Meso Scale Research Articles

Clinical evaluation of a novel plasma pTau217 electrochemiluminescence immunoassay in Alzheimer’s disease

A growing literature suggests that plasma levels of tau phosphorylated at amino acid 217 (pTau217) performs similarly to cerebrospinal fluid (CSF) biomarkers and PET imaging to detect amyloid pathology and to provide diagnostic and prognostic information in Alzheimer’s disease (AD), but a significant limiting factor thus far has been a lack of widely available immunoassays. We evaluated a novel pTau217 S-PLEX® assay developed by Meso Scale Discovery (MSD; Rockville, MD) in plasma from 131 individuals with AD confirmed by CSF biomarkers and controls. Technical performance of the assay was excellent with an LLOQ of 1.84 pg/mL and intra/interplate CVs of 5.5% (0.3–15.0%) and 5.7% (range 0.3–13.4%), respectively. The pTau217 plasma assay differentiated AD and controls with an AUC of 0.98 (95% CI 0.96–1.0) and pTau217 levels were 3.9-fold higher in individuals with AD. This performance was significantly better than what was observed for plasma pTau181, performed in parallel, and comparable to published data on existing pTau217 assays. While further clinical validation and head-to-head comparisons are needed to fully establish the role for the novel pTau217 S-PLEX assay, these data demonstrate the utility of the assay to detect AD pathology.

Comparison Study of the Bio-Plex and Meso Scale Multiplexed SARS-CoV-2 Serology Assays Reveals Evidence of Diminished Host Antibody Responses to SARS-CoV-2 after Monoclonal Antibody Treatment.

Assessing the breadth and duration of antigen-specific binding antibodies provides valuable information for evaluating interventions to treat or prevent SARS-CoV-2 infection. Multiplex immunoassays are a convenient method for rapid measurement of antibody responses but can sometimes provide discordant results, and antibody positive percent agreement for COVID-19 diagnosis can vary depending on assay type, disease severity, and population sampled. Therefore, we compared two assays marked for research applications, MSD and Bio-Plex Pro, to evaluate qualitative interpretation of serostatus and quantitative detection of antibodies of varying isotypes (IgG, IgM, and IgA) against receptor binding domain (RBD) and nucleocapsid (N) antigens. Specimens from ACTIV-2/A5401, a placebo-controlled clinical trial of the SARSCoV-2 monoclonal antibody (mAb) bamlanivimab to prevent COVID-19 disease progression, were used to evaluate the concordance of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 Serology Assay and the Meso Scale Discovery (MSD) V-PLEX COVID-19 Panel 1 serology assay in detecting and quantifying IgG, IgA, and IgM binding anti-SARS-CoV-2 antibody responses against the RBD and N antigens. Data were disaggregated by study arm, bamlanivimab dose, days post-enrollment, and presence of emerging resistance. We observed 90.5% (412 of 455 tests) concordance for anti-RBD IgG and 87% (396 of 455) concordance for anti-N IgG in classifying samples as negative or positive based on assay-defined cutoffs. Antibody levels converted to the WHO standard BAU/mL were significantly correlated for all isotypes (IgG, IgM, and IgA) and SARS-CoV-2 antigen targets (RBD and N) tested that were common between the two assays (Spearman r 0.65 to 0.92, P < 0.0001). Both assays uncovered evidence of diminished host-derived IgG immune responses in participants treated with bamlanivimab compared to placebo. Assessment of immune responses in the four individuals treated with the 700 mg of bamlanivimab with emerging mAb resistance demonstrated a stronger anti-N IgG response (MSD) at day 28 (median 2.18 log BAU/mL) compared to participants treated with bamlanivimab who did not develop resistance (median 1.55 log BAU/mL). These data demonstrate the utility in using multiplex immunoassays for characterizing the immune responses with and without treatment in a study population and provide evidence that monoclonal antibody treatment in acute COVID-19 may have a modest negative impact on development of host IgG responses.

Statistical Characteristics of Multi‐Scale Auroral Arc Width Based on Machine Learning

AbstractArc width is important for understanding the generation mechanism of auroral arcs. However, the continuity or discreteness of the distribution of small and meso‐large scale auroral arc widths has not been determined in previous studies. This study employs machine learning techniques to investigate the distribution of arc widths across multiple scales using multi‐field‐of‐view (multi‐FOV) auroral observations. Based on the 180°, 47°, and 19° auroral observations at the Antarctic Zhongshan Station from February to October 2012, the statistical results demonstrate that the auroral arc width spectrum is continuously distributed across small, meso, and large scales, suggesting that the mechanisms responsible for their generation are capable of producing arcs at all scales. Furthermore, the arc width distribution at each FOV can be well fitted with a log‐normal function. We also find that the main widths observed at different FOVs depend on the spatial resolution of the instruments. Our work provides new observational evidence for the generation mechanism of auroral arcs.

