Functional Decline In Patients Research Articles

Advanced MRI metrics improve the prediction of baseline disease severity for individuals with degenerative cervical myelopathy

Background contextDegenerative cervical myelopathy (DCM) is the most common form of atraumatic spinal cord injury globally. Degeneration of spinal discs, bony osteophyte growth and ligament pathology results in physical compression of the spinal cord contributing to damage of white matter tracts and grey matter cellular populations. This results in an insidious neurological and functional decline in patients which can lead to paralysis. Magnetic resonance imaging (MRI) confirms the diagnosis of DCM and is a prerequisite to surgical intervention, the only known treatment for this disorder. Unfortunately, there is a weak correlation between features of current commonly acquired MRI scans (“community MRI, cMRI”) and the degree of disability experienced by a patient. PurposeThis study examines the predictive ability of current MRI sequences relative to “advanced MRI” (aMRI) metrics designed to detect evidence of spinal cord injury secondary to degenerative myelopathy. We hypothesize that the utilization of higher fidelity aMRI scans will increase the effectiveness of machine learning models predicting DCM severity and may ultimately lead to a more efficient protocol for identifying patients in need of surgical intervention. Study design/settingSingle institution analysis of imaging registry of patients with DCM. Patient sample296 patients in the cMRI group and 228 patients in the aMRI group. Outcome measuresPhysiologic measures: Accuracy of machine learning algorithms to detect severity of DCM assessed clinically based on the modified Japanese Orthopedic Association (mJOA) scale. MethodsPatients enrolled in the Canadian Spine Outcomes Research Network registry with DCM were screened and 296 cervical spine MRIs acquired in cMRI were compared with 228 aMRI acquisitions. aMRI acquisitions consisted of diffusion tensor imaging, magnetization transfer, T2-weighted, and T2*-weighted images. The cMRI group consisted of only T2-weighted MRI scans. Various machine learning models were applied to both MRI groups to assess accuracy of prediction of baseline disease severity assessed clinically using the mJOA scale for cervical myelopathy. ResultsThrough the utilization of Random Forest Classifiers, disease severity was predicted with 41.8% accuracy in cMRI scans and 73.3% in the aMRI scans. Across different predictive model variations tested, the aMRI scans consistently produced higher prediction accuracies compared to the cMRI counterparts. ConclusionsaMRI metrics perform better in machine learning models at predicting disease severity of patients with DCM. Continued work is needed to refine these models and address DCM severity class imbalance concerns, ultimately improving model confidence for clinical implementation.

Sarcopenia as the Mobility Phenotype of Aging: Clinical Implications.

Sarcopenia, which is characterized by an age-related decline in muscle mass and function, poses significant challenges to geriatric care. Its definition has evolved from muscle-specific criteria to include muscle mass, muscle function, and physical performance, recognizing sarcopenia as a physical frailty. Sarcopenia is associated with adverse outcomes, including mortality, falls, fractures, cognitive decline, and admission to long-term care facilities. Neuromechanical factors, protein-energy balance, and muscle protein synthesis-breakdown mechanisms contribute to its pathophysiology. The identification of sarcopenia involves screening tests and a comprehensive assessment of muscle mass, strength, and physical function. Clinical approaches aligned with the principles of comprehensive geriatric assessment prioritize patient-centered care. This assessment aids in identifying issues related to activities of daily living, cognition, mood, nutrition, and social support, alongside other aspects. The general approach to factors underlying muscle loss and functional decline in patients with sarcopenia includes managing chronic diseases and evaluating administered medications, with interventions including exercise and nutrition, as well as evolving pharmacological options. Ongoing research targeting pathways, such as myostatin-activin and exercise mimetics, holds promise for pharmacological interventions. In summary, sarcopenia requires a multifaceted approach, acknowledging its complex etiology and tailoring interventions to individual patient needs.

