Further workup, including renal ultrasound, urine protein, urine eosinophils, complement and free light chain levels, and creatinine kinase, were unrevealing for cause of intrinsic renal injury. He was managed with intravenous fluids and his creatinine improved to 2.03 mg/dL. Given the acute onset of the patient’s renal failure and recent initiation of Ozempic, it was determined that this medication was the cause of his renal failure, and it was discontinued on discharge. He has since followed up with nephrology and endocrinology. He remains off Ozempic and is doing well. Conclusions: Our case highlights a rare but significant adverse effect of semaglutide on renal function. As the use of semaglutide has increased due to its rising popularity for weight loss and glycemic control in type II diabetes mellitus, the potential for renal injury should be considered and discussed with patients. Furthermore, it is imperative that semaglutide associated renal injury be considered as a cause for ARF in patients taking this medication. This case demonstrates that instances of ARF associated with semaglutide treatment are a cause for concern and further exploration. Presentation: 6/1/2024

Exploring the characteristics and antecedents of clinically significant long COVID: A longitudinal cohort study

BackgroundA significant number of coronavirus disease 2019 (COVID-19) survivors are experiencing long COVID, with symptoms lasting beyond three months. While diverse long COVID symptoms are established, there are gaps in understanding its long-term trends, intensity, and risk factors, requiring further investigation. AimsThis study aimed to investigate the long COVID characteristics and associated factors by following COVID-19 survivors for one year post-infection and comparing them with healthy counterparts. Main methodsIn this longitudinal, correlational study, COVID-19 survivors diagnosed between November 2021 and February 2023 were monitored every three months for a year. Participants aged ≥18 years who had reported a positive COVID-19 test were recruited via social media and healthcare provider referrals. Key findingsOut of 182 survivors who initially agreed to participate, 176 completed the study. The mean age was 47.56 years (SD = 16.2), and 51.1 % were female. There was a clinically significant decline in cognitive function and health-related quality of life over time, with symptoms like shortness of breath, reduced physical fitness, and increased health concerns. Those with severe acute COVID-19 symptoms experienced greater cognitive and physical declines and more shortness of breath a year later. Lower financial status was linked to poorer health-related quality of life and increased health concerns. SignificanceA year post-infection, COVID-19's impact on cognitive function and health-related quality of life remains significant, affecting individuals and communities. Survivors with severe initial symptoms and economic disadvantages need more attention. Future research should identify additional predictors of severe long COVID.

Four-dimensional automated quantitative echocardiography assessment of right heart remodeling in patients with functional tricuspid regurgitation.

Functional tricuspid regurgitation (FTR) has a pathophysiological connection with right heart remodeling. Given the increasing focus on right atrial remodeling in recent years, a comprehensive study of all aspects of right heart remodeling is crucial for understanding the progression and treatment of FTR. In the scientific literature, there is a lack of comprehensive exploration of right atrial remodeling in patients with FTR, and no reports on the potential correlation between the degree of this remodeling and the severity of tricuspid regurgitation (TR) have been published. This study aimed to evaluate the relationship between right heart parameters measured by four-dimensional (4D) automated quantitative echocardiography and the severity of TR in patients with FTR. In this prospective case-control study, 100 patients diagnosed with FTR by echocardiography at The First Affiliated Hospital of Guangxi Medical University from February 2022 to March 2023 were prospectively and consecutively selected as the case group, comprising 50 patients with mild FTR and 50 patients with moderate or severe FTR. Additionally, 30 healthy participants served as the control group. Routine echocardiography was employed to obtain two-dimensional (2D) and three-dimensional (3D) images, which was followed by 4D automated quantitative echocardiograph assessment. Analysis of variance (ANOVA) or Kruskal-Wallis tests were used to compare differences between groups, Pearson correlation coefficient analysis was used to discern the relationship between parameters and TR volume, multivariate linear regression was used to identify factors associated with TR volume, and logistic regression was employed to predict the severity of FTR. The case group consisted of 50 patients with mild FTR (26 males, 52%; age range, 31-78 years; mean age ± SD: 58±11.4 years) and 50 patients with moderate-to-severe FTR (21 males, 42%; age range, 29-87 years; mean age ± SD: 60±13.0 years). Additionally, 30 healthy participants (13 males, 43%; age range, 19-81 years; mean age ± SD: 58±13.3 years) constituted the control group. Patients with moderate-to-severe FTR had significant right heart dilatation and functional decline. The TR volume was highly correlated with right atrium minimum volume (RAVmin; r=0.864; P<0.001), and linear regression showed that the RAVmin was independently correlated with the severity of TR in patients (β=0.820; P<0.001). There were several predictive variables that were significantly associated with increased FTR severity, including right atrial reservoir strain [RASr; odds ratio (OR) =0.702; 95% confidence interval (CI): 0.575-0.857; P=0.001], right atrial conduit strain (RAScd; OR =1.308; 95% CI: 1.098-1.558; P=0.003), and right atrial reservoir circumferential strain (RASr-c; OR =0.823; 95% CI: 0.684-0.990; P=0.04). 4D automated quantitative echocardiography allows for the dynamic assessment of right heart volume and function. To determine the development of FTR, RA dilation appears to be more significant than right ventricular dilation. The RASr, RAScd, and RASr-c are directly correlated with FTR severity.

What Do We Know about Peripartum Cardiomyopathy? Yesterday, Today, Tomorrow

Peripartum cardiomyopathy is a disease that occurs during or after pregnancy and leads to a significant decline in cardiac function in previously healthy women. Peripartum cardiomyopathy has a varying prevalence among women depending on the part of the world where they live, but it is associated with a significant mortality and morbidity in this population. Therefore, timely diagnosis, treatment, and monitoring of this disease from its onset are of utmost importance. Although many risk factors are associated with the occurrence of peripartum cardiomyopathy, such as conditions of life, age of the woman, nutrient deficiencies, or multiple pregnancies, the exact cause of its onset remains unknown. Advances in research on the genetic associations with cardiomyopathies have provided a wealth of data indicating a possible association with peripartum cardiomyopathy, but due to numerous mutations and data inconsistencies, the exact connection remains unclear. Significant insights into the pathophysiological mechanisms underlying peripartum cardiomyopathy have been provided by the theory of an abnormal 16-kDa prolactin, which may be generated in an oxidative stress environment and lead to vascular and consequently myocardial damage. Recent studies supporting this disease mechanism also include research on the efficacy of bromocriptine (a prolactin synthesis inhibitor) in restoring cardiac function in affected patients. Despite significant progress in the research of this disease, there are still insufficient data on the safety of use of certain drugs treating heart failure during pregnancy and breastfeeding. Considering the metabolic changes that occur in different stages of pregnancy and the postpartum period, determining the correct dosing regimen of medications is of utmost importance not only for better treatment and survival of mothers but also for reducing the risk of toxic effects on the fetus.

Specific peptides targeting the myocardiocyte are prognostic markers for heart attack: Function of α-SMA protein

Myocardial infarction (MI) is a serious cardiovascular disease that often results in a significant decline in heart function and associated complications. α-SMA (α-smooth muscle cell actin) is an important biomarker in the process of cardiac remodeling and repair, and its expression level is closely related to myocardial remodeling and prognosis. Therefore, the purpose of this study was to investigate the potential of nanoparticles containing cardiomyocyte targeting peptides in predicting prognosis and α-SMA protein expression after myocardial infarction, with a view to providing new therapeutic strategies and clinical guidelines. In this study, a novel targeting nanoparticle was constructed, using cardiomyocyte specific peptides as targeting ligands, and characterized by loading different drugs. Subsequently, a mouse model of myocardial infarction was used to systematically evaluate the effect of nanoparticles on α-SMA protein expression and prognosis prediction ability after MI. The expression level of α-SMA was analyzed by Western blot and immunohistochemistry, and the prognosis was evaluated by cardiac function assessment. The study found that nanoparticles containing cardiomyocyte targeting peptides significantly increased α-SMA expression levels and improved heart function in animal models of myocardial infarction. Compared with the control group, the application of targeted nanoparticles was closely related to the level of myocardial cell repair and fibrosis, and could effectively predict the prognosis after myocardial infarction. Therefore, nanoparticles containing cardiomyocyte targeting peptides can not only effectively improve the expression of α-SMA, but also serve as an important prognostic tool after myocardial infarction.