High deformation and delamination mechanisms explained through mesoscale and nanoscale phenomena in pearlitic steel wires

Pearlitic steel wires subjected to severe cold drawing deformation exhibit a unique combination of high strength and excellent ductility, making them suitable for critical applications such as hanging bridge cables, crane cables and tire cord. Torsion tests up to rupture are commonly used in the industry for quality control purposes. A flat fracture surface is indicative of wire aptitude, while a delaminated surface suggests degradation of mechanical properties. This paper aims to expand the understanding of the structural evolution and deformation mechanisms that occur during wire drawing, as well as the origin of delamination problems. Different deformation and strengthening mechanisms are identified and discussed, applying different microscopy techniques (optical microscopy, scanning electron microscopy, electron backscatter diffraction), synchrotron diffraction and atom probe tomography. The information is correlated with the cementite stability on the structure studied at meso, nano, and atomic scale, reaching an understanding of the compositional evolution of cementite and ferrite even at the very lowest level. All the obtained information, including thermal analysis and thermodynamic simulation results, allow to identify the deformation mechanisms present during cold drawing and at the delamination process. In addition, the compositional evolution of cementite and ferrite is also clarified by atom probe tomography.

Research on optimization of ecosystem service function in mudslide disaster area by landscape ecological engineering technology

Abstract At present, the prevention and control of mudslide disasters are mainly based on geotechnical engineering measures, supplemented by landscape and ecological engineering measures, ignoring the important role of ecological prevention and control engineering in mudslide management. In this paper, the Bailong River Basin is taken as the main research object at the macro scale, supplemented by the municipal districts along the route as the typical mudslide disaster research area at the meso and micro scales. The InVEST model was utilized to evaluate the ecological service functions of each land and pinpoint the sensitive areas that are influencing the evolution of ecological service functions. The quantitative regulation model for landscape ecological integrated planning in the mudslide disaster area was proposed from the perspective of ecological disaster prevention and mitigation through landscape ecological engineering technology. Combined with the successful case of landscape ecological regulation in Region X, it was found that the AWMSI index of the region increased from 56.78 to 79.03 during the regulation period, and the diversity of patches within the landscape was enhanced, which was favorable to species exchange and biodiversity conservation. The mean value of the Habitat Quality Index (HQI) increased from 0.6147 to 0.6579, and the overall level of habitat quality was improved. The annual growth rate of MPI was 0.0002 with a slow growth rate, but the growth rate of MPI increased significantly with the further increase of restoration years. The study's findings can be utilized as a scientific basis for landscape ecological engineering and can also serve as a reference for disaster prevention and ecological restoration in mudflow basins with high activity.

Ocular surface expression of inflammatory cytokines in GvHD and their association with disease development and clinical manifestations

The aim of this study was to investigate the tear cytokine profiles of patients with chronic ocular graft versus host disease (GvHD) and evaluate their association with clinical disease severity. Consecutive patients attending the Haematology clinic with a known or suspected diagnosis of chronic ocular GvHD were invited to participate. To be included, patients had to fulfil either or both of the National Institute of Health (NIH) or the International Chronic Ocular Graft‐vs‐Host‐Disease Consensus Group (ICCGvHD) diagnostic criteria.Clinical parameters recorded included best correct visual acuity (BCVA), Schirmers I test, tear break up time (TBUT), and Oxford surface staining (OSS) along with the overall grading of ocular GvHD severity as defined by the ICCGvHD. Ocular tear samples were collected and levels of cytokine production (IFN‐γ, IL‐1β, IL‐2, Il‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and TNF‐ α) were assayed using Meso Scale Discovery (MSD) multi‐array technology. The results were compared to those of healthy matched controls using unpaired t test. Results were correlated with clinical parameters using Pearson r correlation.Thirteen patients took part in the study (8 male, 61.5%; 5 female, 38.5%) with an average age of 43.9 years (±13.4). With regards to ocular examinations, patients were found to be heavily dependent on lubricant eye drops (average 8.5 times/day). Patients suffered from both aqueous deficient and evaporative DED with an average Schirmer's measurement of 4.2 mm (±5.7, range of 0–21) and average TBUT of 3.8 s (±1.3, range 1–6). The average Oxford surface staining score was 7.9 (±4.2, range of 0–15). According to the ICCGvHD grading system, and using the average data across both eyes, seven of the patients had ‘Mild/Moderate’ disease (53.8%) and the remainder had ‘Severe’ disease (n = 5, 38.5%).The levels of IFN‐γ, IL‐1β, IL‐2, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and TNF‐ α were found to be statistically elevated when compared to healthy age and gender matched controls (FDR p value&lt;0.05). In those with early‐stage disease (n = 5), IFN‐γ was found to strongly correlate with lubricant usage (0.98, p = 0.03), and IL‐2 with the severity of ocular surface staining grade (1.00, p = 0.03), implying that these cytokines in particular may play a role in the development of chronic ocular GvHD and represent promising treatment targets for patients in the initial stages of disease.This study demonstrates that ocular tear cytokines are elevated in patients with chronic ocular GvHD, reiterating the role of inflammation in the pathogenesis of disease. Furthermore, the correlation of IFN‐γ and IL‐2 with clinical parameters of disease severity suggest that these cytokines play a role in early disease development. These findings support the implementation of anti‐inflammatory treatment such as topical calcineurin inhibitors, in conjunction with tear replacement and preservation to avoid irreparable damage to the ocular surface, and this may be best utilized in the initial stages of the disease development.

