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The MR1/MAIT cell axis reduces phagocytosis and dystrophic neurites in Alzheimer’s disease
No full textBackground:
Plaques are a hallmark feature of Alzheimer’s disease (AD). We found the loss of mucosal‐associated invariant T (MAIT) cells and its antigen‐presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting microglial response and dystrophic neurites. This study aims to understand the impact of MAIT cells and microglial MR1 in AD.
Method:
Brain tissue from various ages of 5XFAD mice and those that are MR1‐deficient (MR1KO), was analyzed for the presence of MAIT cells. Methoxy‐X04 was used to analyze the phagocytic capacity of microglia ± MR1. Immunofluorescent microscopic analysis of dystrophic neurites in the brain was performed with antibodies against microglia, Aβ, Lamp1, Ubiquitin, and nAPP.
Result:
Injection of Methoxy‐X04 in 5XFAD and 5XFAD/MR1KO mice revealed reduced levels of Methoxy‐X04 uptake in CD11b+CD45low cells in the MR1 KO group (P < 0.05). However, this remained unaltered in the CD11b+CD45high cells. In the 5XFAD/MR1 KO group there was reduced expression of LAMP1, Ubiquitin, and nAPP in the hippocampus at 8 months compared to 5XFAD mice (P < 0.001). In the cortex only nAPP remained reduced in the 5XFAD/MR1 KO mice (P < 0.001).
Conclusion:
The loss of MR1 and MAIT cells reduced the phagocytic capacity of microglia and dystrophic neurite formation in the hippocampus. Our data indicate a potential detrimental role for MR1 and/or MAIT cells in AD pathology. Understanding this axis of the innate immune system could provide new clues as to the overall role of innate immunity in AD and its potential as a therapeutic target in AD
The prevalence of tau‐PET positivity in aging and dementia
No full textBackground
Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates.
Method
This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis.
Result
The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2).
Conclusion
This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs
2024 Annual Impact Report
No full textThis is an accounting of the Bowen Center for Health Workforce Research and Policy's impact for the year 2024
A 24-year longitudinal study on a STEM gateway general chemistry course and the reduction of achievement disparities
No full textThe "First Year Experience" is a critical component of retention of STEM majors. Often, general chemistry has been labeled as a "gatekeeper" course for STEM careers due to a high attrition rate and a course that leads to increased time for graduation when students are inadequately prepared. We demonstrate that the active learning strategy Peer-Led Team Learning (PLTL) model increases student retention (%DFW calculated from earned grades A through F plus withdrawals, W) and success (%ABC calculated from earned grades A through F). We have analyzed approximately 24 years of data in general chemistry I (~20,000 students), using Analysis of Covariance (ANCOVA), which showed progressive, significant improvement in both student success and completion metrics. A Hierarchical Linear Modeling (HLM), using a combination of course and student-level variables, demonstrated the impact of PLTL on internal exam metrics and overall course grades. Further, HLM modeling assessed the impact of PLTL controlling for various student demographics. PLTL strongly impacted URM student completion rates to a greater degree than well-represented students, reducing the URM/non-URM achievement gap
Social Determinants of Inequities in Neurodegenerative Disease Readmissions in Northwest Indiana: An Advocacy Opportunity
No full textBackground: Neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, pose significant challenges given their progressive nature and multifaceted care needs. This research examined the intricate interplay between social determinants of health (SDOH) and hospital readmissions among individuals with neurodegenerative diseases. It is part of a Participatory Research partnership between Indiana University School of Medicine-Northwest and an urban health system in Northwest Indiana (NWI).
Methods: This retrospective study analyzed a dataset generated from routine SDOH screenings and referrals in Epic using the Protocol for Responding to and Assessing Patients’ Assets, Risks, and Experiences (PRAPARE) for inpatient admissions from 3 NWI urban hospitals between January 2021 to April 2024. Data analysis was conducted in SPSS 29.0 with descriptive statistics, bivariate analysis (Chi-square), and multivariate analysis (binary logistic regression). This study received exemption from Indiana University Human Research Protection Program (IRB #14040).
Results: The sample consisted of 1,338 patients admitted for neurodegenerative diseases. Patients were predominantly older adults (73 ± 14), publicly insured (91.5%), and 31% racial/ethnic minorities. The bivariate analysis found that readmission was significantly associated with age (p<0.001), insurance type (p=0.003), hospital (p<0.001), physical activity level (0.034), and length of stay (p<0.001). After adjusting for these factors, the multivariate analysis found higher odds of hospital readmission among patients with public insurance (OR=76.1%; p=0.028), prolonged hospital stay (OR=8.5%; p<0.001), and within a small hospital in a medically underserved area (MUA) (OR=69.6%; p<0.001).
