Disease Clinical Trials Research Articles

A Recombinant Vesicular Stomatitis Virus-Based Vaccine Provides Postexposure Protection Against Bundibugyo Ebolavirus Infection.

The filovirus Bundibugyo virus (BDBV) causes severe disease with a mortality rate of approximately 20%-51%. The only licensed filovirus vaccine in the United States, Ervebo, consists of a recombinant vesicular stomatitis virus (rVSV) vector that expresses Ebola virus (EBOV) glycoprotein (GP). Ervebo was shown to rapidly protect against fatal Ebola disease in clinical trials; however, the vaccine is only indicated against EBOV. Recent outbreaks of other filoviruses underscore the need for additional vaccine candidates, particularly for BDBV infections. To examine whether the rVSV vaccine candidate rVSVΔG/BDBV-GP could provide therapeutic protection against BDBV, we inoculated seven cynomolgus macaques with 1000 plaque-forming units of BDBV, administering rVSVΔG/BDBV-GP vaccine to 6 of them 20-23 minutes after infection. Five of the treated animals survived infection (83%) compared to an expected natural survival rate of 21% in this macaque model. All treated animals showed an early circulating immune response, while the untreated animal did not. Surviving animals showed evidence of both GP-specific IgM and IgG production, while animals that succumbed did not produce significant IgG. This small, proof-of-concept study demonstrated early treatment with rVSVΔG/BDBV-GP provides a survival benefit in this nonhuman primate model of BDBV infection, perhaps through earlier initiation of adaptive immunity.

HPR39 A Time-to-Event Framework for Quantifying Clinical Significance of Effect in Alzheimer’s Disease Clinical Trials

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease associated with significant costs. Many AD therapeutic trials fail to demonstrate clinical significance. This work presents a method for reframing clinical significance in terms of a meaningful delay in time to the level of cognitive functioning associated with substantial new costs (e.g., increased home care needs [HCN] or care facility admission [CFA]).

Associations of patient‐specific resting state variability with CSF and clinical biomarkers: Data from Alzheimer’s disease clinical trials

AbstractBackgroundChanges of brain functional connectivity assessed using MRI in patients with Alzheimer’s disease (AD) have been previously reported. However, factors contributing to the variability among patients have not been sufficiently investigated. Here, we investigated the association of patient‐specific resting state parameters with CSF markers and clinical measures.MethodWe analyzed the baseline rs‐fMRI of 158 patients (87 female, age 50‐89) with mild AD collected in the Marguerite RoAD trial of gantenerumab in mild AD (NCT02051608) and 132 cognitively unimpaired adults (88 female, age 56‐90) from ADNI. We investigated the within‐ and between‐subjects’ variability in five brain networks (Sensory Motor, Cerebellar, Visual, Default Mode and Cognitive Control), inferred from the two groups using a Bayesian probabilistic model (PROFUMO, Harrison‐Smith‐2015; Harrison‐Woolrich‐2020). We computed spatial maps, BOLD amplitude changes, and spatial (temporal) functional connectivity between‐ and within‐networks for each subject. Those metrics were compared between groups using T‐tests. In AD patients we used linear models to investigate associations of the extracted metrics with CSF markers (Amyloid Beta 42, p‐Tau217, pTAU/Abeta 1‐42 ratio and Neurogranin) and cognitive scores (ADAS‐Cog 13, MMSE and ADCS‐ADL), while controlling for age, sex and MRI‐scanner type. All results were corrected for multiplicity using FDR.ResultOn average the signal amplitude was lower in the Cognitive Control and the Sensory Motor (p < 0.0001) networks in AD patients compared to cognitively unimpaired adults. Interestingly, in AD patients the lower amplitude observed in the cognitive control network was associated with cognitive decline (β = 0.02, p = 0.01). Moreover, significant associations were observed in AD patients between lower signal amplitude and higher CSF levels of ABeta 42 (β = ‐0.02, p = 0.036) and cognitive decline (β = 0.02, p = 0.008) (Fig.2). AD group showed on average reduced functional connectivity compared to the healthy one. Furthermore, the within‐AD patients’ analysis showed weak between‐ and strong within‐networks connectivity (T‐test, q < 0.05, Fig.1).ConclusionIn patients with mild AD, the signal amplitude and connectivity in the cognitive control and DMN networks were associated with both CSF level of ABeta42 and cognitive scores.