The Clinical Values of Circulating Tumor Cells and T Lymphocyte Subsets in Predicting a Prognosis of Lung Cancer.

Lung cancer is the most lethal cancer in men and women. Recently, it has been reported that circu-lating tumor cells (CTCs) are sensitive and reliable biomarkers for tracing relapse and metastasis of cancer patients. Many studies also showed that immune cellular dysfunctions in lung cancer patients are major reasons for cancer development. In this study, we explored the clinical significance of CTCs and T lymphocyte subtypes in lung cancer patients. A total of 92 patients with diagnosed lung cancer, including 23 squamous-cell carcinoma and 69 adenocarcinoma, were enrolled in this study. Another 10 patients with non-carcinoma nodules in their lungs were also recruited as a control group. Peripheral blood samples were drawn from the patients with lung cancer and from the control cases before the treatment. The identification of CTCs was carried out by a PatrolCTC detection method. The T lymphocyte subtypes were characterized by flow cytometry (FACS). Cytokines interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-17A (IL-17A), interleukin-10 (IL-10), and interferon  (IFN-) were detected by meso scale discovery (MSD) assay. Out of the enrolled patients, 69 (75%) patients with non-small cell lung cancer (NSCLC) were male and 23 (25 %) were female. Smoking and non-smoking history was 50% (46 cases) each. The case numbers for I - IV tumor-node-metastasis (TNM) stages were 23 (25.0%), 28 (30.4%), 16 (17.4%), and 25 (27.2%), respectively. The positive rates of the CTCs before treatment were 8.7% (2/23), 17.6% (5/28), 81.3% (13/16), and 100% (25/25) in stage I, II, III, and IV patients, respectively. Total CTCs, mixed CTCs, and mesenchymal CTCs (MCTCs) were strongly related to the progression-free survival (PFS) of the patients. In addition, total CTCs (≥ 6) and positive MCTCs also significantly correlated with recurrence and metastasis. The patients with high CTCs also had low levels of CD4, CD4/CD8 ratio, IL-2, and IFN. In contrast, IL-10 in high CTCs patients was significant elevated. These results indicate that the CTC numbers in lung cancer patients are an independent indicator for a worse PFS. Higher total CTCs, mixed CTCs, and MCTCs in peripheral blood were significant biomarkers for predicting the prognosis of lung cancer patients. High CTCs also had a strong correlation with weak cellular immunity functions.

Analysis of SARS-CoV-2 antibody seroprevalence in Northern Ireland during 2020–2021

