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Two randomized, open-label, noninferiority phase 3 trials compared the prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with incident or prevalent chronic kidney disease who were undergoing dialysis. Vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting millions worldwide. The clinical presentation of AD is heterogenous and often complicated by the presence of multiple co-pathologies, which can overlap with features of other neurodegenerative disorders, underscoring the need for tools to aid accurate and timely diagnosis. Biomarkers for AD span multiple modalities and are being increasingly used in clinical settings to aid diagnosis, monitor disease progression, and assess eligibility and response to disease-modifying therapies. Here, we provide an overview of current clinical applications of fluid, imaging, and digital biomarkers for AD. We also discuss biomarkers under development and challenges associated with the implementation of these modalities in clinical settings.

Objectives Conestat alfa, a recombinant human C1 esterase inhibitor, is a multi-target inhibitor of inflammatory cascades including the complement, the kinin-kallikrein and the contact activation system. The study objective is to investigate the efficacy and safety of conestat alfa in improving disease severity and short-term outcome in COVID-19 patients with pulmonary disease. Trial design This study is an investigator-initiated, randomized (2:1 ratio), open-label, parallel-group, controlled, multi-center, phase 2a clinical trial. Participants This trial is conducted in 3 hospitals in Switzerland, 1 hospital in Brazil and 1 hospital in Mexico (academic and non-academic). All patients with confirmed SARS-CoV-2 infection requiring hospitalization for at least 3 calendar days for severe COVID-19 will be screened for study eligibility. Inclusion criteria: - Signed informed consent - Age 18-85 years - Evidence of pulmonary involvement on CT scan or X-ray of the chest - Duration of symptoms associated with COVID-19 ≤ 10 days - At least one of the following risk factors for progression to mechanical ventilation on the day of enrolment: 1) Arterial hypertension 2) ≥ 50 years 3) Obesity (BMI ≥ 30 kg/m2) 4) History of cardiovascular disease 5) Chronic pulmonary disease 6) Chronic renal disease 7) C-reactive protein > 35mg/L 8) Oxygen saturation at rest of ≤ 94% when breathing ambient air Exclusion criteria: - Incapacity or inability to provide informed consent - Contraindications to the class of drugs under investigation (C1 esterase inhibitor) - Treatment with tocilizumab or another IL-6R or IL-6 inhibitor before enrolment - History or suspicion of allergy to rabbits - Pregnancy or breast feeding - Active or anticipated treatment with any other complement inhibitor - Liver cirrhosis (any Child-Pugh score) - Admission to an ICU on the day or anticipated within the next 24 hours of enrolment - Invasive or non-invasive ventilation - Participation in another study with any investigational drug within the 30 days prior to enrolment - Enrolment of the study investigators, their family members, employees and other closely related or dependent persons Intervention and comparator Patients randomized to the experimental arm will receive conestat alfa in addition to standard of care (SOC). Conestat alfa (8400 U followed by 4200 U every 8 hours) will be administered as a slow intravenous injection (5-10 minutes) over a 72-hour period (i.e. 9 administrations in total). The first conestat alfa treatment will be administered on the day of enrolment. The control group will receive SOC only. SOC treatment will be administered according to local institutional guidelines, including supplemental oxygen, antibiotics, corticosteroids, remdesivir, and anticoagulation. Main outcomes The primary endpoint of this trial is disease severity on day 7 after enrolment assessed by an adapted WHO Ordinal Scale for Clinical Improvement (score 0 will be omitted and score 6 and 7 will be combined) from 1 (no limitation of activities) to 7 (death). Secondary outcomes include (i) the time to clinical improvement (time from randomization to an improvement of two points on the WHO ordinal scale or discharge from hospital) within 14 days after enrolment, (ii) the proportion of participants alive and not having required invasive or non-invasive ventilation at 14 days after enrolment and (iii) the proportion of subjects without an acute lung injury (defined by PaO 2 /FiO 2 ratio of ≤300mmHg) within 14 days after enrolment. Exploratory outcomes include virological clearance, C1 esterase inhibitor pharmacokinetics and changes in routine laboratory parameters and inflammatory proteins. Randomisation Subjects will be randomised in a 2:1 ratio to treatment with conestat alfa in addition to SOC or SOC only. Randomization is performed via an interactive web response system (SecuTrial®). Blinding (masking) In this open-label trial, participants, caregivers and outcome assessors are not blinded to group assignment. Numbers to be randomised (sample size) We will randomise approximately 120 individuals (80 in the active treatment arm, 40 in the SOC group). Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels α p = 0.0221. The results of the interim analysis will allow adjustment of the sample size (Lehmacher, Wassmer, 1999). Trial Status PROTECT-COVID-19 protocol version 3.0 (July 07 2020). Participant recruitment started on July 30 2020 in one center (Basel, Switzerland, first participant included on August 06 2020). In four of five study centers patients are actively recruited. Participation of the fifth study center (Mexico) is anticipated by mid December 2020. Completion of trial recruitment depends on the development of the SARS-CoV-2 pandemic. Trial registration Clinicaltrials.gov, number: NCT04414631 , registered on 4 June 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively. The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms ( = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms ( = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug. The study results do not support the use of ConA to prevent COVID-19 progression. https://clinicaltrials.gov, identifier NCT04414631.

