Citations

AbstractBackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non‐Hispanic White (NHW) population. To address this, Accelerating Medicines Partnership in AD (AMP‐AD) aimed to promote inclusivity in multi‐omics AD research, to unravel unique molecular signatures and pathways. The study aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial groups.MethodDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (980 unique individuals), 322 were from African American donors, 214 from Latino Americans, 551 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG samples, 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag‐based mass spectrometry (TMT‐MS). Following quality control (QC), proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. Differential protein expression was conducted within and across races after adjusting for batch using regression‐analysis.ResultIn total, 9,180 proteins from the DLPFC, and 9,734 proteins from STG brain tissues were quantified by TMT‐MS. Further analysis identified approximately 3,000 differentially abundant proteins in AD brains compared to controls within race. The AD‐associated differentially abundant proteins were strongly correlated between DLPFC and STG regions and with CERAD and Braak. Protein levels of MAPT and APP demonstrated equivalent disease‐related elevations in both African American and NHW individuals with AD. Notably, after adjusting for AD, significant differences in protein levels were identified across race.ConclusionThe proteomics approach employed by AMP‐AD sheds light on the brain proteome in AD across diverse racial groups, emphasizing the importance of inclusive research in establishing robust and generalizable discoveries. The identified proteins here could underscore racial disparities beyond disease association, contributing to a more nuanced understanding of AD pathophysiology.

AbstractBackgroundThe quantification of neurofilament light chain (NfL) in blood and cerebrospinal fluid (CSF) has proved useful in many contexts, for the diagnosis and prognosis of various neurological disorders. There is, however, a diversity of practices between centers, essentially linked to the context of use (COU), analytical methods, consideration of comorbidities, determination of cut‐points or use of interpretation scales. Finally, for the same biochemical profile, the interpretation and reporting of results may differ from one center to another, raising the question of test commutability. To date, no consensus has been reached between the different laboratories involved to define the most appropriate conclusions/comments based on COU and cut‐points. This work is an essential step towards consensual harmonization of the clinical use of NfL after CSF and/or blood analysis in various neurological contexts, as advocated by the Alzheimer's Association "Biofluid Based Biomarkers PIA" working group.MethodThis international project involves 58 clinical laboratories in 16 countries, specializing in the biochemical diagnosis of neurological disorders. By means of a questionnaire, we obtained a description of the COU, pre‐analytical and analytical (biological fluid and method used to quantify NfL) protocols of all the centers involved.ResultsOf the centers, 42% quantified NfL in CSF, 29% in serum and 28% in plasma, and 1% in dried blood spot. The COUs were as follows: Frontotemporal dementia (FTD, 17%), Alzheimer's disease (AD, 16%), multiple sclerosis (MS, 16%), amyotrophic lateral sclerosis (ALS, 11%), psychiatric syndrome (PS, 10%), Creutzfeldt‐Jakob disease (CJD, 8%), Parkinson's disease (PD, 8%), peripheral neuropathy (PN, 7%) and traumatic brain injury (TBI, 7%). Most centers define pathological cut‐points based on published literature and take age into account (50%).ConclusionOur initial results highlight the state of the art in terms of the clinical use of NfL analysis in CSF and blood in the context of different neurological diseases. We have now defined a coordinator for each COU subgroup and are organizing consensus meetings to harmonize the use and reporting of NfL measurements for the identified clinical applications. The results of these next steps will be presented.