BackgroundWith the spread of SARS-CoV-2 impacting upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread during the pandemic. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strategy. MethodsSera/plasma samples from clinical biochemistry laboratories were analysed for anti-SARS-CoV-2 antibodies. Samples were assessed using an Elecsys anti-SARS-CoV-2 or anti-SARS-CoV-2 S ECLIA (Roche) on an automated cobas e 801 analyser. Samples were also assessed via an anti-SARS-CoV-2 ELISA (Euroimmun). A subset of samples assessed via the Elecsys anti-SARS-CoV-2 ECLIA were subsequently analysed in an ACE2 pseudoneutralisation assay using a V-PLEX SARS-CoV-2 Panel 7 for IgG and ACE2 (Meso Scale Diagnostics). ResultsAcross three testing rounds (June–July 2020, November–December 2020 and June–July 2021 (rounds 1–3 respectively)), 4844 residual sera/plasma specimens were assayed for anti-SARS-CoV-2 antibodies. Seropositivity rates increased across the study, peaking at 11.6 % (95 % CI 10.4 %–13.0 %) during round 3. Varying trends in SARS-CoV-2 seropositivity were noted based on demographic factors. For instance, highest rates of seropositivity shifted from older to younger demographics across the study period. In round 3, Alpha (B.1.1.7) variant neutralising antibodies were most frequently detected across age groups, with median concentration of anti-spike protein antibodies elevated in 50–69 year olds and anti-S1 RBD antibodies elevated in 70+ year olds, relative to other age groups. ConclusionsWith seropositivity rates of <15 % across the assessment period, it can be concluded that the significant proportion of the Northern Ireland population had not yet naturally contracted the virus by mid-2021.

Diagnosing Alzheimer's disease: Which dementia screening test to use in elderly Puerto Ricans with mild cognitive impairment and early Alzheimer's disease?

Typically, Alzheimer's disease (AD) diagnosis is not made at its earliest period, for instance, at mild cognitive impairment (MCI) and early AD (E-AD). Our study aims to demonstrate a correlation between the screening tools, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR), and the biological biomarkers in the cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ42), phosphorylated tau (p-tau) proteins and total tau (t-tau)/Aβ42 ratio in Puerto Ricans>55 years old with MCI and E-AD. We evaluated 30 participants, including demographics, memory scales, and CSF biomarkers. Twenty-eight CSF biomarkers (Aβ42, p-tau protein, and t-tau/Aβ42 ratio) were analyzed using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MoCA, MMSE, CDR) and CSF markers were performed using Spearman rho correlation. Our study revealed a statistical association favoring a direct relationship between MMSE and MoCA with t-tau/Aβ42 ratio in CSF (P=0.022, P=0.035, respectively). We found a trend toward significance with an inverse relationship with MMSE and Aβ42 (P=0.069) and a direct relationship with MMSE and p-tau (P=0.098). MMSE and MoCA screening tests were identified with a statistically significant association with the CSF biomarkers, specifically t-tau/Aβ42 ratio, in elderly Puerto Ricans with MCI and E-AD. Puerto Ricans>55 years old with MCI and E-AD could be screened confidently with MMSE and MoCA for a higher likelihood of earlier detection and, thus, initiation of disease-modifying treatment and prompt non-pharmacological interventions.

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV.

HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). β-amyloid (Aβ) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aβ42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV- controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aβ42 (p = 0.0003) compared with HIV- controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aβ42 was decreased (p = 0.0002) and CSF EV Tau/Aβ42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aβ42 (p < 0.0001) and an increased CSF EV Tau/Aβ42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aβ42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aβ42 and an increased Tau/Aβ42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies.

Crack propagation and non-uniform deformation analysis in hydraulic asphalt concrete: Insights from X-ray CT scanning and digital volume correlation

This study investigates the crack propagation and internal non-uniform deformation field of hydraulic asphalt concrete (HAC) under triaxial compression. Utilizing in situ triaxial compression tests at temperatures of 5 °C and 20 °C, the investigation incorporated X-ray computed tomography (CT) scanning to observe internal changes. Through digital volume correlation (DVC), the deformation field within HAC was analyzed in detail. Results indicated that the crack fraction of longitudinal sections at 20 °C was smaller across various deformation stages than that at 5 °C. The displacement and strain fields within the material displayed increased heterogeneity with increasing deformation. It was observed that the probability density distributions of both equivalent and volumetric strains conformed to a normal distribution at different deformation stages. By analyzing the crack propagation and the internal non-uniform deformation field, the progressive failure process of HAC with sub-voxel accuracy at 5 °C and 20 °C was clarified. This research confirmed the presence of both shear deformation failure and volumetric deformation characteristics, which undergo a transition from shear shrinkage to shear expansion at the meso scale.

Origami Metamaterials Enable Low-Stress-Driven Giant Elastocaloric Effect.