Patients' experiences with methylcobalamin injections in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no definitive treatment. Vitamin B12 is not a Food and Drug Administration-approved treatment in the United States, although it has been prescribed off-label as ultra-high-dose methylcobalamin, which has been shown to be safe and effective in slowing functional decline in patients with ALS. This study evaluates the impact of Vitamin B12 injections on the quality of life of five patients. Semi-structured interviews were conducted with the patients and caregivers. The data was carefully read, coded, and organized into themes and sub-themes by two independent researchers. The study found four themes and 11 subthemes from the data, including initial circumstances, administration of the injection, subjective experience with Vitamin B12, and outcomes and expectations. All participants recognized some benefits from Vitamin B12 injections, specifically increased energy, reduced fatigue, and improved balance. However, some patients had difficulty monitoring its specific effect due to the progressive nature of the disease. The flexibility offered by this intervention is beneficial for patients with declining mobility and strength who wish to adapt their treatment to their schedule. This work is a modest call to fill the existing gap in the literature and push for more randomized controlled trials investigating and clarifying the effects of Vitamin B12 injections on disease progression, muscle function, and quality of life in a small but diverse pool of patients with ALS.

Bidirectional Relationship between HIV/HBV Infection and Comorbid Depression and/or Anxiety: A Systematic Review on Shared Biological Mechanisms.

Mental disorders that are comorbid with chronic infectious diseases may worsen clinical outcomes and patients' quality of life. We hypothesized that depression and/or anxiety syndromes or symptoms comorbid with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection might stem from shared biological mechanisms. We conducted a systematic review applying the PRISMA statement by searching into the PubMed, APA PsycInfo, and Scopus databases. We examined the literature on HIV/HBV infection comorbid with depression and/or anxiety in adults ≥18 years. Thirty-one studies on HIV and three on HBV were analyzed. The Tat protein contributed to HIV-associated mood disorders due to the protein's ability to cause neurodegeneration and induce hypothalamic-pituitary-adrenal (HPA) axis dysregulation in response to natural stressors. The decreased brain-derived neurotrophic factor (BDNF) levels also emerged as a mechanism involved in HIV neuropathogenesis and the associated mood symptoms. Neuroinflammation was implicated in depression and/or anxiety onset in patients with HIV/HBV infections. Microglial activation and release of cytokines, in particular, appeared as potential pathogenetic mechanisms. Furthermore, an altered balance between quinolinic acid and kynurenic acid production emerged in HIV patients with comorbid depression, indicating a glutamatergic dysfunction. Inflammatory cytokine production and the downregulation of cellular immune responses contributed to persisting inflammation, delayed healing, and functional decline in patients with chronic hepatitis B (CHB) infection. A shift in type 1-type 2 cytokine balance might be implicated in HBV-related immune pathogenesis, and depression and anxiety might be considered immunomodulatory factors. Cytokines also caused HPA axis hyperactivity, frequently observed in HIV/HBV patients with comorbid depression/anxiety. The present systematic review showed, for the first time, that HIV/HBV and depression and/or anxiety might have several biological mechanisms as common denominators. The longitudinal course of the highlighted biological mechanisms should be explored to establish the causative interrelationship among the involved mechanisms. In addition, future research should investigate the possibility that a patient's clinical outcome might improve using pharmacological treatments acting on the biological mechanisms we described as common denominators of chronic inflammatory infective diseases and depression/anxiety.

Variations in metabolic risk factors for dementia do not affect APOE‐mediated cognitive or functional decline in patients with Alzheimer’s disease from São Paulo, Brazil