Impact of study partner type on primary endpoint volatility in a phase 3 registration trial of mild‐to‐moderate Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD) clinical trials, participants are required to enroll with a study partner (SP) who ensures compliance and completes outcomes assessing participant cognitive and functional ability. The SP role is commonly filled by spouses and other family members. Spouse and non‐spouse SPs differ in numerous ways, including average time in contact with the participant. These differences may impact volatility of SP‐reported assessments, which may in turn impact trial integrity. We quantified the impact of SP type on the variance of SP‐reported Disability Assessment for Dementia (DAD) scores.MethodWe analyzed data from the Bapineuzumab 301 (ApoE e4 non‐carriers) and 302 (ApoE e4 carriers) phase 3 trials in mild‐to‐moderate AD, provided by the trial sponsor, Janssen Research & Development, LLC for use in these analyses. We compared the sample variances of end‐of‐study DAD scores for spousal and non‐spousal SPs in each trial. 95% confidence intervals (CIs) for the corresponding parameters were computed via bootstrapping. We used similar methods to compare the variances in the difference between baseline and end‐of‐study DAD scores for SP types.ResultAmong the 1,232 and 1,121 participants analyzed from trials 301 and 302, 818 (66.4%) and 837 (74.7%) had spousal SPs at baseline, respectively (Table 1). On the other hand, 665 (665/973 = 68.3%) and 697 (697/924 = 75.4%) spousal SPs in each trial completed the end‐of‐study visit, respectively. In trial 301, the variance of end‐of‐study DAD scores for spousal SPs were observed to be 14% lower compared to non‐spousal SPs (spousal/non‐spousal = 630.41/746.55 = 0.84, 95% CI = [0.71, 1.03]). In trial 302 this relative decrease was observed to be 9%, though with less precision (spousal /non‐spousal = 610.85/673.86 = 0.91, 95%CI = [0.77, 1.12]). Neither trial had significant differences in spousal vs non‐spousal variances of the change‐from‐baseline DAD scores (Trial 301: spousal/non‐spousal = 378.10/425.17 = 0.91, 95%CI = [0.66, 1.22]; Trial 302: spousal/non‐spousal = 354.38/352.22 = 1.01, 95%CI = [0.77, 1.35]). DAD variance over time is depicted in Figure 1. Differences in the linear trend of DAD variance did not significantly differ between SP types in either trial (Trial 301 Est.: ‐1.74, 95%CI: [‐3.58, 0.23]; Trial 302 Est.: 0.94, 95%CI: [‐5.83, 4.31]).ConclusionSP type was not associated with variation in SP‐reported study endpoints in this study.

Asia-Pacific Leukemia Consortium: An innovative and collaborative initiative to improve care of leukemia and related diseases in the Asia-Pacific region.

The burden of leukemia and related diseases is rapidly growing in Asia. Currently, there is a paucity of regional collaborative groups/initiatives that focus exclusively on the management of leukemia in the Asia-Pacific (APAC) region. The Asia-Pacific Leukemia Consortium (APLC) was established on the 8 September 2021 to understand the status quo, unmet needs, and ways to improve the management of leukemia and related diseases in the APAC region. The APLC working group set up a group of experts from various countries (Singapore, Malaysia, Thailand, Hong Kong, Japan, South Korea, Taiwan, China, and Australia) to discuss on the status of: (i) clinical trials; (ii) disease registry database; (iii) genetic and tissue repository; (iv) patient advocacy and care; and (v) disease prevention and education in the APAC region. Low levels of awareness about leukemia amongst the public, lack of financial support, and limited access to newly approved therapies were identified as barriers to the implementation of effective leukemia management in low- or mid-income Asian countries. Patients often enroll in clinical trials to gain access to novel/approved therapies. The APLC group aims to address the growing threat of leukemia through a collaborative approach to advance disease prevention, research, clinical trials, and education.

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). A total of 11,292 AD patients were analyzed. Patients were 70.8±9.0years old, 54.9% female, and with 12.0±3.3years of education. Within 1year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but<1% from moderate to severe AD. After 10years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was<5% after 1year and>15% after 10years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p<0.01). This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

Procedure-Related Complications in Sham Surgeries for Parkinson's Clinical Trials: A Meta-analysis.