Elastocaloric materials, capable of achieving reversible thermal changes in response to a uniaxial stress, have attracted considerable attention for applications in advanced thermal management technologies, owing to their environmental friendliness and economic benefits. However, most elastocaloric materials operating on the basis of first/second-order phase transition often exhibit a limited caloric response, field hysteresis, and restricted working temperature ranges. This study resorts to origami engineering for realizing multifunctional metamaterials with exceptional elastocaloric effects at both nano (exemplified by computational simulations for graphene) and meso (demonstrated by experimentation on thermoplastic polyurethane elastomers) scales. The findings uncover that the graphene origami exhibits low-stress-driven reversible and giant elastocaloric effects without a hysteresis loss and with a high elastocaloric strength. These effects are achieved across a wide working temperature range (100-600 K) and are tailorable by fine-tuning the topological parameters and configurational status of the origami metamaterials. We demonstrate the scalability of the origami design strategy for magnifying the elastocaloric effect by the 3D printing of a mesoscale origami-inspired thermoplastic polyurethane metastructure that showcases enhanced elastocaloric performance at room temperature. This study presents the potential for the realization of architected elastocaloric materials through surface functionalization and origami engineering. The findings impart exciting prospects of elastocaloric origami metamaterials as the next generation of multiscale and sustainable thermal management technologies.

Multi-{Physics, Phase, Scale} Computational Modeling of Interface-Coupled Problems in Redox Flow Battery Design

Motivated by an urgent need to deploy large-scale energy storage technologies to integrate intermittent renewables, redox flow batteries (RFBs) are gaining prominent attention due to their interesting features including higher durability and power-energy decoupling. RFBs are rechargeable electrochemical systems in which an electrolyte solution containing dissolved or suspended active species is stored in external tanks and pumped through the electrochemical stack - consisting of flow fields, porous electrodes, and membranes - where the active species undergo electrochemical reactions to charge/discharge the battery. However, large-scale deployment of RFBs has feasibility issues regarding costs and efficiency, which can be tackled by tuning their multi-scale design parameters [1].Developing a coupled multi-scale computational model for RFBs can facilitate our understanding of the interplay between intricate phenomena occurring at several length and time scales (depicted schematically in the figure), ranging from transport phenomena, i.e., mass, charge, momentum, and heat, on the cell level (macro and meso scales) to microstructure effects and wettability behavior on the pore-scale (micro and nano scales). Furthermore, the modeling framework should capture the reaction kinetics and multi-phase chemistry of emerging flow battery concepts (e.g. metal-air) including plating and stripping reactions [2].In this research, we are developing a multi-{physics, phase, scale} model for the optimization of next-generation RFBs in the cell-, electrode-, and pore-scale. The model includes free fluid flow (representing flow field channels) over a porous medium (porous electrode) and solves the transport mechanisms over the entire computational domain with a focus on the electrolyte-electrode interface. The model is developed using finite element/volume methods combined with pore network modeling techniques, implemented using various open-source modeling frameworks including OpenFOAM [3], FEniCS [4], and OpenPNM [5].In this presentation, I will first discuss the structure of the modeling framework including the continuum transport models, the pore network model, and the employed numerical schemes. Then, I will present the coupling between continuum and porous medium models. Finally, I will highlight some initial results focused on the efficiency of the coupling of the electrolyte fluid transport with the porous medium and pore network representation of the electrode [6]. We hope that the developed model can be a functional tool to assess and optimize RFB materials and operating conditions and can be broadly adopted to model emerging flow battery chemistries. References K. Chakrabarti et al., Sustainable Energy & Fuels. 4, 5433–5468 (2020).Hein et al., ACS Applied Energy Materials. 3, 8519–8531 (2020).G. Weller et al., Computers in Physics. 12, 620 (1998).Alnæs et al., Archive of Numerical Software, in press, doi:10.11588/ANS.2015.100.20553.Gostick et al., Computing in Science & Engineering. 18, 60–74 (2016).van der Heijden et al., Journal of The Electrochemical Society. 169, 040505 (2022). Figure 1

AGE-FRIENDLY COMMUNITIES IN THE ANDES: CONSIDERATIONS TO IMPROVE UPTAKE

Abstract Despite the demographic aging of the Global South, the uptake of WHO’s age-friendly cities framework remains extremely low. The Andean region of Latin America is currently represented by only four cities, out of more than 1,400 globally. Causes may include the partial inadequacy of the eight WHO domains for communities in the Andean region. We argue for a broader human ecological framework to address the macro, meso and micro levels to better address the context, challenges and opportunities for age-friendly cities in the Andean region. WHO’s age-friendly city domains are focused primarily at the meso (community) scale – on built environment, services and participation. We call for more attention to the macro policy scale, in societies where robust social security systems cannot be assumed. We also call for more attention to the micro scale, to recognize the critical role of family and informal care supports. We question whether the WHO domains are the result of a design bias, with Global North settings in mind for its development. We find the domains of UNICEF’s child-friendly cities initiative, which give more attention to the realities of the Global South, helpful to broaden WHO’s age friendly framework.