AbstractBackgroundMidlife cerebrovascular risk, low education and copies of APOE‐ε4 are risk factors for Alzheimer’s disease (AD), whereas metabolic derangements have been associated with dementia onset. This prospective study aimed to explore the impacts of variations in metabolic risk factors on progression of AD in São Paulo, Brazil.MethodsOutpatients with late‐onset AD according to National Institute on Aging – Alzheimer’s Association criteria were assessed for APOE haplotypes (rs7412 & rs429358 genotyped by way of TaqMan® Real‐Time Polymerase Chain Reaction technology) and variations in one year of the following potential metabolic predictors: fasting glycemia, TSH, free T4, vitamin B12, and folic acid. Metabolic variations were assessed in accordance with concurrent variations in the Clinical Dementia Rating Sum‐of‐Boxes, the Index of Independence in Activities of Daily Living, Lawton’s Scale for Instrumental Activities of Daily Living, and the Mini‐Mental State Examination in multiple linear regression models for all patients, and after stratification according to APOE‐ε4 carrier status, with the threshold of significance set at p<0.05.ResultsOf 122 patients, there were 81 women (66.4%) and 41 men (33.6%), 69 APOE‐ε4 carriers (56.5%) and 53 APOE‐ε4 non‐carriers (43.5%). The mean estimated age at AD onset was 73.13±7.1 years‐old. Overall, 120 patients used a cholinesterase inhibitor (98.4%), and 90 patients used Memantine (73.8%). All test scores were significantly different at the end of one year (p<0.01), except for the Mini‐Mental State Examination (p = 0.13). None of the potential metabolic predictors varied significantly after one year (p>0.16), and no variations in metabolic risk factors were concurrently associated with variations in the Clinical Dementia Rating Sum‐of‐Boxes (p>0.17), the Index of Independence in Activities of Daily Living (p>0.09), Lawton’s Scale for Instrumental Activities of Daily Living (p>0.22), or the Mini‐Mental State Examination (p>0.40), neither for APOE‐ε4 carriers (p>0.28), nor for APOE‐ε4 non‐carriers (p>0.07).ConclusionsLifetime metabolic risk factors may affect onset of AD, but concurrent variations in metabolic parameters seem to have no associations with cognitive or functional decline in such patients, regardless of APOE‐ε4 carrier status. (Supported by FAPESP grant #2015/10109‐5)

Acoustic radiation force impulse shear wave elastography quantifies upper limb muscle in patients with Duchenne muscular dystrophy

We investigated whether the upper limb muscle stiffness quantified by the acoustic radiation force impulse shear wave elastography (ARFI/SWE) is a potential biomarker for age-related muscle alteration and functional decline in patients with Duchenne muscular dystrophy (DMD). 37 patients with DMD and 30 typically developing controls (TDC) were grouped by age (3–8, 9–11, and 12–18 years). ARFI/SWE measured the biceps and deltoid muscle's shear wave velocities (SWVs). Performance of Upper Limb Module (PUL 1.2 module) assessed muscle function in DMD patients. Mann Whitney test compared muscle SWVs between DMD and TDC, stratified by three age groups. We used analysis of variance with Bonferroni correction to compare muscle SWVs between DMD and TDC and correlated muscle SWVs with PUL results in the DMD group. Results showed that the SWVs of biceps differentiated DMD patients from TDC across age groups. Younger DMD patients (3–8 years) exhibited higher SWVs (p = 0.013), but older DMD patients (12–18 years) showed lower SWVS (p = 0.028) than same-aged TDC. DMD patients had decreasing biceps SWVs with age (p < 0.001), with no such age effect in TDC. The SWVs of deltoid and biceps positively correlated with PUL scores (r = 0.527 ∼ 0.897, P < 0.05) and negatively correlated with PUL timed measures (r = −0.425 ∼ −0.542, P < 0.05) in DMD patients. Our findings suggest that ARFI/SWE quantifying the SWVs in upper limb muscle could be a potential biomarker to differentiate DMD from TDC across ages and that DMD patients showed age-related muscle alteration and limb functional decline.

Periodic discharges plus fast activity on EEG predict worse outcomes in post-stroke epilepsy.

Post-seizure functional decline is a concern in post-stroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and post-seizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. In this study, 307 patients with PSE (median age, 75; range, 35-97 years; 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 (20%) vs. 8 (3.2%), p < 0.001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval (CI), 1.44-12.6; p = 0.009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = 0.003), prolonged hyperperfusion (100% vs. 62%, p = 0.023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR, 22.0; 95% CI, 1.87-259.4; p = 0.014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR, 4.21; 95% CI, 1.27-13.88; p = 0.018). In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of post-seizure short- and long-term functional decline.