Despite extensive research, open questions about the biological underpinnings of Alzheimer’s disease (AD) remain. Neuroimaging biomarkers based on positron emission tomography (PET) and magnetic resonance imaging (MRI) offer in vivo insights into these complex biological changes and interactions. However, most evidence to date comes from cross-sectional studies, limiting our understanding of disease progression. Longitudinal studies enable the investigation of biological changes within individuals, revealing how pathology evolves over time. With this review, we provide an overview of how longitudinal imaging biomarker studies have advanced the field and how they can contribute to future research. We highlight longitudinal biomarker studies that have provided critical insights into disease trajectories, staging, and individual variability. We further assess longitudinal multimodal studies which have elucidated interactions between AD-specific pathology, amyloid-β and tau, and broader biological changes like neurodegeneration, neuronal dysfunction, vascular disease, and inflammation. Further, we discuss associations of brain changes with symptomatology and clinical outcomes and conclude with challenges and future directions.

There is an unmet medical need for effective treatments for hospitalized patients with coronavirus disease 2019 (COVID‐19). Ribavirin is a broad‐spectrum antiviral with demonstrated in vitro activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). This trial evaluated the potential of ribavirin inhalation solution (ribavirin aerosol) to reduce COVID‐19 disease severity in adults with confirmed SARS‐CoV‐2 infection and a diagnosis of respiratory distress. This phase I, multicenter, open‐label, nonrandomized trial was conducted from February 2021 through August 2021. Patients received ribavirin aerosol (100 mg/ml for 30 min or 50 mg/ml for 60 min) twice daily for up to 6 days. The primary end point was change from baseline in clinical status severity, rated on a 7‐point scale (1 [death]; 7 [not hospitalized; no limitations on activities]), at day 7 (or end‐of‐treatment/early termination) and day 30 (follow‐up). Fifty‐one patients were treated with ribavirin aerosol (mean age, 51.5 years; 78.4% men); mean number of doses was 9.7 (range, 1–12). Improvement of ≥1 level in clinical status severity was observed in 31.4% (16/51) and 78.4% (40/51) of patients at end‐of‐treatment and day 30, respectively. Of 21 patients who required a ventilator, 16 (76.2%) were able to discontinue ventilator use. Five patients (9.8%) died between end‐of‐treatment and day 30. Three patients (5.9%) discontinued study treatment due to adverse events. No deaths were considered related to study treatment. These data provide preliminary evidence that ribavirin aerosol may be an efficacious treatment for respiratory distress in adults with COVID‐19.

Background Depressive symptoms are common in older adults and have been associated with both the risk for and symptoms of dementia. We examined the association between Alzheimer’s Disease and Related Dementias (ADRD) biomarkers and depressive symptoms in a large community‐based sample, taking into account cognition and a range of other participant characteristics, including BMI and kidney function which are known to influence biomarker levels. As depressive symptoms differ by gender and APOE4 carrier status, we also examined whether these factors modified the associations. Method This cross‐sectional study included 11,947 non‐demented adults aged≥65 years at enrollment in ASPREE. Depressive symptoms were measured using the CESD‐10. ADRD blood‐based biomarkers (BBMs) included the Aβ42/40 ratio, ptau181, NfL, and GFAP measured on the Simoa platform. Linear regressions were used to examine associations between ADRD BBMs and depressive symptoms. Interactions between gender or APOE4 carrier status and BBMs were examined. Result In unadjusted models, lower ptau181, and higher NfL or GFAP were associated with higher depressive symptoms. In multivariable models adjusting for participant characteristics, health conditions and behaviors, and cognition (see table), higher NfL and GFAP remained significantly associated with depressive symptoms. After additionally adjusting for antidepressant use and history of depression, only GFAP remained significantly associated with depressive symptoms. We did not observe significant interactions between any BBMs with gender or APOE4 carrier status. Conclusion In this large, community‐based cohort of older adults, we demonstrate an association between higher plasma GFAP and greater depressive symptoms. Future research will longitudinally assess the relationship between ADRD BBMs and depressive trajectories and symptoms.