Modelling Radiative Coolers for the Built Environment in the Urban Context

AbstractRadiative Coolers (RCs) represent an emerging technology that has the potential to significantly reduce urban heat and improve indoor/outdoor thermal comfort in the built environment. Broadband and Selective Radiative Coolers (BRCs and SRCs, respectively) are the two main types of RCs that have been proposed for application in the built environment. Being both typically characterized by high solar reflectance, the former emits thermal radiation within the overall infrared spectrum, whilst the latter emits thermal radiation mainly within the Atmospheric Window (AW) waverange. A variety of both types of RCs have been developed and tested in both in‐lab and in‐field experimental campaigns. Yet, all experiments comprise small scale specimens that do not represent real‐life scale components of the built environment. In addition, no meso scale assessments have been performed with respect to the RCs' performance at a city scale. Here, for the first time, the thermo‐optical performance of both BRCs and SRCs is introduced and investigated in a multilayer Urban Canopy Model (UCM) coupled with extended Weather Research and Forecasting model (WRF) and we simulated 20 different scenarios representing the vast majority of urban layouts. The outcomes show that both types of RCs maintain lower surface temperature and air temperature at 2 m height inside the canyon, compared to conventional roofs. In addition, a city scale application of RCs has been found capable of decreasing ambient temperature up to 1.6°C as potentially experienced by pedestrians.

A novel fluid biomarker for TDP‐43 loss of function

AbstractBackgroundTDP‐43 nuclear clearance and cytoplasmic aggregation occur in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD), Alzheimer’s disease (AD), and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Nuclear clearance of TDP‐43 leads to its failure to repress splicing of nonconserved cryptic exons. This loss of TDP‐43 splicing repression is well‐documented in postmortem tissues, but there is currently no method of detecting TDP‐43 dysfunction in living patients. As some cryptic exons are spliced in‐frame and translated into proteins carrying novel epitopes, we hypothesize that these “cryptic peptides” may be found in patient CSF as biomarkers of TDP‐43 dysfunction.MethodWe generated novel monoclonal antibodies against several TDP‐43 cryptic exon targets and then developed a sandwich ELISA using the Meso Scale Discovery (MSD) platform, which we validated in cells deficient in TDP‐43 for the cryptic exon target in HDGFL2. We then screened CSF samples of C9ORF72‐mutation carriers with or at risk of ALS‐FTD and control individuals for the presence of this cryptic peptide.ResultThe MSD signal for cryptic HDGFL2 was elevated in CSF of C9ORF72‐mutation carriers with ALS (n = 5, mean = 1601) compared to those of controls (n = 5, mean = ‐64.10; p&lt;0.013), so we examined a larger cohort of C9ORF72‐mutation carriers. In symptomatic individuals (n = 27), cryptic peptide levels showed a correlation nearing significance with symptom duration (r = ‐0.368, p = 0.059), suggesting that levels of the cryptic peptide tend to be higher during the earlier symptomatic phase. We also found elevated cryptic peptide levels in CSF of several pre‐symptomatic individuals. To clarify cryptic peptide dynamics during disease progression, we began to assess longitudinal CSF samples and found that in 82.35% (14/17) of symptomatic individuals, levels of the cryptic peptide decreased with disease progression.ConclusionOur findings indicate that loss of TDP‐43 splicing repression occurs early in disease progression in ALS‐FTD, even pre‐symptomatically, and that detection of HDGFL2’s cryptic neoepitope may facilitate earlier diagnosis of TDP‐43‐related diseases. Further efforts linking the presence of cryptic HGDFL2 to TDP‐43 co‐pathology in AD may help expand biomarker development in AD. Additionally, evaluating dynamics of these biomarkers could provide a way of measuring target engagement for new therapeutics aimed at restoring TDP‐43 function.