Outcomes of retropupillary iris claw lens implantation in patients with intraocular lens dislocation and low (less than 1000 cells/mm2) corneal endothelial cell density

BackgroundPosterior chamber intraocular lens (IOL) dislocation is a common complication of cataract surgery. Dislocated IOLs often require surgical intervention due to the potentially severe risks of leaving this condition untreated. If a patient with extremely low corneal endothelial cell density (ECD) presents with IOL dislocation, the surgeon faces a crucial dilemma of choosing the most optimal surgical treatment option. We sought to investigate the efficacy and safety of retropupillary iris claw intraocular lens (R-IOL) implantation in patients with IOL dislocation and extremely low (< 1000 cells/mm2) ECD.MethodsWe retrospectively reviewed the medical records of nine patients (all men) whose pre-operative ECD was < 1000 cells/mm2 and who underwent R-IOL implantation due to intraocular subluxation or total dislocation into the vitreous cavity between 2014 and 2020. We evaluated corneal endothelial function and visual outcomes after surgery.ResultsNine patients were included in this study. The mean age at diagnosis was 64.89 ± 7.15 years (range 57–76 years), and the follow-up duration was 37.93 ± 23.72 months (range 18.07–89.07 months). No patients developed bullous keratopathy during follow-up. Compared to the initial ECD, corneal thickness (CT), coefficient variation of cell area (CV) and percentage of hexagonal cells (HEX), there was no statistically significant decrease in the ECD, CV, and HEX at last follow-up (P = 0.944, 0.778, 0.445, 0.443). There was significant improvement in the mean uncorrected distance visual acuity (UDVA) at the last follow-up (average 0.13 logMAR, 20/27 Snellen) compared to the pre-operative mean UDVA (average 1.09 logMAR, 20/250 Snellen) (P < 0.01).ConclusionsR-IOL implantation did not result in a statistically significant decline in corneal endothelial function in patients with preoperatively low ECD, and it significantly improved the mean UDVA postoperatively. R-IOL implantation appears to be a safe and effective treatment modality for intraocular lens dislocation in patients with low ECD (< 1000 cells/mm²); however, long-term follow-up studies are warranted to corroborate these findings.

COPD Pathogenesis and Alterations in the Oral, Lung, and Gut Microbiomes

Chronic obstructive pulmonary disease (COPD) is a respiratory and systemic disease affecting more than 300 million people globally every year, and it also becomes a substantial economic burden. COPD is commonly comorbid with various underlying diseases such as cancer, cardiovascular diseases, cerebrovascular diseases, diabetes mellitus, osteoporosis, etc. It has been shown that statins can improve a significant decline in pulmonary function among COPD patients due to their pleiomorphic effect. Some systematic reviews also reported that statins reduced the risk of COPD-related events such as cancer and cardiovascular events, eventually resulting in more favorable outcomes than for non-statin user COPD patients. However, the physiological mechanism is still elucidated. Recently, it has been reported that statins influence the gut microbial composition with increased relative abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii and act with pleiomorphic effects such as anti-inflammatory and anti-cancer effects through modulating gut dysbiosis. We described this review to focus on whether statins can be a useful preventive option for COPD.

The reduction of LEDD leads to visual dysfunction in patients with PD after STN-DBS: a randomized clinical trial

Background: Medication adjustment after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson’s disease (PD) may influence visual function. However, no clinical trials have been designed specifically to investigate this effect. Objectives: To compare the effects of levodopa equivalent daily dose (LEDD) reduction and non-reduction on visual function in patients with Parkinson’s disease (PD) following STN-DBS. Methods: This was a multi-center, prospective, randomized, double-blinded clinical trial. A total of 208 patients with Parkinson’s disease were referred for DBS between June 2019 and July 2021 and analyzed between June 2023 and July 2023. STN-DBS was performed, and the LEDD was reduced in one study arm but not in the other. The primary outcome measure was visual impairment in Parkinson’s disease questionnaire (VIPD-Q) with or without LEDD reduction 12 months postoperatively, and the secondary outcomes included retinal nerve fiber layer (RNFL) thickness, vessel density, eye-tracking system results, contrast sensitivity and visual field. Results: During the short-term follow-up, DBS implantation and stimulation did not significantly affect visual function (VIPD-Q, baseline vs. 1 month, 9.269±8.385 vs. 8.938±7.666, Mann–Whitney U tests; P=0.6746). In the long-term follow-up, the reduction group demonstrated a significant decline in visual function, RNFL thickness, and vessel density after STN-DBS compared with the control group without STN-DBS (P&lt;0.001). Conclusions: Visual dysfunction, particularly a thinner RNFL and lower vessel density, is related to LEDD reduction after STN-DBS. Prolonged administration of dopamine-mimetic drugs prevents visual symptoms. Thus, physicians should consider LEDD adjustment when patients report visual dysfunction before surgery or severe visual symptoms after STN-DBS.

