Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.

BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+. METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and sarcoendoplasmic reticulum Ca2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post-myocardial infarction (MI), causing regional hypoinnervation that is associated with supersensitivity of ß-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypoinnervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord, and ß-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct region of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct versus remote region. Action potential duration (APD) dispersion and tendency for induction of ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI but not sham hearts. SNS decreased APD at 80% repolarization (APD80) in MI but not sham hearts, whereas isoproterenol decreased APD80 in both groups. Isoproterenol also shortened Ca2+ transient duration at 80% repolarization in both groups but to a greater extent in MI hearts. Our data suggest that sympathetic remodeling post-MI is similar between rodents and rabbits, with CSPGs associated with sympathetic hypoinnervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated ß-adrenergic responsiveness, which may underlie increased APD dispersion and tendency for VT/VF.NEW & NOTEWORTHY Here, we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypoinnervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between rodents and rabbits, with hypoinnervation likely associated with enhanced ß-adrenergic sensitivity.

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished ß-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

Correlative Light, Electron Microscopy and Raman Spectroscopy Workflow To Detect and Observe Microplastic Interactions with Whole Jellyfish.

Many researchers have turned their attention to understanding microplastic interaction with marine fauna. Efforts are being made to monitor exposure pathways and concentrations and to assess the impact such interactions may have. To answer these questions, it is important to select appropriate experimental parameters and analytical protocols. This study focuses on medusae of Cassiopea andromeda jellyfish: a unique benthic jellyfish known to favor (sub-)tropical coastal regions which are potentially exposed to plastic waste from land-based sources. Juvenile medusae were exposed to fluorescent poly(ethylene terephthalate) and polypropylene microplastics (<300 µm), resin embedded, and sectioned before analysis with confocal laser scanning microscopy as well as transmission electron microscopy and Raman spectroscopy. Results show that the fluorescent microplastics were stable enough to be detected with the optimized analytical protocol presented and that their observed interaction with medusae occurs in a manner which is likely driven by the microplastic properties (e.g., density and hydrophobicity).

The aging brain: risk factors and interventions for long term brain health in women.

PURPOSE OF REVIEW: Poor cognitive aging and dementia pose a significant public health burden, and women face unique risks compared to men. Recent research highlights the role of genetics, menopause, chronic disease, and lifestyle in risk and resilience in women's cognitive aging. This work suggests avenues for clinical action at midlife that may change the course of brain health in aging. RECENT FINDINGS: Studies indicate women's risk for poor cognitive aging relates in part to hormone changes at menopause, a time when memory, brain structure and function, and Alzheimer's pathology may be observed in women and not men. Medical and lifestyle risks including diabetes, hypertension, and low physical activity also contribute to women's unique risks. At the same time, literature on resilience suggests women may benefit from lifestyle and chronic disease intervention, possibly more than men. Current studies emphasize the importance of interacting genetic and lifestyle risks, and effects of social determinants of health. SUMMARY: Women have greater risk than men for poor cognitive aging; however, by treating the whole person, including genetics, lifestyle, and social environment, clinicians have an opportunity to support healthy cognitive aging in women and reduce the future public health burden of dementia.

The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications.

Normal cardiac function requires that intracellular Ca2+ concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca2+ concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca2+ concentration. It then considers how the control of systolic and diastolic intracellular Ca2+ concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.

Story Memory Impairment Rates and Association with Hippocampal Volumes in a Memory Clinic Population.

OBJECTIVE: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes. METHOD: Archival records from 1617 older adults (Mage = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants (n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes. RESULTS: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes (r's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures. CONCLUSIONS: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.

Inflammatory cytokine levels implicated in Alzheimer's disease moderate the effects of sex on verbal memory performance.

Despite having an initial verbal memory advantage over men, women have greater rates of Alzheimer's disease and more rapid cognitive decline once diagnosed. Moreover, although Alzheimer's disease is influenced by inflammation, which itself has known sex differences, no study has investigated whether sex differences in memory are moderated by peripheral inflammatory activity. To address this issue, we analyzed data from 109 individuals (50 women, Mage = 71.62, range = 55-87) diagnosed as cognitively normal, or having mild cognitive impairment or Alzheimer's disease dementia. We then followed the sample for 12 months, as part of a longitudinal study of aging and Alzheimer's disease. At baseline, we assessed levels of the inflammatory cytokines interleukin (IL)-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in plasma. At baseline and 12 months, we assessed verbal memory using the Rey Auditory Verbal Learning Test and nonverbal memory using the Brief Visuospatial Memory Test-Revised. As hypothesized, for the full sample, women exhibited stronger verbal (but not nonverbal) memory than men. In women, but not men, higher IL-1ß at baseline related to poorer verbal learning across both time points and delayed recall at 12 months. The effect of sex on memory also differed by IL-1ß level, with women exhibiting a memory advantage both at baseline and 12 months, but only for those with low-to-moderate IL-1ß levels. Therefore, high peripheral inflammation levels may lead to a sex-specific memory vulnerability relevant for Alzheimer's disease.