TNFα‐mediated inflammation in mouse models of VCID

AbstractBackgroundTumor necrosis factor alpha (TNFα) is a prominent pleiotropic cytokine with dichotomous effects. Primarily produced in the brain by glial cells, TNFα interacts with two subtypes of TNF receptors (TNFRs) that dictate the cellular response, be that pro‐ or anti‐inflammator. The diverse cellular responses include cell survival, cell death, proliferation, and angiogenesis. Due to the critical role inflammation plays in the pathogenesis of Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID), understanding the specific roles of pleiotropic cytokines like TNFa in dementia‐causing diseases will provide mechanistic and therapeutic insights. Both inhibition of soluble TNFα (sTNFα) and deletion of pro‐inflammatory TNF receptor 1 (TNFR1) have been shown to decrease severity of amyloid deposition in AD models. However, similar studies have not been conducted regarding VCID outcomes.MethodThis study sought to examine gene and protein expression of TNFα and the two receptors, TNFR1 and TNFR2, within two mouse models of VCID; the hyperhomocysteinemia (HHcy)‐induced VCID co‐morbid with amyloid deposition and aged Tg2576 with severe cerebral amyloid angiopathy (CAA)‐associated VCID. Measures were taken via qPCR for mRNA assessment and Meso Scale Discovery assays (MSD) for protein quantification.ResultIn HHcy‐induced VCID, TNFα mRNA levels were significantly increased regardless of the presence of amyloid deposition. Similarly, protein levels of TNFα trended higher in HHcy groups compared to their controls regardless of amyloid presence. Levels of TNFR1 mRNA trended lower in the HHcy model but was significantly increased in HHcy‐amyloid co‐morbid mice. When investigated in aged Tg2576 mice with CAA, TNFR1 protein expression increased at older timepoints compared to younger, and against wild type controls. Anti‐inflammatory and innate immune‐associated TNFR2 was increased at 20 months in CAA mice when compared to age‐matched controls.ConclusionThese findings display differences in gene and protein expression of TNFa and its receptors in two models of VCID. The unique expression in these models merits further research into the differences in TNF‐mediated inflammation in VCID. Further research is also necessary to determine potential therapeutic advantages of drugs such as TNFα inhibitors in cases of VCID with and without amyloid deposition.

Effects of biomarker timing on preclinical cognitive trajectories and tau PET accumulation

AbstractBackgroundThe timing of AD biomarker positivity may be important for defining optimal anti‐amyloid therapy windows for secondary prevention. This work characterizes the AD biological cascade and investigates biomarker onset timing and associations of timing with preclinical cognitive decline and tau PET accumulation using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodWRAP participants (N = 172; mean(SD) age at last plasma = 69.4(6.6) years; 159 unimpaired, 9 MCI, 3 dementia, 1 impaired non‐AD) with available plasma pTau217, amyloid PET, and longitudinal cognitive assessments were included. Plasma pTau217 was quantified using an immunoassay on the Meso Scale Discovery platform (Lilly Research Laboratories). Amyloid burden was quantified using cortical 11C‐PiB DVR (cerebellum GM reference region). Positivity thresholds were defined using group‐based trajectory modeling applied to participants with longitudinal (≥2) biomarker observations (Ptau217, n = 162; PiB, n = 155). Sampled iterative local approximation (SILA) was used to model longitudinal PiB and pTau217 trajectories and estimate biomarker onset ages. Biomarker timing groups were defined as: PiB(‐)/pTau217(‐); coincident (PiB(+) and pTau217(+) onsets within 2 years of each other); PiB(+) first; or pTau217(+) first. We used a linear mixed effects model (random intercept and age‐related slope; unstructured covariance) to investigate the impact of biomarker timing group on cognitive decline measured by a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). In a subset with tau PET (n = 120), we assessed regional tau burden (18F‐MK‐6240 SUVRs; 70‐90min, inferior cerebellar GM reference region) relative to plasma pTau217(+) and PiB(+) timing.ResultIn the PiB(+)/pTau217(+) subset (n = 60; 35%), PiB(+) onset generally preceded pTau217(+), but with considerable heterogeneity in this timing (Figure 1A‐H). Older age at PiB(+) onset was associated with shorter time to pTau217(+) onset (Figure 1G‐H). In PACC‐3 analyses, post‐hoc analyses of the significant biomarker timing group*age interaction showed fastest decline in the pTau217(+) first group (Figure 2). Both PiB(+) and pTau217(+) durations predicted MK‐6240 accumulation; ∆AICc indicated better fit with pTau217(+) time (Figure 3).ConclusionIn this mostly preclinical sample, the timing of PiB(+) and plasma pTau217(+) were differentially associated with cognitive decline and tau PET accumulation. These preliminary findings suggest secondary AD prevention with anti‐amyloid therapy may be most beneficial before pTau217 onset.