Clinically defined aspiration pneumonia is an independent risk factor associated with long-term hospital stay: a prospective cohort study

BackgroundLong-term hospital stay is associated with functional decline in patients with pneumonia, especially in the elderly. Among elderly patients with pneumonia, aspiration pneumonia is a major category. Clinical definition is usually used because it can occur without apparent aspiration episodes. It is still not clear whether a long-term hospital stay is due to aspiration pneumonia itself caused by underlying oropharyngeal dysfunction or simply due to functional decline in elderly patients with multiple comorbidities during acute infection. The aim of this study is to identify whether clinically defined aspiration pneumonia itself was associated with a long-term hospital stay.MethodsA prospective observational study on community-acquired (CAP) or healthcare-associated pneumonia (HCAP) was conducted from January 2012 through January 2014. Aspiration pneumonia was clinically defined as pneumonia not only occurring in patients after documented aspiration episodes, but also occurring in those with underlying oropharyngeal dysfunction: chronic disturbances of consciousness and/or chronic neuromuscular diseases. We defined thirty-day hospital stay as a long-term hospital stay and compared it with logistic regression analysis. Potential confounders included age, sex, HCAP, body mass index (BMI), long-term bed-ridden state, heart failure, cerebrovascular disorders, dementia, antipsychotics use, hypnotics use, and CURB score which is a clinical prediction tool used to assess the severity, standing for; C (presence of Confusion), U (high blood Urea nitrogen level), R (high Respiratory rate), and B (low Blood pressure). In a sub-analysis, we also explored factors associated with long-term hospital stay in patients with aspiration pneumonia.ResultsOf 2,795 patients, 878 (31.4%) had aspiration pneumonia. After adjusting potential confounders, the aspiration pneumonia itself was significantly associated with long-term hospital stay (adjusted odds ratio 1.44; 95% confidence interval 1.09—1.89, p < 0.01), as were higher age, male sex, high CURB score, HCAP, low BMI, heart failure, cerebrovascular disease, and antipsychotics use. Sub-analysis revealed factors associated with long-term hospital stay in the aspiration pneumonia, which included male sex, and multi-lobar chest X-ray involvement.ConclusionsClinically defined aspiration pneumonia itself was independently associated with long-term hospital stay. This result could potentially lead to specific rehabilitation strategies for pneumonia patients with underlying oropharyngeal dysfunction.

Acute Myocardial Infarction and Risk of Cognitive Impairment and Dementia: A Review.

Cognitive impairment (CI) shares common cardiovascular risk factors with acute myocardial infarction (AMI), and is increasingly prevalent in our ageing population. Whilst AMI is associated with increased rates of CI, CI remains underreported and infrequently identified in patients with AMI. In this review, we discuss the evidence surrounding AMI and its links to dementia and CI, including pathophysiology, risk factors, management and interventions. Vascular dysregulation plays a major role in CI, with atherosclerosis, platelet activation, microinfarcts and perivascular inflammation resulting in neurovascular unit dysfunction, disordered homeostasis and a dysfunctional neurohormonal response. This subsequently affects perfusion pressure, resulting in enlarged periventricular spaces and hippocampal sclerosis. The increased platelet activation seen in coronary artery disease (CAD) can also result in inflammation and amyloid-β protein deposition which is associated with Alzheimer's Dementia. Post-AMI, reduced blood pressure and reduced left ventricular ejection fraction can cause chronic cerebral hypoperfusion, cerebral infarction and failure of normal circulatory autoregulatory mechanisms. Patients who undergo coronary revascularization (percutaneous coronary intervention or bypass surgery) are at increased risk for post-procedure cognitive impairment, though whether this is related to the intervention itself or underlying cardiovascular risk factors is debated. Mortality rates are higher in dementia patients with AMI, and post-AMI CI is more prevalent in the elderly and in patients with post-AMI heart failure. Medical management (antiplatelet, statin, renin-angiotensin system inhibitors, cardiac rehabilitation) can reduce the risk of post-AMI CI; however, beta-blockers may be associated with functional decline in patients with existing CI. The early identification of those with dementia or CI who present with AMI is important, as subsequent tailoring of management strategies can potentially improve outcomes as well as guide prognosis.

Lecanemab (Leqembi) granted full approval for early Alzheimer's disease.

Lecanemab-irmb (Leqembi – Eisai/Biogen), the IV amyloid-directed monoclonal antibody that received accelerated approval from the FDA in January 2023 for treatment of early Alzheimer’s disease, has now received full approval from the FDA based on a trial showing that it slowed cognitive and functional decline in patients with mild cognitive impairment (MCI) or mild Alzheimer’s disease dementia and confirmed presence of brain amyloid.

Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.

Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS. We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival. Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up. Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.

Treatment Outcomes for Patients With Amyotrophic Lateral Sclerosis Receiving Intravenous Edaravone From a Home and Alternative-Site Infusion Provider (P6-4.005)

<h3>Objective:</h3> To describe real-world treatment outcomes in patients with ALS treated with IV edaravone collected by a provider of home/alternative-site infusions. <h3>Background:</h3> Intravenous (IV) edaravone was US Food and Drug Administration approved in May 2017 after it was shown to slow the rate of physical functional decline in patients with amyotrophic lateral sclerosis (ALS). Information on real-world use of IV edaravone is limited. <h3>Design/Methods:</h3> A retrospective cohort study was conducted utilizing de-identified data collected from Amerita Specialty Infusion Services, a US-based provider of home/alternative-site infusions that has treated and collected data from patients with ALS receiving IV edaravone since the time of commercial availability. Patients with ALS who received their first IV edaravone dose between September 25, 2017, and December 31, 2020, were included. Patient status was confirmed through March 31, 2021. Variables collected included patient demographics, revised ALS Functional Rating Scale (ALSFRS-R) and forced vital capacity (FVC) scores, and treatment outcomes. <h3>Results:</h3> Patients (N=153) receiving IV edaravone were included in this analysis; 66.0% were male, mean±SD age was 61.4±10.8 years, and 27.5% were covered by commercial insurance. In patients who had healthcare provider-recorded ALSFRS-R (n=61) and FVC (n=38) assessed ±100 days from start of care, mean±SD scores were 33.7±9.3 and 66%±24%, respectively. At the end of the study period, 105 (68.6%) patients had discontinued treatment. The most frequent reason for discontinuation was death/hospice (42.9%), doctor choice (19.0%), patient choice (18.1%), and insurance/care change (14.3%). Mean±SD treatment duration for patients who discontinued was 314±260 days. As of March 31, 2021, 48 (31.4%) patients were still receiving treatment with IV edaravone and their mean±SD treatment duration was 446±292 days. <h3>Conclusions:</h3> This analysis describes treatment outcomes in IV edaravone-treated patients with ALS in a real-world setting. This information may be useful to clinicians who prescribe IV edaravone for patients with ALS. <b>Disclosure:</b> Mrs. Da Silva has nothing to disclose. Malgorzata Ciepielewska has received personal compensation for serving as an employee of Mitsubishi Tanable Pharma America . Mr. Do has nothing to disclose. Miss Anderson has nothing to disclose. Mrs. Martin has received personal compensation for serving as an employee of Amerita Specialty Infusion. Dr. Ortlip has nothing to disclose.

Longer Milestone-Free Time in Patients With Amyotrophic Lateral Sclerosis Treated With IV Edaravone vs Not Treated With IV Edaravone: Results From a US Administrative Claims Analysis (S14.007)

<h3>Objective:</h3> To estimate time-to-progression milestones in IV edaravone–treated vs non–IV edaravone-treated patients with ALS in a real-world setting. <h3>Background:</h3> Intravenous (IV) edaravone was US Food and Drug Administration-approved in May 2017 based on a slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Information on real-world outcomes in patients with ALS treated with IV edaravone is limited. <h3>Design/Methods:</h3> This retrospective observational analysis included patients with ALS who were continuously enrolled in Optum’s de-identified Clinformatics® Data Mart database between August 8, 2017, and September 30, 2021. Propensity score matching (1:1) identified IV edaravone–treated patients (cases) and non–IV edaravone-treated patients (controls) matched for covariates: age, race, geographic region, gender, pre-index disease duration (period between the first claim for ALS diagnosis and the first claim for IV edaravone [cases] or August 2017 [controls]), insurance, cardiovascular disease history, riluzole prescription, gastrostomy tube placement, artificial nutrition, noninvasive ventilation, and all-cause hospitalization. Milestones were defined according to the Healthcare Common Procedure Coding System and included the use of canes/walkers/wheelchairs (M1); artificial nutrition (M2); noninvasive ventilation (M3); invasive ventilation/speech-generating devices (M4); and hospice (M5). Difference between cases and controls in cause-specific restricted mean time lost (RMTL) was estimated to examine IV edaravone benefit. <h3>Results:</h3> Cases (n=360) were matched to controls (n=360); mean age in years (SD) was 62.9 (10.2) and 62.8 (10.2) in cases and controls, respectively. In the post-index period, differences in RMTL (95% CI) in months indicate longer milestone-free time in cases than controls: 2.50 (0.93–4.07), 4.30 (2.88–5.72), 2.92 (1.56–4.28), 4.12 (3.00–5.23), and 2.33 (1.31–3.34) for M1, M2, M3, M4, and M5, respectively. <h3>Conclusions:</h3> This analysis describes the time to milestones in patients with ALS treated with IV edaravone in a real-world setting. This information may be useful to payers and clinicians in evaluating use of IV edaravone. <b>Disclosure:</b> Malgorzata Ciepielewska has received personal compensation for serving as an employee of Mitsubishi Tanable Pharma America . Jeffrey Zhang has received personal compensation for serving as an employee of Princeton Pharmatech. Jeffrey Zhang has received stock or an ownership interest from CalciMedica. Ying Liu has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for MPTA. Dr. Hagan has received personal compensation for serving as an employee of Mitsubishi Tanabe Pharma America.