Additional Commentary on the Detection and Quantification of Plastic Micro- and Nanoparticles in Tea Samples.

The study of plastic particles, particularly those in the micro-, sub-micro-, and nano-size ranges, within food and beverages has gained increasing interest within recent years. However, many analytical techniques have limits of detection which hinder their use for the study of these particles in these sample matrices. In addition, remaining contaminants from the matrices can interfere with the signals from plastic particles. Thus, great care must be given to sample preparation and data interpretation to ensure accurate results. This study proposes the use of sample purification through chemical digestion protocols to facilitate the study of plastic particles present in tea samples, and serves to highlight technical limitations which must be overcome in future studies.

Sex Differences in Cognitive Changes in De Novo Parkinson's Disease.

OBJECTIVE: To evaluate the sex differences in cognitive course over 4 years in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls. METHODS: Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson's Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared. RESULTS: Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period). CONCLUSIONS: Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

Calcium and Excitation-Contraction Coupling in the Heart.

Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.

Increased Ca buffering underpins remodelling of Ca2+ handling in old sheep atrial myocytes.

KEY POINTS: Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart. Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur. We report alterations to the atrial systolic Ca2+ transient that have implications for the function of the atrial in the elderly. We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca2+ in the old atria. The present study helps us to understand how the processes regulating atrial contraction are remodelled during ageing and provides a basis for future work aiming to understand why dysfunction develops. ABSTRACT: Many cardiovascular diseases, including those affecting the atria, are associated with advancing age. Arrhythmias, including those in the atria, can arise as a result of electrical remodelling or alterations in Ca2+ homeostasis. In the atria, age-associated changes in the action potential have been documented. However, little is known about remodelling of intracellular Ca2+ homeostasis in the healthy aged atria. Using single atrial myocytes from young and old Welsh Mountain sheep, we show the free Ca2+ transient amplitude and rate of decay of systolic Ca2+ decrease with age, whereas sarcoplasmic reticulum (SR) Ca content increases. An increase in intracellular Ca buffering explains both the decrease in Ca2+ transient amplitude and decay kinetics in the absence of any change in sarcoendoplasmic reticulum calcium transport ATPase function. Ageing maintained the integrated Ca2+ influx via ICa-L but decreased peak ICa-L . Decreased peak ICa-L was found to be responsible for the age-associated increase in SR Ca content but not the decrease in Ca2+ transient amplitude. Instead, decreased peak ICa-L offsets increased SR load such that Ca2+ release from the SR was maintained during ageing. The results of the present study highlight a novel mechanism by which increased Ca buffering decreases systolic Ca2+ in old atria. Furthermore, for the first time, we have shown that SR Ca content is increased in old atrial myocytes.

Implementing a Multipartner HPV Vaccination Assessment and Feedback Intervention in an Integrated Health System.

CONTEXT: Human papillomavirus (HPV) vaccine initiation rates are persistently lower than rates for other adolescent-recommended vaccines. Assessment and feedback interventions are a recommended strategy for improving vaccination rates. OBJECTIVE: To provide a guide for implementing a multipartner intervention to increase HPV vaccine initiation rates. SETTING: Nine primary care facilities within the Kaiser Permanente Northwest (KPNW) health care system. INTERVENTION: In 2015-2016, we implemented a system-wide assessment and feedback intervention to promote HPV vaccination. In partnership with the Centers for Disease Control and Prevention, the Oregon Immunization Program, and KPNW's leadership, we developed an education session combining information on HPV infection, parental communication strategies, and facility-specific coverage data. RESULTS: Twelve months postintervention, HPV dose 1 vaccination coverage increased from 71% to 72% among females and from 65% to 68% among males. CONCLUSIONS: A collaborative approach was critical to engaging leadership and enlisting support from providers and to developing appropriate materials for clinical audiences. Information provided here can be used as a guide for conducting assessment and feedback interventions focused on HPV vaccination initiation.

Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1).

RATIONALE: Transverse tubules (t-tubules) regulate cardiac excitation-contraction coupling and exhibit interchamber and interspecies differences in expression. In cardiac disease, t-tubule loss occurs and affects the systolic calcium transient. However, the mechanisms controlling t-tubule maintenance and whether these factors differ between species, cardiac chambers, and in a disease setting remain unclear. OBJECTIVE: To determine the role of the Bin/Amphiphysin/Rvs domain protein amphiphysin II (AmpII) in regulating t-tubule maintenance and the systolic calcium transient. METHODS AND RESULTS: T-tubule density was assessed by di-4-ANEPPS, FM4-64 or WGA staining using confocal microscopy. In rat, ferret, and sheep hearts t-tubule density and AmpII protein levels were lower in the atrium than in the ventricle. Heart failure (HF) was induced in sheep using right ventricular tachypacing and ferrets by ascending aortic coarctation. In both HF models, AmpII protein and t-tubule density were decreased in the ventricles. In the sheep, atrial t-tubules were also lost in HF and AmpII levels decreased. Conversely, junctophilin 2 levels did not show interchamber differences in the rat and ferret nor did they change in HF in the sheep or ferret. In addition, in rat atrial and sheep HF atrial cells where t-tubules were absent, junctophilin 2 had sarcomeric intracellular distribution. Small interfering RNA-induced knockdown of AmpII protein reduced t-tubule density, calcium transient amplitude, and the synchrony of the systolic calcium transient. CONCLUSIONS: AmpII is intricately involved in t-tubule maintenance. Reducing AmpII protein decreases t-tubule density, reduces the amplitude, and increases the heterogeneity of the systolic calcium transient.