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

Abstract Purpose Medical student education in geriatrics is a critical need for every doctor-in-training as the population ages, with fewer than 7,000 geriatricians, and older patients, who now approach 20% of the U.S. population, having unique health care needs. This study presents the updated competencies in geriatrics for graduating medical students, framed by the Geriatrics 5Ms (Mind, Mobility, Medications, Multicomplexity, and What Matters Most). Method From 2019–2022, a working group of the American Geriatrics Society (AGS) drafted the updated medical student geriatrics education competencies, using a modified Delphi approach. The working group reviewed the literature, conducted an initial survey of working group members, and drafted and refined proposed updates to the competencies. The 27 resulting competencies were disseminated as a national survey to geriatrics experts and medical school education deans. Following the national survey, the competencies were updated and presented at the 2021 AGS Annual Scientific Meeting and open to public comment before they were finalized. Results The 27 updated geriatrics competencies for medical students included several new competencies, such as a focus on health equity, frailty, deprescribing, and patient priorities. A total of 211 respondents completed the national survey, including geriatrics experts (187/398, response rate: 47.0%) and education deans (24/191, response rate: 12.6%). All 27 proposed competencies met the predetermined threshold of 70% cumulative agreement, with a range of 93.0% (174/187) to 100% (187/187) among geriatrics experts and 87.5% (21/24) to 100% (24/24) among education deans. Conclusions The updated Geriatrics Competencies for Graduating Medical Students met with broad agreement among the geriatrics experts and medical school education deans who responded to the national survey. By focusing on the Geriatrics 5Ms, the competencies highlight key knowledge and skills graduating medical students need for the first day of internship to be prepared to deliver age-friendly care to older adults under their care.

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non‐Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer’s Disease (AMP‐AD) Diversity Working Group was launched to generate multi‐omics data from post‐mortem brain tissue from donors of predominantly AA and LA descent. Here, we focus on genomic and transcriptomics measures, made available through the AD Knowledge Portal (ADKP).MethodBrain tissue from dorsolateral prefrontal cortex (DLPFC), caudate nucleus (CN), superior temporal gyrus (STG) and temporal pole (TP) regions of AA (N = 299), LA (N = 344) and NHW (N = 532) donors was obtained through Mayo Clinic, Mt. Sinai School of Medicine, Emory, Columbia, Rush Alzheimer’s Disease Center, Banner Sun Health, and 1Florida. DNA extracted from DLPFC tissue samples (n = 641) was utilized for whole genome sequencing (WGS) at New York Genome Center (NYGC). RNAseq of 2,224 samples was conducted either at Mayo, Rush or NYGC. Sequencing reads were processed through GenomeGPS and MAPRseq pipelines for WGS and RNAseq data, respectively. Following quality control (QC), RNAseq data was normalized and assessed for sources of variation (SOV). Integration of WGS and RNAseq data to perform comparative eQTL analysis across multi‐ethnic populations and brain regions is ongoing.ResultWGS data for 621 donors, and RNAseq data generated at Mayo (n = 1,136 samples), Rush (n = 627), and NYGC (n = 779) sequencing centers, were deposited to the ADKP. Consensus processing of RNAseq data revealed site, sex, race/ethnicity, RIN, AD diagnosis, age at death and/or library batch as SOV across various sites and brain regions. Principal component analysis of gene expression measures revealed no major stratification by disease or brain region. Accompanying clinical metadata of donors have been distributed through ADKP.ConclusionThese multi‐omics data made available to the research community is expected to be an initial step towards bridging our data and knowledge gap to elucidate conserved and distinct AD related pathways across these underrepresented at‐risk populations.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

AbstractBackgroundClinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false‐positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer’s disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1‐ vs. 2‐test criteria for cognitive impairment in former American football players to examine whether 2‐test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration.Method169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p‐tau, t‐tau) and an in‐house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1‐test criteria (≥1.5 SD below norms on one test in either domain) and 2‐test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1‐ or 2‐test criteria, separately, predicted log‐transformed CSF p‐tau181, p‐tau231, t‐tau, and NfL, and hippocampal volumes.Result37 of the 99 football players that were impaired by 1‐test criteria did not meet 2‐test criteria, and four uniquely met 2‐test but not 1‐test criteria (see Figure). Cognitive impairment by 2‐test but not 1‐test criteria predicted higher log‐CSF NfL (2‐test: B = 0.24, p = .007; 1‐test: B = 0.06, p = .53), smaller left hippocampal volume (2‐test: B = ‐195.84, p = .01; 1‐test: B = ‐131.52, p = .08), and smaller right hippocampal volume (2‐test: B = ‐161.19, p = .045; 1‐test: B = ‐134.88, p = .08). Neither criterion predicted p‐tau181, p‐tau231, or t‐tau.Conclusion2‐test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.

AbstractBackgroundPrior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.MethodThe ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.ResultAt baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).ConclusionHearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.

PURPOSE In light of evolving evidence that some patients with node-positive estrogen receptor–positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy. METHODS In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers. RESULTS Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not. CONCLUSION At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.