Double-blind, sham-controlled neurosurgical trials for neurodegenerative disorders are debated as an ethical dilemma, particularly regarding subjects randomized to the sham surgery group with general anesthesia. The objective of this study was to examine the safety of sham surgeries in Parkinson's disease (PD) clinical trials through complications related to the procedure. A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Rates and odds ratios (OR) were compared using random effects analysis. Seven studies, all randomized, double-blind, sham surgery-controlled trials, with 309 patients with PD, were qualitatively and quantitatively analyzed: 141 patients in sham groups and 168 patients in the experimental arms of gene or cell therapy trials. Sham subjects had lower rates of gastrointestinal, positioning, incision-site, respiratory (hypoxic or hypercapnic respiratory failure), cardiovascular, thromboembolism, postoperative cognitive decline, skull fracture, and intracranial or spinal complications when compared with active treatment subjects. Sham subjects, however, had a higher rate of perioperative respiratory infections, such as pneumonia or sinusitis. Further, sham subjects were less likely to experience postoperative cognitive decline (OR, 0.23; 95% confidence interval [CI]: 0.11-0.47), intracranial or spinal complications (OR, 0.10; 95% CI: 0.01-0.75), total major morbidity (OR, 0.30; 95% CI: 0.19-0.47), or overall complications (OR, 0.59; 95% CI: 0.47-0.75) when compared with patients receiving experimental therapy. Patients with PD in the sham surgery control arm of cell transplantation or gene therapy clinical trials have a low risk of procedure-related adverse events overall and fewer complications than patients in the experimental groups. There were no reported deaths attributed to sham surgery-controlled PD clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Trend of clinical trials of new drugs for rare diseases in China in recent 10 years

BackgroundRare disease is a general term for a disease that affects a small number of people but recognized as a global public health priority. Governments worldwide are paying more and more attention to the academical research and drug investment of rare diseases. The conduct of rare disease clinical trials is still difficult, despite the promotion of government policies and the awakening of social consciousness. In this article, we outlined the characteristics and obstacles of clinical trials of rare diseases in China and expected to provide reference for subsequent clinical trials in this field.ResultsIn recent years, China has made some progress in clinical trials of rare diseases in the past 10 years. There were 481 clinical trials on rare diseases in total, covering more than 10 rare diseases with high incidence. Clinical trial applications on rare diseases for a total of 481 were submitted and with an average annual growth rate of 28.2% from 2013 to 2022. The number of clinical trial application for rare diseases in 2016 dramatically increased by 80% compared to 2015 due to the policy document issued by China for clinical research in rare diseases in 2015. Besides, about 70% of applications registering for clinical trials could recruit subjects as expected. Despite this, the number of clinical trials of rare diseases in China was less compared with the United States, Europe and Japan, and the types of infant drugs were limited to biological products and chemical drugs lacking other new treatments.ConclusionsEfforts have been made in recent years to develop clinical research on rare diseases in China. The number of clinical trials for rare diseases in China was growing steadily every year, which was inseparable from the support of the country, society and rare disease patients. Still, there was a large gap between China and other developed countries in this field and this merit further investigation.

A Call to Action to Address Sex Differences in Alzheimer Disease Clinical Trials

This Viewpoint calls for comprehensive investigations into sex differences associated with treatments in existing Alzheimer disease and integration into future Alzheimer disease and related dementia clinical trials.

‘Time Saved’ As a Demonstration of Clinical Meaningfulness and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings

In Alzheimer’s disease (AD) clinical trials, disease-modifying therapies are expected to slow the rate of disease progression. Treatment effects are evaluated using a validated clinical scale as the difference between treatment and placebo in mean change from baseline to endpoint. Understanding the clinical relevance of this metric is not necessarily intuitive. Expressing active treatment-placebo difference as a time metric (i.e., months saved with treatment) has potential to provide a metric that is more easily and consistently interpreted. Using data from the TRAILBLAZER-ALZ study, time component tests (TCTs) were employed to determine the time saved with donanemab (an amyloid lowering drug) treatment. At study endpoint (Week 76), disease progression was delayed by 5.3 months and 5.2 months as measured by the Integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), respectively.

Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures.

There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment. A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside.

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

Prioritizing Racial Representation in Treating People with Parkinson’s Disease: An Assessment of Racial Inclusion Among Parkinson’s Disease Clinical Trials between 1999–2022. (P10-11.006)

