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Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy
No full textLimbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided
211. Defining Optimal Sampling Times for Cefepime Therapeutic Drug Monitoring in Clinical Practice
No full textBackground:
Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach.
Methods:
De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT >MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R.
Results:
116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT>MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P >0.05 for all comparisons; Fig4).
Conclusion:
Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach
P-547. Efficacy and Safety of B/F/TAF in Treatment-Naïve People With HIV Aged ≥ 50 Years: 5-Year Follow-Up From Two Phase 3 Studies
No full textBackground:
An increasing proportion of people with HIV (PWH) are aged ≥ 50 years, with a greater burden of age-related comorbidities; however, long-term analyses of this population are limited. We present key treatment outcomes through 5 years of first-line therapy with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in PWH ≥ 50 vs < 50 years.
Methods:
Studies 1489 (NCT02607930; B/F/TAF vs dolutegravir/abacavir/lamivudine [DTG/ABC/3TC]) and 1490 (NCT02607956; B/F/TAF vs DTG+F/TAF) were randomized, double-blind, multicenter Phase 3 studies in adult PWH. This pooled analysis reports outcomes for participants ≥ 50 vs < 50 years who received B/F/TAF in the 144-week (W) randomization phase and the 96W open-label extension. Baseline demographics and clinical characteristics; proportion of participants with HIV-1 RNA < 50 copies/mL (missing=excluded); adherence; changes in CD4 cell count and metabolic, renal, and bone parameters; and treatment-emergent adverse events (TEAEs) are presented.
Results:
Overall, 634 participants received B/F/TAF up to W240; 96 (15.1%) were ≥ 50 years and 538 (84.9%) were < 50 years. Baseline demographics, clinical characteristics, and outcomes are shown in the Table. Higher rates of baseline comorbidities were observed in those aged ≥ 50 vs < 50 years. Both groups had high rates of HIV suppression at W240. A greater proportion of participants aged ≥ 50 vs < 50 years had ≥ 95% adherence (82.8% vs 66.3%; P=0.0015). Changes in CD4 count, weight, eGFR, fasting total cholesterol to high-density lipoprotein ratio, and hip and spine bone mineral density were similar between groups. Proportions of participants with study drug-related TEAEs were similar between groups, with few participants experiencing a TEAE leading to study drug discontinuation. Proportions of TE hypertension and diabetes were modestly higher in the ≥ 50 group vs the < 50 group.
Conclusion:
Over 5 years, participants ≥ 50 years were more likely to have high adherence to B/F/TAF treatment vs those < 50 years, with low rates of discontinuations due to AEs in both groups. B/F/TAF maintained high rates of virologic suppression, was well tolerated, and resulted in similar changes in metabolic, renal, and bone parameters in both groups, supporting its use for long-term management of HIV in older PWH
Glial changes as result of cerebral amyloid angiopathy progression
No full textBackground:
Cerebral Amyloid Angiopathy (CAA) occurs at the intersection of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID). In the human brain it occurs when amyloid beta (Aβ) aggregates in small/medium‐sized cerebral blood vessels, which contribute to hypoperfusion and cognitive decline by altering vascular function and integrity. The current study seeks to track the progression of CAA and associated neuroinflammation and glial cell changes in Tg2576 mice.
Method:
Tg2576 mice were aged to 8‐, 14‐, 20‐, and 27‐months and assessed for CAA pathology via histology. Gene expression was evaluated in hippocampal tissue by qPCR and posterior cortex by nanostring (ncounter Mouse Neuroinflammation and Mouse CVD Pathophysiology panels; in progress) to compare 8‐ and 20‐month APP and wildtype groups. Protein expression was evaluated via digital spatial profiling in the same APP mice, grouped by age or CAA presence compared to wildtype controls. CAA presence was defined as Aβ surrounding lectin‐positive vessels. Regions of interest were categorized as either positive or negative for CAA based on this criterion.
Result:
Congophillic plaque deposition along the vasculature increased in width, length, and area in a time dependent manner in both the frontal cortex and hippocampus. Astrocyte marker GFAP and proinflammatory receptor TNFR1 gene expression both increased at 20 months compared to 8 months in the APP group. Of the protein profile assessed (Mouse Neural Cell Profiling and Mouse Glial Cell Subtyping), the most consistent changes were found in astrocyte markers. Both Aldh1l1 and S100B were increased at 20 months compared to 8 months of age in both APP and WT mice. GFAP protein expression was found to increase with both age and CAA.