Deciphering the role of lipoproteins and lipid metabolic alterations in ageing and ageing-associated renal fibrosis.

Fibrosis is the ultimate pathological feature of many chronic diseases, and ageing a major risk factor for fibrotic diseases. Current therapies are limited to those that reduce the rate of functional decline in patients with mild to moderate disease, but few interventions are available to specifically target the pathogenesis of fibrosis. In this context, new treatments that can significantly improve survival time and quality of life for these patients are urgently needed. In this review, we outline both the synthesis and metabolism of lipids and lipoproteins associated with ageing-associated renal fibrosis and the prominent contribution of lipids and lipidomics in the discovery of biomarkers that can be used for the prevention, diagnosis, and treatment of renal ageing and fibrosis. Next, we describe the effect of dyslipidaemia on ageing-related renal fibrosis and the pathophysiological changes in the kidney caused by dyslipidaemia. We then summarize the enzymes, transporters, transcription factors, and RNAs that contribute to dysregulated lipid metabolism in renal fibrosis and discuss their role in renal fibrosis in detail. We conclude by discussing the progress in research on small molecule therapeutic agents that prevent and treat ageing and ageing-associated renal fibrosis by modulating lipid metabolism. A growing number of studies suggest that restoring aberrant lipid metabolism may be a novel and promising therapeutic strategy to combat ageing and ageing-associated renal fibrosis.

Use of hip- versus wrist-based actigraphy for assessing functional decline and disease progression in patients with motor neuron disease

BackgroundActigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND.MethodsIn this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97; hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline.ResultsPatients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12; variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16).ConclusionsActigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.

Sensory stimulation improves daily functions in Alzheimer’s disease

AbstractBackgroundAbnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to the pathogenesis of the disease has been recently proposed. It has been demonstrated that induction of synchronized gamma oscillation of neuronal networks by sensory stimulation reverses AD‐related pathological markers in transgenic mice carrying AD‐related human pathological genes. The current study evaluated whether non‐invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for patients in AD spectrum.MethodThe data studied here is from Overture clinical trial (NCT03556280). The study included a treatment group, where participants received daily, 1‐hour, 40Hz gamma visual and auditory stimulation for 6‐months at home, and a placebo group. To assess the treatment efficacy on daily functional abilities, the Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale was used. Assessments were made at baseline and every four weeks throughout the study. ADCS‐ADL consists of 23‐items where each item aims to assess different functional abilities. The change in ADCS‐ADL as well as change in each individual item’s score between the treatment group (n = 33) and the placebo group (n‐ = 19) were compared using a mixed model for repeated measures (MMRM).ResultWe observed that treatment group participants were able to maintain their functional abilities while placebo group participants showed a decline as assessed by ADCS‐ADL, p&lt;0.001. Within the instrumental ADCS‐ADL individual items, the most significant differences between the two groups, all favoring treatment group, were observed in: (1) Attentive participation in conversations, p&lt;0.001, and (2) Finding personal belongings, p&lt;0.043.ConclusionOur results suggest that daily, 1‐hour 40Hz gamma sensory stimulation may help prevent functional decline in patients with AD spectrum disorder. Preventing functional loss would help both patients and caregivers. Furthermore, it may reduce the need for institutionalization and reduce healthcare costs. Larger studies are planned to confirm these initial findings on the benefits of gamma sensory stimulation on function.