<h3>Objective:</h3> The primary goal is to evaluate the inclusion of racial data in Parkinson’s Disease (PD) clinical trials. The secondary goal is to assess the racial proportions among PD trials reporting racial data. <h3>Background:</h3> Racial disparities exist in clinical trials across many disciplines. Collection of racial data and inclusion of racial subgroups in a proportionate manner is essential to ensuring scientific knowledge on clinical effectiveness and adverse effects of medications and other therapeutics in a diverse patient population. The current study focuses on racial representation within neurological clinical trials, specifically PD. <h3>Design/Methods:</h3> In this meta-analysis, the publicly available ClinicalTrials.Gov database was accessed on August 27th 2022, with search term “Parkinson’s Disease” , which resulted in 3284 trials. Microsoft Excel was used for data collection and analysis. 5 independent reviewers extracted study level data and performed data checks to confirm accuracy and consistency. After applying filters for “complete” “interventional” “with results,” 330 trials remained. 208 trials did not contain racial data. Among 122 trials with racial data, 12 trials were omitted due to: missing location (n=3), inconsistent race/gender reporting (n=2), different condition type (n=7). <h3>Results:</h3> 208 (63%) trials did not report racial data. The secondary analysis of 110 trials revealed the following subgroup proportions: White (86.2%), Black (1.8%) Asian (5.9%) and Other, including American Indian/Alaskan Native, Native Hawaiian/Other Pacific Islander, and unknown/not reported, (6.1%). Analysis of gender enrollment in PD clinical trials that reported race, revealed female (36%) and male (64%). <h3>Conclusions:</h3> Our findings reveal that the majority of PD trials did not report racial data. Furthermore, among those trials reporting racial data, White participants were disproportionately represented compared to Black, Asian and Other participants. These results highlight an urgent need to address racial representation within PD trials; specifically, research must elucidate barriers to equitable clinical trial recruitment and access. <b>Disclosure:</b> Ms. Pandit has nothing to disclose. Mr. Rashid has nothing to disclose. Mr. Osias has nothing to disclose. Ms. Dawson has nothing to disclose. Dr. Mammadli has nothing to disclose. Dr. Etienne has nothing to disclose.

Using Predictive Models to Reduce Heterogeneity in Alzheimer’s Disease Clinical Trials (S26.005)

Using Predictive Models to Reduce Heterogeneity in Alzheimer’s Disease Clinical Trials (S26.005)

Community-Academic Initiative to Measure and Improve Underrepresented Group Participation in Parkinson’s Disease Research (P10-11.002)

<h3>Objective:</h3> To better understand the reason for lack of racial and ethnic diversity in Parkinson’s Disease (PD) clinical trials by measuring community members’ baseline knowledge of PD, trust of researchers, and willingness to participate in research. <h3>Background:</h3> PD clinical trial participants are disproportionately non-Hispanic Caucasian, creating limited generalizability of research findings. It is unclear why there is incommensurate rates of underrepresented group (URG) research participation; lower health literacy and lack of trust have been suggested as contributors. Community engagement through education on PD and associated studies has the potential to improve awareness and understanding of research, and in turn increase participation rates. <h3>Design/Methods:</h3> Four educational workshops with a total of 92 participants were held at community centers in URG-predominant Chicago neighborhoods. Pre- and post-workshop surveys qualitatively assessed participants’ knowledge of PD symptoms and signs, trust in medical researchers, and willingness to participate in clinical trials. <h3>Results:</h3> The majority of participants identified as either African American (35.9%) or Asian (37%). Survey results indicated that on the whole, community members were trustful of clinical researchers and had positive feelings towards research and researchers’ intentions. Participants were most open to participate in studies that could be done within their homes or offered financial compensation, and were least open to participate in studies that involved obtaining biological samples. Very few respondents had ever been asked to participate in a PD clinical trial before (8.1%). Respondents had a basic baseline understanding of PD, and tremor was the symptom most commonly identified as an early sign of PD (32.6%). <h3>Conclusions:</h3> Surveying predominantly AA and Asian community members of URG-rich Chicago communities revealed moderate to high levels of trust of researchers in these groups, and a willingness to participate in patient-centered clinical trials that mitigate barriers and include facilitators. <b>Disclosure:</b> An immediate family member of Ms. Marre has received personal compensation for serving as an employee of EMD Serono, Inc.. An immediate family member of Ms. Marre has received personal compensation for serving as an employee of MFS Investment Management. Ms. Marre has received research support from Office of Undergraduate Research which is administered by Northwestern University’s Office of the Provost. Emily Zivin has nothing to disclose. Karen Williams has nothing to disclose. Mr. Shramuk has received personal compensation for serving as an employee of Northwestern University. Ms. Lancki has nothing to disclose. Dr. Adrissi has nothing to disclose. Dr. Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for Acadia Pharmaceuticals.

Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease: ADAPT-PD clinical trial methodology and early data (P1-11.002)

Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease: ADAPT-PD clinical trial methodology and early data (P1-11.002)

Brain Hemisphere Dissimilarity, a Self-Supervised Learning Approach for alpha-synucleinopathies prediction with FDG PET.