Relationship between norepinephrine metabolism and plasma markers of tau pathology

AbstractBackgroundThe brainstem locus coeruleus (LC) constitutes the primary source of norepinephrine (NE) in the central nervous system and has been reported as one of the earliest accumulation sites of hyperphosphorylated tau protein in Alzheimer’s disease (AD). Autopsy and animal studies suggested that this aggregation of hyperphosphorylated tau in the LC is associated with hyperactivity in LC neurons and elevated concentrations of NE metabolites. Here, we investigated whether elevated concentrations of 3‐methoxy‐4‐hydrophenylglycol (MHPG), a NE metabolite measured in the plasma, is associated with plasma phosphorylated tau, a biomarker of AD pathology.MethodNinety‐eight cognitively unimpaired participants (age = 59.82 ± 13.13 [30‐84] y, 52 females, Table 1) underwent a blood draw. Plasma MHPG concentrations were measured and adjusted for NE. Levels of total tau, phosphorylated tau at threonine 181 (pTau181) and threonine 231 (pTau231) were quantified by single molecule array (Simoa), while phosphorylated tau at threonine 217 (pTau217) was quantified by the Meso Scale Discovery (MSD) platform. Multiple linear regression models tested for the relationship between MHPG concentrations and plasma levels of tau‐related measures, while controlling for age and sex.ResultPTau231 and MHPG concentrations were positively correlated (t = 2.26, p = .03, Figure 1). No significant relationships were found between MHPG and other phosphorylated tau biomarkers (all p &gt; .23), but we observed a trend for a positive association with plasma total tau levels (t = 1.88, p = .06).ConclusionConsistent with previous CSF studies as well as animal studies, we found that elevated NE metabolism co‐occurs with the earliest events in the phosphorylation cascade of tau proteins, suggesting an important role of a dysregulated NE system early in the AD pathophysiologic cascade. Future work will need to determine the evolution of theses associations as the disease progresses, potential effect modifications by beta‐amyloid and the downstream effects of these processes on cognition and behavior.

Effects of biomarker timing on preclinical cognitive trajectories and tau PET accumulation

AbstractBackgroundThe timing of AD biomarker positivity may be important for defining optimal anti‐amyloid therapy windows for secondary prevention. This work characterizes the AD biological cascade and investigates biomarker onset timing and associations of timing with preclinical cognitive decline and tau PET accumulation using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodWRAP participants (N = 172; mean(SD) age at last plasma = 69.4(6.6) years; 159 unimpaired, 9 MCI, 3 dementia, 1 impaired non‐AD) with available plasma pTau217, amyloid PET, and longitudinal cognitive assessments were included. Plasma pTau217 was quantified using an immunoassay on the Meso Scale Discovery platform (Lilly Research Laboratories). Amyloid burden was quantified using cortical 11C‐PiB DVR (cerebellum GM reference region). Positivity thresholds were defined using group‐based trajectory modeling applied to participants with longitudinal (≥2) biomarker observations (Ptau217, n = 162; PiB, n = 155). Sampled iterative local approximation (SILA) was used to model longitudinal PiB and pTau217 trajectories and estimate biomarker onset ages. Biomarker timing groups were defined as: PiB(‐)/pTau217(‐); coincident (PiB(+) and pTau217(+) onsets within 2 years of each other); PiB(+) first; or pTau217(+) first. We used a linear mixed effects model (random intercept and age‐related slope; unstructured covariance) to investigate the impact of biomarker timing group on cognitive decline measured by a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). In a subset with tau PET (n = 120), we assessed regional tau burden (18F‐MK‐6240 SUVRs; 70‐90min, inferior cerebellar GM reference region) relative to plasma pTau217(+) and PiB(+) timing.ResultIn the PiB(+)/pTau217(+) subset (n = 60; 35%), PiB(+) onset generally preceded pTau217(+), but with considerable heterogeneity in this timing (Figure 1A‐H). Older age at PiB(+) onset was associated with shorter time to pTau217(+) onset (Figure 1G‐H). In PACC‐3 analyses, post‐hoc analyses of the significant biomarker timing group*age interaction showed fastest decline in the pTau217(+) first group (Figure 2). Both PiB(+) and pTau217(+) durations predicted MK‐6240 accumulation; ∆AICc indicated better fit with pTau217(+) time (Figure 3).ConclusionIn this mostly preclinical sample, the timing of PiB(+) and plasma pTau217(+) were differentially associated with cognitive decline and tau PET accumulation. These preliminary findings suggest secondary AD prevention with anti‐amyloid therapy may be most beneficial before pTau217 onset.