Conclusion:
This study showed increased vascular amyloid deposition and astrocyte gene and protein expression over time, further supporting a role for astrocytes in etiology and/or reaction to CAA
Longitudinal neurodegeneration in Early‐Onset Alzheimer’s Disease: A summary of MRI‐derived atrophy in LEADS
No full textBackground:
Prior work has advanced our understanding of cortical atrophy in early‐onset Alzheimer’s disease (EOAD), but longitudinal data are sparse. Current longitudinal MRI studies point to progressive atrophy in cerebral cortex exhibiting a posterior‐to‐anterior gradient, but these studies include small samples with mostly amnestic EOAD. Here, we analyzed a large sample of sporadic EOAD patients from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) to test the central hypothesis that areas in our recently described EOAD signature (Touroutoglou et al., 2023) affected at baseline in the posterior lateral temporal cortex, inferior parietal lobule, and PCC/precuneus will continue to degenerate and additional longitudinal atrophy will be found in the medial temporal lobe and frontal regions as cognitive decline progresses over time in multiple domains.
Method:
We investigated longitudinal changes in cortical thickness by analyzing structural MRI data collected from 367 patients with EOAD and 99 cognitively unimpaired (CN) older adults, totaling 839 MRI scans across the cohorts with up to 4 years of follow‐up. MRI data were longitudinally processed in FreeSurfer 6.0. Linear mixed effects models were constructed to estimate the rate of cortical atrophy with random intercepts and slopes for individual participants while controlling for baseline age and sex.
Result:
EOAD patients exhibited cortical atrophy at a faster rate than controls in widespread areas of the cerebral cortex. As expected, the regions exhibiting accelerated longitudinal atrophy included not only the EOAD signature regions as a whole (EOAD: ‐0.052±0.002 mm/year vs. CN: 0.0001±0.002 mm/year; Dslopes = ‐0.052, p<.001), but also those that were minimally atrophied at baseline, such as superior frontal gyrus (EOAD: ‐0.052+/‐0.004 vs. CN: ‐0.001+/‐0.004, Dslopes = ‐ 0.051, p<.001) and medial temporal lobe (EOAD: ‐0.083±0.005 mm/year vs. CN: 0.001±0.006 mm/year; Dslopes = ‐0.082, p<.001). We observed no difference in the rate of atrophy in the calcarine fissure (a control region not expected to change; Dslopes = ‐0.002, p£.69).
Conclusion:
Our findings show that neurodegeneration in EOAD accelerates over time in the EOAD signature regions and spreads to additional areas within large‐scale brain networks (consistent with those observed in late‐onset AD) contributing to the worsening of symptoms over time
Genetic and Sex Associations with Earlier Estimated Onset of Amyloid Positivity from over 4000 Harmonized Positron Emission Tomography Images
No full textBackground:
New techniques have been developed to estimate the age when someone converted to amyloid positivity (EAOA) from PET, oftentimes offering information about a participant decades before they joined a research study. EAOA is variable across populations but we do not know the causes for these differences. This study aims to validate APOE associations with EAOA and explore genetic and sex‐based factors with EAOA.
Methods:
Data from six cohorts were analyzed. Our analysis included 4220 non‐Hispanic white people (57.6% women; 86.7% cognitively unimpaired at baseline scan). Amyloid PET data were harmonized using gaussian mixture models. EAOA was calculated using the sampled iterative local approximation (SILA) algorithm. Sex differences in EAOA were compared using t‐tests amongst amyloid positive individuals. A genome‐wide association study of EAOA was performed. Gene analyses were conducted using MAGMA.
Results:
Average EAOA was 81.1 years across all individuals regardless of amyloid status. APOE e2 homozygotes had slightly later EAOA than e3/e3 homozygotes. APOE e4 homozygotes converted to amyloid positivity 8.2 years before e3/e4 heterozygotes and over two decades earlier than e3 homozygotes. APOE e2/e4 converted to positivity roughly three years later than e3/e4 and nearly ten years earlier than e3 homozygotes. APOE genotype differences in EAOA described were statistically significant (p < .01). There were significant sex differences between men and women when examining amyloid positivity. Men converted to amyloid positivity over 2 years later than women (65.3 vs 63.2 years, p=3.23x10‐5). The rs12981369 polymorphism in ABCA7 was associated with EAOA (β = 2.14, p=9.27×10−9). Brain eQTL databases indicate associations between rs12981369 and gene expression of ABCA7. Gene‐level analyses revealed significant associations for ABCA7, HMHA1, and KIF13B.
Conclusion:
This study further describes the role of APOE and reveals roles for ABCA7 and KIF13B on amyloid onset. We identified a novel variant on chromosome 19 correlating with later amyloid onset conversion and highlight important differences between sexes. These findings highlight EAOA as a powerful endophenotype of AD and offer insights into potential drug‐targetable mechanisms for early AD intervention
2024 Indiana Physician Workforce Data Report
No full textPhysicians play an integral role in health care delivery by performing duties such as diagnosing and treating injuries or illness, addressing health maintenance, providing preventive health care, and counseling patients. This report examines the demographics, education, and practice characteristics of licensed physicians serving Hoosiers
Integration of GWAS summary statistics with cell type‐specific eQTLs prioritizes potential causal genes for Alzheimer’s disease
No full textBackground:
Analyzing disease‐linked genetic variants via expression quantitative trait loci (eQTLs) is crucial for identifying disease‐causing genes. Previous research prioritized genes by integrating Genome‐Wide Association Study (GWAS) results with tissue‐level eQTLs. Recent studies explored brain cell type‐specific eQTLs, but they lack a systematic analysis across various AD GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type‐specific eQTL datasets. Here, we integrated brain cell type‐specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level.