Depressive symptoms are common in older adults and have been associated with both the risk for and symptoms of dementia. We examined the association between Alzheimer's Disease and Related Dementias (ADRD) biomarkers and depressive symptoms in a large community-based sample, taking into account cognition and a range of other participant characteristics, including BMI and kidney function which are known to influence biomarker levels. As depressive symptoms differ by gender and APOE4 carrier status, we also examined whether these factors modified the associations. This cross-sectional study included 11,947 non-demented adults aged≥65 years at enrollment in ASPREE. Depressive symptoms were measured using the CESD-10. ADRD blood-based biomarkers (BBMs) included the Aβ42/40 ratio, ptau181, NfL, and GFAP measured on the Simoa platform. Linear regressions were used to examine associations between ADRD BBMs and depressive symptoms. Interactions between gender or APOE4 carrier status and BBMs were examined. In unadjusted models, lower ptau181, and higher NfL or GFAP were associated with higher depressive symptoms. In multivariable models adjusting for participant characteristics, health conditions and behaviors, and cognition (see table), higher NfL and GFAP remained significantly associated with depressive symptoms. After additionally adjusting for antidepressant use and history of depression, only GFAP remained significantly associated with depressive symptoms. We did not observe significant interactions between any BBMs with gender or APOE4 carrier status. In this large, community-based cohort of older adults, we demonstrate an association between higher plasma GFAP and greater depressive symptoms. Future research will longitudinally assess the relationship between ADRD BBMs and depressive trajectories and symptoms.

INTRODUCTION Depressive symptoms are common in older adults and have been associated with the risk of Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), but the mechanisms and biomarkers underlying this association remain unclear. METHODS We included baseline data from 11,947 non‐demented adults aged ≥ 70 years at enrollment in the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial. Linear regressions were used to examine cross‐sectional associations between AD/ADRD blood‐based biomarkers (BBMs) and baseline depressive symptoms. Interactions between sex or apolipoprotein E (APOE) ε4 carrier status and BBMs were examined. RESULTS Higher glial fibrillary acidic protein (GFAP) was associated with higher depressive symptoms. We did not observe an association between amyloid beta 42/40 ratio, phosphorylated tau181, or neurofilament light chain with depressive symptoms; interactions between sex or APOE ε4 with depressive symptoms were not significant. DISCUSSION In this large, community‐based cohort of older adults, plasma GFAP was associated with greater depressive symptoms. Highlights Plasma glial fibrillary acidic protein was associated with depressive symptoms. Neuroinflammation may underlie depressive symptoms in this group. Future research is needed to examine sex differences in this association.

Neuropsychiatric symptoms (NPS) in the Alzheimer's Disease (AD) clinical spectrum are common, yet the pathological underpinnings are unclear. Prior research has been inconsistent, attributed in part to concomitant co-pathologies. Additionally, prior modeling approaches have disregarded the distributional properties of right-skewed NPS data and utilized predominantly racially homogenous cohorts. Thus, we examined the relationship between NPS and markers of vascular injury and neurodegeneration using generalized linear models (GLM) in a diverse community-based sample. Of additional interest was whether these relationships differed by cognitive status or race. We evaluated cross-sectional relationships of brain white matter hyperintensity volume (WMHv) and plasma neurofilament light chain (pNfL) to NPS (NPI-Q total severity scores) in 588 Wake Forest ADRC Clinical Core study participants. Analyses included participants with consensus diagnoses of cognitively unimpaired (CU; N = 348) and mild cognitive impairment (MCI; N = 240). WMHv and pNfL were log-transformed prior to model entry. GLMs included age, sex, education, race, and cognitive status as covariates and pathologies as predictor variables. Secondary models included aforementioned covariates and pathology by (a) cognitive status and (b) race interaction terms to investigate how these associations differed. WMHv was not significantly associated with NPS (N = 561; β = 0.203; p = 0.053); further, we did not observe an interaction between cognitive status and WMHv (N = 561; β = -0.055; p = 0.800). However, a significant race by WMHv interaction on NPI-Q was demonstrated (N = 561; β = -0.414; p = 0.016). In White participants, elevated WMHv was significantly related to elevated NPS (N = 434; β = 0.325; p = 0.006); whereas in Black/African American participants elevated WMHv was significantly related to lower NPS (N = 119; β = -0.239; p = 0.049). pNfL was not significantly associated with NPS (N = 506; β = 0.149; p = 0.576). A significant pNfL by cognitive status interaction on NPI-Q was found (N = 506; β = -1.055; p = 0.029; Figure 2), where elevated pNfL was related to elevated NPS in MCI participants (N = 198; β = 1.656; p = 0.004) but not CU participants (N = 308; β = -0.316; p = 0.260). However, we did not observe an interaction between race and pNfL (N = 506; β = 0.185; p = 0.678). Consistent with previous work we demonstrate associations of pNfL and WMHv with NPS. Future analyses with this cohort will examine additional biomarkers, including amyloid-beta and tau measured in CSF, plasma, and PET.