Citations

Abstract INTRODUCTION Multi‐omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP‐AD) expanded brain multi‐omics profiling to multi‐ethnic donors. RESULTS We generated multi‐omics data and curated and harmonized phenotypic data from BA ( n = 306), LA ( n = 326), or BA and LA ( n = 4) brain donors plus non‐Hispanic White ( n = 252) and other ( n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION The inclusion of traditionally underrepresented groups in multi‐omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. Highlights Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi‐ethnic populations. Brain multi‐omics data is generated from Black American, Latin American, and non‐Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Introduction: Acute ischemic stroke (AIS) is thesecond leading cause of death globally, accounting for approximately 11% of alldeaths, long-term disability, and functional impairments in survivors. TheCOVID-19 pandemic has raised concerns about its impact on AIS patients. Aim: This study aimed to assess the outcomes,including mortality and severity of disability in AIS hospitalizations withCOVID-19. Methods: We performed a retrospective cross-sectionalanalysis of the Nationwide Inpatient Sample (NIS-2020) in adulthospitalizations for AIS to compare the outcomes [death & APRDRGseverity/disability] in COVID-19 patients using ICD-10 codes. We performedweighted analyses using chi-square, unpaired t-test, and multivariate logisticregression models to evaluate COVID-19-associated poor outcomes amongst AISpatients. Results: Out of 504,460 AIS patients, 7,590 had AIStriggered by COVID-19. Amongst AIS hospitalizations, COVID-19 was more frequentin age group >65 year old 63.2%, male 52.6%, White race (51.4%), patientwith Medicare (58.7%), median household income 0-25 percentile (33.6%), Southzone (43.4%), and hypertensives (83.7%). AIS patients with COVID-19 had ahigher mortality (10.93% vs 3.8%) and severe/extreme disability (93.21% vs37.43%) rates in comparison to patients without COVID-19. (p<0.0001) Inregression analysis COVID-19 was associated with 213% higher odds of mortality(aOR: 3.13, 95% CI: 2.90-3.38, p<0.0001, c:0.671) and higher odds of severe/extreme disability(26.85, 24.53-29.39, p<0.0001, c:0.686) compared to AIS patients withoutCOVID-19. Conclusion: These findings emphasize the substantialimpact of COVID-19 on AIS patients by elevating mortality and risk of severedisability compared to their counterparts. Efforts should be directed towards earlyidentification of stroke population that is at higher risk ofCOVID-19-associated poor outcome and prompt management tomitigate the burden of the both diseases.

This study examines the characteristics of various scanning trajectories or patterns under the influence of scanning parameters in order to develop a theory to define their corresponding image resolutions. The lack of an accurate estimation of pixel size for a specified set of scanning parameters and their connection is a key challenge with existing scanning methods. Thus, this research aimed to propose a novel approach to estimate the pixel size of different scanning techniques. The findings showed that there is a link between pixel size and a frequency ratio NP, which is the ratio of two waveform frequencies that regulates the density of the scanning pattern. A theory has been developed in this study to explain the relationship between scanning parameters and scanning density or pixel size, which was not previously considered. This unique theory permitted the a priori estimate of the image resolution using a particular set of scanning parameters, including the scan time, frequencies, frequency ratio, and their amplitudes. This paper presents a novel and systematic approach for estimating the pixel size of various scanning trajectories, offering the user additional flexibility in adjusting the scanning time or frequency to achieve the desired resolution. Our findings also reveal that in order to achieve a high-quality image with high signal-to-noise and low error, the scanning trajectory must be able to generate a fairly uniform or regular pattern with a small pixel size.

AbstractOn May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed at https://www.heartrhythm365.org/URL/asiasummit‐22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life‐threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region because of differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.

Abstract This article presents a comprehensive review of current Magnetic Imaging Techniques (MIT), specifically Magnetic Particle Imaging (MPI) and Magnetic Resonance Imaging (MRI) methods as well as their impacts and potential in biomedical applications. The paper particularly focuses on several perspectives of MPI and MRI techniques including technical considerations, advantages, limitations, applications, future trends. Surprisingly, there are not many review articles that focused on MPI and MRI. This review will give a complete overview of present technology, perspectives, and potential future developments for MPI and MRI. MIT has become an essential and integral part of medical diagnosis in many large medical clinics and hospitals. This area is rapidly developing and evolving to meet the huge demands in medical diagnosis and prevention. MPI and MRI are promising technologies that provide reliable and effective diagnosis for many diseases including cancer. MIT uses non‐invasive scanning to obtain a detailed image of the body's tissues or organs without the necessity for surgery. These techniques allow us to detect symptoms of serious diseases at an early stage. Early detection also gives patients the chance to get the right care before their illnesses advance to a late, incurable stage, potentially saving many lives.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.