Method:
To prioritize disease‐causing genes, we used summary data‐based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the AD GWAS summary statistics with cell type‐specific eQTLs in human brain. We utilized five latest AD GWAS datasets and a cell type‐specific eQTL dataset comprising 424 participants of the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) cohort. We replicated our analysis using a cell type‐specific eQTL dataset of 192 participants from Bryois et al., 2021. For comparison, we utilized a previous tissue‐level metabrain eQTL dataset from a meta‐analysis of 14 datasets. Furthermore, we visualized the colocalization of novel candidate causal genes using eQTpLot.
Result:
We identified 17 cell type‐specific candidate causal genes using the ROSMAP eQTL dataset. Our results showed that the largest number of candidate causal genes are identified in microglia, followed by astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and oligodendrocyte progenitor cells (OPCs). Four candidate causal genes were common across different cell types. Interestingly, JAZF1, detected as a candidate causal gene affected by the same leading variant in both microglia and OPCs, showed a congruous (same direction) colocalized SNP effect on the gene expression level and AD in OPCs, but an incongruous (opposite direction) colocalized SNP effect in microglia. After comparing our results with previously known prioritized causal genes, we identified PABPC1 in astrocyte as a novel potential causal gene.
Conclusion:
We systematically prioritized AD candidate causal genes based on cell type‐specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD‐related genetic variants and facilitates the interpretation of AD GWAS results
Indiana Medical Education Pipeline-to-Practice Study Project Summary Report
No full textRetention of medical students and residents is crucial to ensuring a strong physician workforce. This report examines retention within Indiana's medical education pipeline between 2019 and 2024, challenges faced by residency program directors, trends in physician workforce capacity at Indiana hospitals, and existing initiatives supporting medical education and training in Indiana.
This work was completed in collaboration with the Indiana Department of Health. It is our hope that this report can inform discussions and policies targeting medical education in Indiana
Assessment of Interest and Resources Needed for the Development of Scalable Healthcare Professionals Facilitated Strategies to Diversify Alzheimer’s Disease Research Participation
No full textBackground:
Increasing underrepresented racial and ethnic minority group (URG) participation in early‐stage Alzheimer’s disease and related dementias (ADRD) research is critical to inclusive characterization of underlying pathology and testing of disease‐modifying treatments. One promising recruitment strategy to accelerate URG participation is for healthcare professionals (HCPs) to facilitate referrals. The use of HCP‐facilitated recruitment strategies across the Alzheimer’s Disease Research Center (ADRC) network, a major referral source for ADRD multisite observational and clinical trials, has not been examined. We hypothesized that there would be interest in the development of scalable HCP‐facilitated recruitment strategies to accelerate URG participation across the ADRC network.
Methods:
We emailed Outreach, Recruitment and Engagement (ORE) Cores within the NIA‐funded ADRC network to complete a web‐based REDCap™ survey on their current HCP‐facilitated recruitment strategies for URG participants, resources enhancing use of these strategies, and their interest in strategy development. We conducted descriptive statistics using SPSS 29.0.
Results:
Out of 37 ADRCs, 27 (73.0%) completed the survey. Although the majority of ADRCs (66.7%, N = 18) reported HCPs referring URG participants (Table 1), they mostly relied on HCP faculty based at the ADRC (48.1%, N = 13) or the ADRC affiliated academic medical center (51.9%, N = 14) (Table 2). Nearly all (92.5%, N = 25) ORE Cores expressed interest in participating in or learning more about future efforts to develop HCP‐facilitated recruitment strategies for increasing URG participation. Resources which would increase use of HCP‐facilitated strategies for URG referrals included guidance on outreach and engagement strategies (70.4%, N = 19), culturally tailored resources for HCPs to refer participants (59.3%, N = 16), technology and informatic recruitment strategies (63.0%, N = 17), and staff effort (63.0%, N = 17) (Table 3).
Conclusions:
Our survey identified key opportunities to develop novel scalable HCP‐facilitated recruitment strategies to accelerate URG participation. Although most ORE Cores expressed interest in expanding their HCP‐facilitated recruitment strategies to have more inclusive research participation, there is need for both higher‐level strategic guidance and ready‐to‐use resources to implement these strategies. Future studies will need to develop and test scalable HCP‐facilitated strategies and resources to systematically accelerate URG research participation