Abstract We132: Genetic Blockade of PKA-mediated Phosphoregulation of 26S Proteasomes Exacerbates Pathology in Both the Brain and Heart of an Alzheimer’s Disease Model

Background: Alzheimer’s disease (AD) patients often display not only cognitive impairment but also cardiac malfunction, but the underlying factors remain elusive. Phosphorylation of Ser14 of RPN6 (p-S14-RPN6) is required for cAMP/protein kinase A (PKA) to activate 26S proteasomes. Proteasome priming is implicated in the protection by cAMP-PKA augmentation against AD, but this remains to be established. Hence, we conducted this study to address these critical gaps. Methods: The Rpn6 S14A knock-in mice recently created for genetic blockade of p-S14-Rpn6 were crossbred with the PS19 tauopathy model (Jackson Lab Stock # 008169). Littermate wild type (WT), PS19, and PS19::S14A mice were compared. Cardiac function was evaluated with echocardiography (Echo). Hippocampal and myocardial tissues were used for western blot analyses (WB) and histopathology. Results: Increases in hippocampal insoluble tau proteins and in total and K48-linked ubiquitin conjugates were markedly greater in PS19::S14A mice than PS19 and WT mice. WBs for PSD95, synaptotagmin, Neu N, GFAP, and IBA1 revealed exacerbated synaptic loss, neuronal loss, gliosis, and microglial activation in the hippocampus of PS19::S14A mice in comparison to PS19 and WT mice. A more significant decline in cognitive function indicated by object recognition index was found in PS19::S14A mice vs. PS19 mice at 6 months. More interestingly, as compared to PS19 and WT littermates, PS19::S14A mice showed greater increases in myocardial tau proteins, ubiquitin conjugates, and cleaved caspase 3 and displayed more cardiac fibrosis, as reflected by increased mRNA expression of collagen 1 and picrosirius red staining. Echo revealed that PS19::S14A had significantly reduced fractional shortening, ejection fraction, stroke volume, and cardiac output at 9 months. Conclusions: The findings of this study demonstrate that genetic blockade of p-S14-RPN6 exacerbates tauopathy pathology in both the brain and heart. This is the first to have established the role of p-S14-RPN6 and, by extension, the significance of PKA-mediated proteasome activation in AD/tauopathy. Proteasome activation via augmentation of cAMP/PKA signaling should be explored for the alleviation of AD-associated brain and cardiac pathologies.

Exploring Cognitive Impairments Associated with Primary Open-Angle Glaucoma and Exfoliation Glaucoma.

This study explored the link between different types of glaucoma and cognitive function in a cohort of 620 Japanese patients. Participants were categorized into primary open-angle glaucoma (PG), exfoliation glaucoma (EG), and non-glaucomatous control groups. The findings revealed a significant decline in cognitive function as indicated by the Mini-Cog test in the EG group (mean ± SD: 4.0 ± 1, 95% CI: 3.9 to 4.2) compared to the PG group (4.4 ± 0.1, 4.3 to 4.5, p < 0.0001). Levels of fingertip measured advanced glycation end-products (AGEs) were significantly higher in the EG group (mean ± SD: 0.45 ± 0.006, 95% CI: 0.44 to 0.46) compared to the PG group (0.43 ± 0.004, 0.42 to 0.44, p = 0.0014). Although the multivariate analysis initially showed no direct association between glaucoma types and Mini-Cog scores, the EG group exhibited higher age and intraocular pressure (IOP) compared to the PG group. Further analysis revealed that high levels of AGEs were associated with cognitive decline and decreased mean visual fields in the EG group. Age was identified as a cofounding factor in these associations. An inverse correlation was observed between the accumulation of AGEs and skin carotenoid levels. Early detection of cognitive decline in glaucoma patients could enable timely intervention to preserve visual fields. Fingertip measurements of skin carotenoids and AGEs offer promising potential as non-invasive, straightforward diagnostic tools that could be widely adopted for monitoring ophthalmic and cognitive health in glaucoma patients.

Revisiting the "Timed Up and Go" test: a 12-s cut-off can predict Hospitalization Associated Functional Decline in older adults.