Three-dimensional structure of the intercalated disc reveals plicate domain and gap junction remodeling in heart failure.

The intercalated disc (ICD) orchestrates electrochemical and mechanical communication between neighboring cardiac myocytes, properties that are perturbed in heart failure (HF). Although structural data from transmission electron microscopy two-dimensional images have provided valuable insights into the domains forming the ICD, there are currently no three-dimensional (3D) reconstructions for an entire ICD in healthy or diseased hearts. Here, we aimed to understand the link between changes in protein expression in an ovine tachypacing-induced HF model and ultrastructural remodeling of the ICD by determining the 3D intercalated disc architecture using serial block face scanning electron microscopy. In the failing myocardium there is no change to the number of ICDs within the left ventricle, but there is an almost doubling of the number of discs with a surface area of <1.0 × 10(8)µm(2) in comparison to control. The 3D reconstructions further revealed that there is remodeling of the plicate domains and gap junctions with vacuole formation around and between the contributing membranes that form the ICDs in HF. Biochemical analysis revealed upregulation of proteins involved in stabilizing the adhesive and mechanical properties consistent with the morphological changes. Our studies here have shown that in tachypacing-induced HF mechanical stresses are associated with both structural and molecular alterations. To our knowledge, these data together provide novel, to our knowledge, insights as to how remodeling at the molecular and structural levels leads to impaired intercellular communication.

Perturbed atrial calcium handling in an ovine model of heart failure: potential roles for reductions in the L-type calcium current.

Heart failure (HF) is commonly associated with reduced cardiac output and an increased risk of atrial arrhythmias particularly during ß-adrenergic stimulation. The aim of the present study was to determine how HF alters systolic Ca(2+) and the response to ß-adrenergic (ß-AR) stimulation in atrial myocytes. HF was induced in sheep by ventricular tachypacing and changes in intracellular Ca(2+) concentration studied in single left atrial myocytes under voltage and current clamp conditions. The following were all reduced in HF atrial myocytes; Ca(2+) transient amplitude (by 46% in current clamped and 28% in voltage clamped cells), SR dependent rate of Ca(2+) removal (kSR, by 32%), L-type Ca(2+) current density (by 36%) and action potential duration (APD90 by 22%). However, in HF SR Ca(2+) content was increased (by 19%) when measured under voltage-clamp stimulation. Inhibiting the L-type Ca(2+) current (ICa-L) in control cells reproduced both the decrease in Ca(2+) transient amplitude and increase of SR Ca(2+) content observed in voltage-clamped HF cells. During ß-AR stimulation Ca(2+) transient amplitude was the same in control and HF cells. However, ICa-L remained less in HF than control cells whilst SR Ca(2+) content was highest in HF cells during ß-AR stimulation. The decrease in ICa-L that occurs in HF atrial myocytes appears to underpin the decreased Ca(2+) transient amplitude and increased SR Ca(2+) content observed in voltage-clamped cells.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. Objective: To develop a new composite score to improve the prediction of outcome change. Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. Results: The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

Submicron- and nanoplastic detection at low micro- to nanogram concentrations using gold nanostar-based surface-enhanced Raman scattering (SERS) substrates.

The presence of submicron- (1 µm-100 nm) and nanoplastic (<100 nm) particles within various sample matrices, ranging from marine environments to foods and beverages, has become a topic of increasing interest in recent years. Despite this interest, very few analytical techniques are known that allow for the detection of these small plastic particles in the low concentration ranges that they are anticipated to be present at. Research focused on optimizing surface-enhanced Raman scattering (SERS) to enhance signal obtained in Raman spectroscopy has been shown to have great potential for the detection of plastic particles below conventional resolution limits. In this study, we produce SERS substrates composed of gold nanostars and assess their potential for submicron- and nanoplastic detection. The results show 33 nm polystyrene could be detected down to 1.25 µg mL-1 while 36 nm poly(ethylene terephthalate) was detected down to 5 µg mL-1. These results confirm the promising potential of the gold nanostar-based SERS substrates for nanoplastic detection. Furthermore, combined with findings for 121 nm polypropylene and 126 nm polyethylene particles, they highlight potential differences in analytical performance that depend on the properties of the plastics being studied.