Idiopathic Rem sleep Behavior Disorder (iRBD) is a significant biomarker for the development of alpha-synucleinopathies, such as Parkinson's disease (PD) or Dementia with Lewy bodies (DLB). Methods to identify patterns in iRBD patients can help in the prediction of the future conversion to these diseases during the long prodromal phase when symptoms are non-specific. These methods are essential for disease management and clinical trial recruitment. Brain PET scans with 18F-FDG PET radiotracers have recently shown promise, however, the scarcity of longitudinal data and PD/DLB conversion information makes the use of representation learning approaches such as deep convolutional networks not feasible if trained in a supervised manner. In this work, we propose a self-supervised learning strategy to learn features by comparing the brain hemispheres of iRBD non-convertor subjects, which allows for pre-training a convolutional network on a small data regimen. We introduce a loss function called hemisphere dissimilarity loss (HDL), which extends the Barlow Twins loss, that promotes the creation of invariant and non-redundant features for brain hemispheres of the same subject, and the opposite for hemispheres of different subjects. This loss enables the pre-training of a network without any information about the disease, which is then used to generate full brain feature vectors that are fine-tuned to two downstream tasks: follow-up conversion, and the type of conversion (PD or DLB) using baseline 18F-FDG PET. In our results, we find that the HDL outperforms the variational autoencoder with different forms of inputs.

Brain health registry updates: An online longitudinal neuroscience platform.

Remote, internet-based methods for recruitment, screening, and longitudinally assessing older adults have the potential to facilitate Alzheimer's disease (AD) clinical trials and observational studies. The Brain Health Registry (BHR) is an online registry that includes longitudinal assessments including self- and study partner-report questionnaires and neuropsychological tests. New initiatives aim to increase inclusion and engagement of commonly underincluded communities using digital, community-engaged research strategies. New features include multilingual support and biofluid collection capabilities. BHR includes>100,000 participants. BHR has made over 259,000 referrals resulting in 25,997 participants enrolled in 30 aging and AD studies. In addition, 28,278 participants are coenrolled in BHR and other studies with data linkage among studies. Data have been shared with 28 investigators. Recent efforts have facilitated the enrollment and engagement of underincluded ethnocultural communities. The major advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, cohort diversity, and generalizability. Brain Health Registry (BHR) is an online, longitudinal platform of>100,000 members. BHR made>259,000 referrals, which enrolled 25,997 participants in 32 studies. New efforts increased enrollment and engagement of underincluded communities in BHR. The major advantages of the BHR approach are scalability and accessibility. BHR provides a unique adjunct for clinical neuroscience research.

Population-Based Mini-Mental State Examination Norms in Adults of Mexican Heritage in the Cameron County Hispanic Cohort.

Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Potential therapeutic action of tauroursodeoxycholic acid against cholestatic liver injury via hepatic Fxr/Nrf2 and CHOP-DR5-caspase-8 pathway.

Cholestasis is a pathophysiologic syndrome with limited therapeutic options. Tauroursodeoxycholic acid (TUDCA) has been employed to treat hepatobiliary disorders and is as effective as UDCA in alleviating cholestatic liver disease in clinical trials. Until now, TUDCA's mechanism of action toward cholestasis remains unclear. In the present study, cholestasis was induced with a cholic acid (CA)-supplemented diet or α-naphthyl isothiocyanate (ANIT) gavage in wild-type and Farnesoid X Receptor (FXR) deficient mice, using obeticholic acid (OCA) as control. The effects of TUDCA on liver histological changes, transaminase level, bile acid composition, hepatocyte death, expression of Fxr and nuclear factor erythroid 2-related factor 2 (Nrf2) and target genes, as well as apoptotic signaling pathways, were investigated. Treating CA-fed mice with TUDCA markedly alleviated liver injury, attenuated bile acids retention in liver and plasma, increased Fxr and Nrf2 nuclear levels and modulated the expression of targets regulating synthesis and transportation of bile acids, including BSEP, MRP2, NTCP and CYP7A1. TUDCA, but not OCA, activated Nrf2 signaling and exerted protective effects against cholestatic liver injury in Fxr-/- mice fed with CA. Furthermore, in both mice with CA- and ANIT-induced cholestasis, TUDCA decreased expression of GRP78 and CCAAT/enhancer-binding protein homologous protein (CHOP), reduced death receptor 5 (DR5) transcription, caspase-8 activation, and BID cleavage, and subsequently inhibited activation of executioner caspases and apoptosis in liver. We confirmed that TUDCA protected against cholestatic liver injury by alleviating BAs burden of dually activating hepatic Fxr and Nrf2. Moreover, inhibiting CHOP-DR5-caspase-8 pathway contributed to the anti-apoptotic effect of TUDCA in cholestasis.