Early detection of functional decline, a major risk among hospitalized older adults, can facilitate interventions that could significantly reduce it. We aimed to examine the contribution of the Timed Up and Go (TUG) test in predicting Hospitalization Associated Functional Decline (HAFD) among older adults, able toindependently ambulate before admission. We used a cross-sectional study design; a total of 310 older adults (age ≥ 65) hospitalized in internal medicine wards between December 2018 and August 2020 were included; exclusion criteria were inability to ambulate, a diagnosis restricting mobility, hospitalization for end-of-life care, or impaired cognition. The Modified Barthel Index was used to assess HAFD; it was administered at admission to evaluate patients' independence in activities of daily living 2weeks prior hospitalization, and at discharge. The TUG test was performed on admission and to predict significant functional decline (defined by a reduction of three points or more in the Modified Barthel Index), while accounting for demographics, length of hospitalization, comorbidity burden (Charlson's comorbidity index), and cognitive function (ALFI-MMSE). Participants were divided into three groups according to their TUG score-under or over a cut-off score of 12s, or inability to complete the test. Adjusting for age, comorbidity, cognitive ability, and duration of hospitalization, the group that performed the test in less than 12s showed no statistically significant change in the Modified Barthel Index, therefore no significant HAFD. The other groups showed a statistically significant decline in function. Risk for significant HAFD is currently underestimated in clinical settings, limited to subjective assessment, and underused in the context of implementing early interventions to prevent HAFD. The TUG may support screening for those at risk of hospitalizing-associated functional decline and could help identify patients suitable for preventative interventions.

Enhancing physical function and activity level in malnourished older adults through oral nutrition supplements: a randomized controlled trial

BackgroundMalnutrition of older individuals, leads to significant functional decline, reducing their quality of life. Lifestyle interventions; dietary improvements and supplementation are explored to enhance the physical function of older adults. The current study aimed to assess the impact of oral nutritional supplements (ONS) on the functional and activity levels of Sri Lankan older adults.MethodsThis randomized controlled trial included; an intervention group (IG) receiving 200 mL of ONS providing 247 kcal per serving, for 12 weeks and a control group (CG) receiving an equivalent volume of water. Changes in handgrip strength, knee extension strength, gait speed, functional and activity levels were assessed.ResultsThe IG showed significant improvements in handgrip strength (43.96 ± 18.61 kg vs. 32.81 ± 17.92 kg; p < 0.001) and knee extension strength (23.45 ± 2.29 kg vs. 16.41 ± 2.09 kg; p < 0.001) following 12 weeks compared to the CG. The IG also exhibited significant improvements in gait speed (1.31 ± 0.52 m/s vs. 0.87 ± 0.26 m/s), Barthel index score, (0.30 ± 0.47 vs. -0.18 ± 0.66), PASE score (0.52 ± 17.79 vs. -1.60 ± 21.77) and IPAQ categories.ConclusionsONS was found to be effective in improving the functional and physical activity levels of malnourished older adults.Trial registration.Sri Lanka Clinical Trial Registry SLCTR/2022/021. Registered on 06/10/2022.

Effects of protein-enriched nutritional support on skeletal muscle mass and rehabilitative outcomes in brain tumor patients: a randomized controlled trial

Patients with brain tumors require extensive and prolonged rehabilitation efforts as they suffer from lesion-induced motor weakness as well as treatment-related side effects, often leading to a significant decline in function. Protein supplements have shown positive effects on promoting muscle strength and physical performance in various tumor etiologies. However, reports on their effects specifically in brain tumor patients remain scarce. This study aims to investigate the feasibility and efficacy of protein supplements in enhancing rehabilitative outcomes via muscle strengthening and functional gain in brain tumor patients with neurological demise. Sixty brain tumor patients were randomly assigned to either a protein supplement or a control group, receiving either protein supplements or a placebo for 6 weeks, in conjunction with conventional rehabilitation therapy. Assessments before and after the intervention included laboratory tests, anthropometric measures using bioimpedance analysis, and functional assessments, which included the MMSE, the modified Barthel Index, the Beck Depression Inventory, the Brief Fatigue Inventory, the Timed Up and Go test, the 6-min walk test, the isokinetic quadriceps muscle strength test, and the handgrip power. After the intervention, the levels of serum hemoglobin, protein, albumin, and C-reactive protein were improved in both groups, however, the change was significant only in the protein group. The muscle strength was enhanced in both groups, however, the significant increase in pinch grasp power was only noted in the protein group (P < 0.05). The distance on 6MWT was also significantly extended at follow-up in the protein group (P < 0.01). In the subgroup analysis according to nutritional status, the moderate malnutrition group showed greater augmentation of muscle mass than those with adequate nutrition (P < 0.05). Interestingly, the amelioration of malnutrition was observed only the in protein group. This study using protein supplements to promote the rehabilitative potential of brain tumor patients revealed a significant effect on improving hemodynamic nutritional indices, muscle power reimbursement, and functional improvement, especially in malnourished patients. The safety and feasibility of protein supplements in brain tumor patients were affirmative in this study. Further studies with more patients may help confirm the secondary functional gain resulting from increased muscle power.Trial registration: This study was retrospectively registered in the Clinical Research Information Service, CRIS no. KCT0009113 on Jan 12, 2024.