Conclusion: Understanding the impact of SDOH on hospital readmissions is crucial for developing multi-level interventions to reduce readmissions, inequities, and healthcare costs. Findings from this research underscore the critical need for policy advocacy and integrated approaches addressing SDOH as part of comprehensive readmission reduction programs. Examples of evidence-based approaches include improving access to quality neurodegenerative care in MUAs, increasing education on at-home neurodegenerative care, and comprehensive SDOH screenings and referrals
Impact of Race and Industry on Stroke Incidence in Northwest Indiana – A Report to Advocate for Targeted Community-Based Interventions
No full textImpact of Race and Industry on Stroke Incidence on Patients in Northwest Indiana – A Report to Advocate for Targeted Community-Based Interventions
Miranda M. Cash¹*, Sahar A. Abdullah¹*, Amy Han, PhD2
Indiana University School of Medicine-Northwest1, Indiana University School of Medicine Department of Psychiatry2
Background & Hypothesis: Stroke is a leading cause of death and disability in the US and studies have shown racial/ethnic disparities in stroke, including in Hispanics/Latinos: the fastest growing segment of the US population. St. Catherine Hospital is located in East Chicago, Indiana and the majority population is Hispanic/Latino (54.8%) and is disproportionately at risk of stroke with a death rate of 79 per 100,000 people. With such disparities in stroke mortality across Northwest Indiana, especially among minority patients, we aim to report which zip codes show particular associations in stroke incidence and report possible social determinants of health (SDoH) between White, Black/African American, and Hispanic/Latino patients that receive treatment at St. Catherine Hospital.
Project Methods: Powers Health System provided data from St. Catherine Hospital in East Chicago, Indiana from January 2022 - March 2024 collecting socio-demographic data from 304 patients residing in the greater Northwest Indiana area. We calculated odds ratios to investigate associations in stroke outcome, race, and zip codes.
Results: In Whiting, IN, stroke is less likely to occur in Hispanics/Latinos compared to Whites. In South Chicago, stroke is more likely to occur in Hispanics/Latinos compared to Blacks/African Americans. Based on U.S Census Bureau metrics, residents of South Chicago face more negative SDoH than residents of Whiting.
Potential Impact: Northwest Indiana has the largest steel making facility in North America; this study aims to provide St. Catherine Hospital with a better understanding of which patients may be at particular risk of stroke based on SDoH (type of employment, pollution levels, and population density) that contribute to increased stroke incidence. Targeted community outreach efforts, such as policy change, patient education/training, and a stroke support group at St. Catherine Hospital, are future steps to increase positive SDoH
Molecular and Synaptic Signatures in Mouse Models of Late‐Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology
Get PDFBackground:
MODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant genetic risk factors. Models expressing human‐relevant risk genetic risk factors are expected to better phenocopy LOAD than widely used transgenic models.
Method:
Here, two genetic risk factors APOE4 and Trem2*R47H, were incorporated into C57BL/6J (B6) mice along with humanized amyloid‐beta to produce the LOAD2 model. LOAD2 and control mice were aged up to 24 months with some being provided in the absence or presence of normal chow or a high fat/high sugar diet (LOAD2 HFD) from two months of age. A phenotyping pipeline was employed to evaluate disease outcomes observed in human patients, including in vivo imaging, brain and blood biomarker and cytokine analyses, multi‐omics (transcriptomics and proteomics), neuropathology and behavior.
Result:
By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2 HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble AΒ42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease‐relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age‐dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2 HFD mice also showed a learning deficit based on a Touchscreen cognitive assay.
Conclusion:
Despite the absence of hallmark amyloid and Tau pathologies, collectively these data support the use of LOAD2 HFD mice reveal this model as important for preclinical studies that target other features of LOAD independent of amyloid and tau
Peer Review of “Predicting Escalation of Care for Childhood Pneumonia Using Machine Learning: Retrospective Analysis and Model Development”
No full textThe Dynamics of Cognitive Decline towards Alzheimer’s Disease Progression: Results from ADSP-PHC’s Harmonized Cognitive Composites
No full textIntroduction: Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer's disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies.
Methods: Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used. A novel double anchoring events-based sigmoidal mixed model was developed using time to the incident of AD diagnosis as the time scale.
Results: Decline in memory occurred before decline in language which was followed by the decline in executive function. Throughout the entire AD continuum, APOE-ε4 non-carriers and non-Hispanic Whites showed better memory performance, respectively, in all three cognitive domains.
Discussion: Using harmonized data across multiple cohorts is the key to accurately characterizing the temporal order of AD biomarkers. Time to incident AD diagnosis should be used as the time scale for reproducibility purposes
