Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.

Background: PSEN1, PSEN2, and APP mutations cause Alzheimer's disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP.

Methods: We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer's disease (FAD) patients harboring mutations in PSEN1, PSEN2, and APP and mechanistically characterized by integrating RNA-seq and ATAC-seq.

Basic Science and Pathogenesis.

Background: Alzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region.

Basic Science and Pathogenesis.

Background: P-tau217 has emerged as a compelling alternative to long-established p-tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer's disease (AD). Understanding the specificity and significance of p-tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.

Methods: We measured p-tau217 phosphorylation by mass spectrometry.

Basic Science and Pathogenesis.

Background: Amyloid PET imaging is a promising biomarker to track the accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Recent large-scale genome-wide association studies (GWAS) reported common risk factors associated with amyloidosis, suggesting that this endophenotype is driven by genetic variants. We hypothesized that genes with multiple variants with deleterious effect are associated with Aβ accumulation.

Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC.

Basic Science and Pathogenesis.

Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relationship between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.

Clinical Manifestations.

Background: Individuals with Down syndrome (DS) typically develop Alzheimer's disease (AD) at an early age. Estimates of the age of decline vary, but typically place it in the early-mid 50s. As AD onset can be difficult to identify in intellectually impaired cohorts, understanding the expected timing of decline may help individuals and caregivers prepare.

Clinical Manifestations.

Background: Recent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer's disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum.

Clinical Manifestations.

Background: Trip chaining occurs when a driver departs from an origin and travels to multiple locations before returning. Increased trip complexity may require higher levels of executive function, memory, and navigational abilities. Subtle behavioral changes are apparent before a clinical diagnosis of Alzheimer Disease (AD); however, the correspondence between preclinical AD pathology (amyloid deposition, tauopathy, neurodegeneration), cognition, and changes in trip chaining behavior is unknown.

Clinical Manifestations.

Background: The newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems.

Methods: Using 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0-4) and clinical (0-4) stages using amyloid PET, tau PET(MK-6240), and clinical measures as described by the working group.

CT Angiography of the Upper Extremities: Review of Acute Arterial Entities.

Historically, evaluation of the upper extremity vasculature was performed using digital subtraction angiography. With the advancement of cross-sectional imaging and submillimeter isotropic data acquisition, CT angiography (CTA) has become an excellent noninvasive diagnostic tool for evaluation of the vasculature of the upper extremities. CTA allows quick evaluation of vessel patency and irregularity and achievement of the anatomic detail needed in preoperative planning.

The Informal, Non-Prescribed Use of Antiretroviral Medications for PrEP Among a National US-Based Sample of Gay, Bisexual, and Other Men Who Have Sex with Men: A Cross-Sectional Study.

This brief report presents findings on informal, non-prescribed PrEP use among an online sample of gay, bisexual and other men who have sex with men (n = 196). Mean age was 33.4.

Dermal CIC-Rearranged Sarcoma With Neuroendocrine Differentiation Mimicking Merkel Cell Carcinoma.

Capicua transcriptional repressor (CIC)-rearranged sarcoma (CRS) is a rare and recently described tumor that most commonly affects patients between 15 and 30 years of age. It is an undifferentiated round cell malignancy, with a disease defining CIC fusion, with double homeobox 4 (DUX4) being the most common partner. Here, we report a 77-year-old woman who presented with a cutaneous thigh mass with a clinical morphology suggesting Merkel cell carcinoma.

Associations Between Patient Characteristics and Progression to Multiple Myeloma Among Patients With Monoclonal Gammopathy of Undetermined Significance: A Systematic Review.

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant condition of multiple myeloma (MM). Evidence suggested old age, black race, male gender, and obesity as risk factors for MGUS development; however, whether they are associated with an increased risk of progression to MM among patients with MGUS is unclear. A systematic search of PUBMED and EMBASE for cohort studies investigating the association between age/race/gender/obesity and progression to MM.

Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries.

Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a, a blood flow responsive transcription factor, expression levels and altered targeting of vSMCs between arteries and veins.

Tramadol as a fentanyl adulterant: Prevalence and management in a ToxIC Fentalog study prospective cohort.

Background: Tramadol is an adulterant of illicit opioids. As it is a serotonin-norepinephrine reuptake inhibitor as well as a μ-opioid agonist, tramadol adulteration may worsen overdose signs and symptoms or affect the amount of naloxone patients receive.

Methods: This is a multicenter, prospective cohort of adult patients with suspected opioid overdoses who presented to one of eight United States emergency departments and were included in the Toxicology Investigators Consortium's Fentalog Study.

Antibodies to watch in 2025.

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025.

Neonatal Seizures and Associated Neurobehavioral Profiles in Preschool Age Children.

Background: Neonatal seizures are common with acute brain injury. Up to 25% of survivors develop postneonatal epilepsy. We hypothesized postneonatal epilepsy diagnosed by age 24 months would increase risk for early markers of neurobehavioral disorders than acute provoked neonatal seizures alone.

Identification of antigen-presenting cell-T cell interactions driving immune responses to food.

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4 T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection.

Nbeal2 Knockout Mice Are Not Protected Against Hypoxia-Induced Pulmonary Vascular Remodeling and Pulmonary Hypertension.

Inflammation drives the initiation and progression of pulmonary hypertension (PH). Platelets, increasingly recognized as immune cells, are activated and increased in the lungs of patients with PH. Platelet activation leads to the release of α-granule chemokines, many of which are implicated in PH.

Youth Generalized Anxiety and Brain Activation States During Socioemotional Processing.

Importance: The brain enters distinct activation states to support differential cognitive and emotional processes, but little is known about how brain activation states differ in youths with clinical anxiety.

Objective: To characterize brain activation states during socioemotional processing (movie stimuli) and assess associations between state characteristics and movie features and anxiety symptoms.

Design, Setting, And Participants: The Healthy Brain Network is an ongoing cross-sectional study of individuals aged 5 to 21 years experiencing difficulties in school, of whom approximately 45% met criteria for a lifetime anxiety disorder diagnosis.