P.165 Clinical outcome study of dysferlinopathy: Lower limb water T2 predicts functional decline in patients with dysferlinopathy

P.165 Clinical outcome study of dysferlinopathy: Lower limb water T2 predicts functional decline in patients with dysferlinopathy

Water T2 could predict functional decline in patients with dysferlinopathy.

Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86m on the 6-min walk than those with a lower T2H2O (<40.6ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0ms in adductor magnus and vastus intermedius, 40.0ms in vastus medialis, and 40.5ms in vastus lateralis from different sites equipped with different MRI systems. In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: An instrumental variable meta-analysis.

Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline. Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD. A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.

Prognostic value of baseline G8 geriatric assessment in a real-life population of elderly metastatic colorectal cancer patients: The Gold Study.

e24015 Background: Colorectal cancer (CRC) is the second most frequent malignancy in patients (pts) aged 70. Elderly patients are often excluded by clinical trials; however, improvements in quality of life and comorbidities management led to expand the access to anticancer treatments irrespectively of age per se. Finding new tools to stratify vulnerability in elderly pts is crucial to guide clinicians in therapeutic decisions. G8 and timed up and go test (TUG) have been related to prognosis and functional decline in patients affected by several solid tumors. However, no studies focused on TUG and G8 prognostic value in CRC pts are available. In this study, we assessed the prognostic value of G8 and TUG in a cohort of real-life elderly pts with metastatic CRC (mCRC). Methods: GOLD was a multicentre, observational, prospective study in which pts aged 70 with mCRC and eligible to 1st line therapy were enrolled. G8 and TUG were performed at screening and at the first documented disease progression (PD). G8 cutoff was 14, as reported in literature; TUG8,5 sec (cutoff set with ROC curve using MedCalc software v 20.027). PFS and OS were described with Kaplan-Meyer curve. All analyzed variables were then compared with multivariate models. Primary endpoint of the study was to assess prognostic value of G8 in OS and PFS. Secondary endpoints were to assess prognostic value of TUG in OS and PFS. Results: Since Oct 2017 to Apr 2019, 109 pts were evaluated in 4 different Oncology Units in Veneto (IT); 4 were not eligible to anticancer treatments and where thus excluded. 105 pts were finally enrolled. Clinical, histological and molecular characteristics were well balanced between pts with G814 vs &gt; 14, with the exception of RASmut, more represented in the G8 &gt; 14 group (p = 0,0195). 39 (37%) pts were aged80; 46 (44%) had ECOG PS1; 55 (53%) had RASmut; 15 (15%) had BRAFmut. 81 (77%) had G814; 78 (75%) had TUG8,5. At a median follow up time of 41,2 months, median OS was 19,41 months (95%CI 15,46-23,19) and median PFS 8,78 months (95% CI 7,53-10,07). OS was longer in patients with G814 (HR 0,61; 95%CI 0,39-0,97; p= 0,0584) and TUG8,5 (HR 0,55; 95%CI 0,35- 0,86; p= 0,0201). PFS was not influenced by G8 (HR 0,86; 95%CI 0,55-1,34; p= 0,5125) nor by TUG (HR 0,71; 95%CI 0,47-1,08). G814 and TUG8,5 conferred better OS also in the subgroup of RASmut (respectively p= 0,0133 and p= 0,0088). Worse OS was observed in presence of &gt; 1 metastatic site (HR = 1,71; 95%CI 1,11 to 2,64; p= 0,0161). At the multivariate analysis, G814 ( p= 0,0202) and single metastatic site ( p= 0,0200) were related to better OS; none of the analysed variables had effect on PFS. Conclusions: In our study G814 and TUG8,5 had prognostic value in OS, but not in PFS, in a real-life population of elderly pts affected by mCRC. G8 and single metastatic site involvement were related to better OS, irrespectively of other clinical, histological and molecular variables.