Associations between maternal plasma concentrations of corticotrophin releasing hormone and the placental transcriptome.

Introduction: The placenta produces corticotrophin releasing hormone (CRH), which rises exponentially in maternal plasma across pregnancy. CRH plays a functional role in fetal development, labor initiation, and the regulation of gestational length. We aimed to understand how maternal plasma CRH during pregnancy reflects placental physiology during parturition by characterizing placental transcriptomic signatures of maternal plasma CRH and comparing to transcriptomic signatures of gestational age at birth.

Development and validation of the BRief Eating Disorder Screener (BREDS) for US veterans in healthcare and community settings.

Objective: To develop a Diagnostic and Statistical Manual of Mental Disorders (DSM-5) eating disorder screener.

Method: Veterans enrolled in VA healthcare (N = 344) completed a survey of screening items and established measures. A validation subset (n = 166) participated in diagnostic interviews to confirm an eating disorder diagnosis.

Comparative overall survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR+/HER2- metastatic breast cancer in the US real-world setting.

Background: Randomized controlled trials have shown inconsistent overall survival (OS) benefit among the three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line (1L) treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients with HR+/HER2- mBC receiving 1L palbociclib, ribociclib, or abemaciclib, in combination with an aromatase inhibitor (AI), in US clinical practice.

ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

Historical and political context for Philip Morris International's continuing medical education courses on harm reduction.

In 2024, Philip Morris International's (PMI) website stated they support 'independent' continuing medical education courses on harm reduction for medical and other healthcare professionals. These courses mirrored industry marketing and political strategies by presenting smokeless tobacco products and e-cigarettes as alternatives to smoking, sometimes without mentioning tobacco cessation. The enactment of the US Family Smoking and Tobacco Control Act gave the US Food and Drug Agency jurisdiction over tobacco products and included the industry's 'continuum of risk' frame, and emboldened tobacco companies to make harm reduction claims about these products, which they had previously avoided for fear of triggering restrictive regulation of cigarettes.

The American Clinical Neurophysiology Society Guideline on Indications for Continuous Electroencephalography Monitoring in Neonates.

Purpose: Continuous EEG (cEEG) monitoring is increasingly used in the management of neonates with seizures. There remains debate on what clinically relevant information can be gained from cEEG in neonates with suspected seizures, at high risk for seizures, or with definite seizures, as well as the use of cEEG for prognosis in a variety of conditions. In this guideline, we address these questions using American Clinical Neurophysiology Society structured methodology for clinical guideline development.

Basic Science and Pathogenesis.

Background: Sleep dysfunction is commonly seen in Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP), potentially worsening these conditions. Investigating early neuropathological changes in human sleep-promoting neurons, which often precede cognitive decline, is crucial for understanding the basis for sleep dysfunction as possible treatments yet remain underexplored. We used postmortem brains of AD and PSP patients to quantify neuronal numbers and tau burden in the intermediate nucleus of the hypothalamus (IntN), VLPO analog, known for its role in sleep maintenance.

Basic Science and Pathogenesis.

Background: Excessive daytime sleepiness is a common and early symptom of Alzheimer's disease (AD). The subcortical wake-promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake-promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor-adrenergic neurons.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) is the most prevalent form of dementia globally. While some familial cases are observed, sporadic AD cases are more common and reflect a high level of complexity, with individual risk determined by the interaction of polygenic and environmental factors.

Objective: To characterize polygenic genetic risk factors in individuals with cognitive impairment and Alzheimer's Disease across four regions of Peru.

Basic Science and Pathogenesis.

Background: The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models.

Method: We used primary hippocampal cultures, amyloid-β oligomers (AβO)-injected or transgenic animal models, and human brain tissue to determine brain proteasome function and subcellular localization.

Basic Science and Pathogenesis.

Background: The atherosclerotic plaque in carotid arteries has been associated with dementia. Clinic radiological studies in older adults suggest that the composition of atherosclerotic plaque in the carotid artery can predict vascular dementia (VD) or mixed dementia. The proposed study aims to assess components of atherosclerotic plaques in the carotid arteries, particularly concerning cerebrovascular lesions using racially diverse autopsy samples.

Basic Science and Pathogenesis.

Background: Integrating clinical and genetic risk factors for dementia in a precision medicine framework can play a crucial role in primary prevention. Here, we ascertained the proportion of individuals who are at heightened risk of developing dementia based on their family history, genetic, and clinical risk factors and evaluated how the additive burden of these risk indicators is associated with incident dementia.

Method: We analyzed longitudinal data from 3,395 diverse older adults, dementia-free at baseline with follow-up and whole genome sequencing, enrolled in the National Alzheimer's Co-coordinating Center and the Alzheimer's Disease Neuroimaging Initiative (Table 1).

Basic Science and Pathogenesis.

Background: The direct and chaperone-associated interactions of E3 ubiquitin ligase CHIP with tau in Alzheimer's disease and other tauopathies, regulates tau turnover, by directly linking it to ubiquitination and proteasomal degradation, as well as through suppression of tau aggregation. Modulation of these CHIP-driven tau clearance mechanisms can be an effective treatment strategy. Antigen-binding antibody fragments (Fabs) are potent tools that can highly-selectively engage target proteins and act as functional probes or inhibitors.

Basic Science and Pathogenesis.

Background: Individuals meeting neuropathological criteria for Alzheimer's disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1.

Basic Science and Pathogenesis.

Background: Currently, it is unclear to what extent late-onset Alzheimer's disease (AD) risk variants contribute to early-onset AD (EOAD). One method to clarify the contribution of late-onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS), EOAD participants will have greater PRS than early-onset amyloid-negative cognitively-impaired participants (EOnonAD) and controls, and investigate the association of AD PRS with age of disease onset (AoO) and cognitive performance.

Basic Science and Pathogenesis.

Background: Most research initiatives have emerged from high-income countries (HIC), leaving a gap in understanding the disease's genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC's unique genetics and socioeconomic factors to identify specific Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.

Method: We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort's unique genetic architecture.

Basic Science and Pathogenesis.

Background: Nitric oxide (NO) is involved in synaptic transmission and cerebral plasticity, playing a role in the memory process. However, in states of brain inflammation, hypoxia, or ischemia, there is induction of inducible nitric oxide synthase (iNOS) expression by astrocytes and pyramidal cells in the brain. Under conditions of chronic activation, there is a decoupling of iNOS dimers, leading to a massive generation of superoxide anion and peroxynitrite, O2.

Basic Science and Pathogenesis.

Background: The amyloid cascade hypothesis posits a sequence of events proceeding from amyloid-β (Aβ) deposition to entorhinal cortical (EC) tau to neocortical (meta-temporal) tau. This study examined how genetics may modify relationships between these variables on the AD pathway.

Methods: We used causal path analyses to model effects of sex, APOE-ε4 (0,1,2 alleles), and genetic risk for neuroinflammation on Aβ, EC tau and meta temporal tau.

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: Effective disease-modifying regimens for Alzheimer's Disease (AD) remain lacking due to insufficient understanding of its pathogenic drivers. It was shown previously that upregulation of the calcium-sensing receptor (CaSR), an excitatory family C GPCR, induces neurodegeneration by interfering with the inhibitory γ-aminobutyric acid (GABA) signaling following acute brain injuries (Ann_Clin_Transl_Neurol, 1:851-66). Herein, we determined whether CaSR overexpression is causally associated with the AD.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease(AD) patients experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus(SCN), which is spatially well-conserved but a tiny nucleus in the hypothalamus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression.