Adjunctive PCSK9 Inhibitor Evolocumab in the Prevention of Early Neurological Deterioration in Non-cardiogenic Acute Ischemic Stroke: A Multicenter, Prospective, Randomized, Open-Label, Clinical Trial.

Background: Early neurological deterioration (END) is associated with a poor prognosis in acute ischemic stroke (AIS). Effectively lowering low-density lipoprotein cholesterol (LDL-C) can improve the stability of atherosclerotic plaque and reduce post-stroke inflammation, which may be an effective means to lower the incidence of END. The objective of this study was to determine the preventive effects of evolocumab on END in patients with non-cardiogenic AIS.

Comparative species delimitation of a biological conservation icon.

The United States Endangered Species Act (ESA) of 1973 set a precedent for biodiversity conservation across the globe. A key requirement of protections afforded by the ESA is the accurate delimitation of imperiled species. We present a comparative reference-based taxonomic approach to species delimitation that integrates genomic and morphological data for objectively assessing the distinctiveness of species targeted for protection by governmental agencies.

Risk factors and retreatment for relapse in childhood primary nephrotic syndrome treated with rituximab.

Background: The effectiveness of rituximab (RTX) for steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS) in children is well documented. However, there are insufficient data on relapse risk factors. Additionally, the retreat regimen for relapsed children requires further investigation.

A prospective, multicenter analysis of the integrated 31-gene expression profile test for sentinel lymph node biopsy (i31-GEP for SLNB) test demonstrates reduced number of unnecessary SLNBs in patients with cutaneous melanoma.

Background: National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy (SLNB) for patients with > 10% risk of positivity, consider SLNB with 5-10% risk, and foregoing with < 5% risk. The integrated 31-gene expression profile (i31-GEP) algorithm combines the 31-GEP with clinicopathologic variables, estimating SLN positivity risk.

Methods: The i31-GEP SLNB risk prediction accuracy was assessed in patients with T1-T2 tumors enrolled in the prospective, multicenter DECIDE study (n = 322).

Myelitis associated with glial fibrillary acidic protein IgG: characterization and comparison with aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG myelitis.

Background: Awareness of the characteristics of glial fibrillary acidic protein autoantibody (GFAP-IgG) associated myelitis facilitates early diagnosis and treatment. We explored features in GFAP-IgG myelitis and compared them with those in myelitis associated with aquaporin-4 IgG (AQP4-IgG) and myelin oligodendrocyte glycoprotein IgG (MOG-IgG).

Methods: We retrospectively reviewed data from patients with GFAP-IgG myelitis at the First Affiliated Hospital of Zhengzhou University and Henan Children's Hospital from May 2018 to May 2023.

Efficacy of methylprednisolone pulse therapy in Chinese children with IgA vasculitis-associated nephritis (IgAVN).

Background: One of the most common secondary glomerular diseases in children is IgA vasculitis-associated nephritis (IgAVN). Determining the best treatment for IgAVN based on current guidelines is controversial. The purpose of this study was to evaluate the efficacy of methylprednisolone pulse therapy in Chinese children with moderate and severe IgAVN.

Distinct immune signatures for predicting the immunotherapy efficacy of esophageal squamous cell carcinoma or adenocarcinoma.

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are distinct histological subtypes of esophageal cancer. The tumor microenvironment of each subtype significantly influences the efficacy of immunotherapy. However, the characteristics of the tumor microenvironments of both subtypes, as well as their specific impacts on immunotherapy outcomes, still require further elucidation.

Slow-Coagulation Transscleral Cyclophotocoagulation in Pseudoexfoliation Glaucoma.

Purpose: To evaluate the outcomes of slow-coagulation transscleral cyclophotocoagulation (SC-TSCPC) in pseudoexfoliation glaucoma (PXG).

Methods: A single-center, retrospective non-comparative study including consecutive patients with medically uncontrolled PXG who underwent SC-TSCPC (1250-milliwatt power and 4-second duration). The primary outcome measure was surgical success (defined as intraocular pressure (IOP) between 6 - 21 mmHg with ≥20% reduction compared to baseline and no need for further glaucoma surgeries or development of vision-threatening complications).

Basic Science and Pathogenesis.

Background: Brain arteriolosclerosis (B-ASC) is a pathologic hallmark characterized by dysmorphic brain arteriolar wall thickening. B-ASC is a common finding at autopsy in aged persons - some degree of B-ASC is seen in >80% of brains beyond age 80 years - and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC.

Basic Science and Pathogenesis.

Background: Recent research reported that cancer patients had lower risk of Alzheimer's disease (AD). Common signaling pathways, hormonal systems, and genetic predispositions have been hypothesized as important factors contributing to this inverse association. However, the exact mechanisms are still unknown.

Basic Science and Pathogenesis.

Background: Apolipoprotein E (ApoE) exists in three protein isoforms: E2, E3, and E4, which differ by only one or two amino acids. These slight differences profoundly effect protein structure and function, allowing each isoform to differentially impact Alzheimer's Disease (AD) risk. Relative to the most common E3 isoform, E4 dramatically increases risk, while E2 confers a substantial decrease in risk.

Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy (LATE) has been recently recognized as a cause of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical presentations, and their neuropathological changes-LATE-NC and ADNC-commonly co-occur in the brains of individuals with dementia. Frontotemporal degeneration (FTLD-TDP) represents another group of TDP-43-associated neurodegenerative diseases.

Basic Science and Pathogenesis.

Background: Compared with the E3 allele of Apolipoprotein E (APOE), E4 increases late-onset Alzheimer's Disease (AD) risk up to 15-fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE-directed therapeutic approaches. Our lab has generated an inducible "switch" mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell-specific manner.

Basic Science and Pathogenesis.

Background: Diagnosis of Alzheimer's disease (AD) via MRI is costly and can be limited by regional availability. With the recent advancements and discovery of amyloid in the retina, diagnosis of AD and the effect of AD pathology on the retina is becoming well characterized. However, the prevalence of vascular contributions to cognitive impairment and dementia (VCID) and its effects on the retina are less well known.

Basic Science and Pathogenesis.

Background: 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.

Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common cause of dementia in older age. LATE-NC was first coined in 2019 with proposed staging criteria of TDP-43 progressing from amygdala (stage 1), to hippocampus (stage 2), to middle frontal gyrus (stage 3). Criteria were updated in 2023 to further categorize stage 1 to either TDP-43 inclusions in amygdala alone (stage 1a) or hippocampus alone (stage 1b).

Basic Science and Pathogenesis.

Background: Chronic, excessive alcohol consumption causes neurodegeneration and is associated with an increased risk for Alzheimer's disease (AD) and other dementias. Moreover, there has been a consistent rise in alcohol consumption in older adults in the past few decades. However, there is minimal research showing how alcohol consumption affects AD neuropathogenesis and biological mechanisms remain unclear.

Basic Science and Pathogenesis.

Background: This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer's disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post-translational modifications, including hyperphosphorylation (p-tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs).

Basic Science and Pathogenesis.

Background: Alzheimer's disease is defined by the pathological aggregation of amyloid-beta and hyperphosphorylated tau. AD patients often exhibit other symptoms like metabolic and sleep dysfunction. Currently, it is unclear if impairments are a cause or consequence of Aβ or tau aggregation.

Basic Science and Pathogenesis.

Background: We recently reported genetic associations with dementia-related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP-43, Aβ/Tau, and a-synuclein related neuropathology endophenotype scores.

Method: Participant data were drawn from the National Alzheimer's Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer's Disease Genetics Consortium (ADGC) genotype data.

Basic Science and Pathogenesis.

Background: Previously, we developed a co-calibrated and harmonized brain pathology score (BPS) across prospective cohort studies with research brain donation that incorporates multiple forms of postmortem neuropathology, using confirmatory factor analysis. We sought to identify genetic loci associated with BPS using a systems-biology approach, combining data from participants in the Adult Changes in Thought (ACT), the Religious Orders Study, and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.

Method: We used PLINK in each cohort separately for genome-wide association studies (GWAS) of BPS using HRC imputed data from European ancestry participants, adjusting for age at death, sex, and population substructure.

Basic Science and Pathogenesis.

Background: The link between stroke and Alzheimer's disease (AD) is recognized. However, the underlying mechanisms are not yet clear. This study seeks to determine if increased AD risk is linked to gut dysbiosis caused by acute ischemic stroke.

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: Aging microglia accumulate lipid droplets (LDs), secrete pro-inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) and is associated with increased neuroinflammation and LD accumulation. Here, we aimed to determine if the effects of aging and the E4 allele are synergistic in causing the accumulation of LDs seen in LOAD.

Basic Science and Pathogenesis.

Background: Compared to the 'neutral' E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15-fold increase in Alzheimer's Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. Here, we aimed to assess the therapeutic potential of cell-type specific allelic 'switching' by investigating the physiological and neuropathological changes associated with an inducible, in vivo APOE4 to APOE2 transition in astrocytes using a novel transgenic mouse model METHOD: The APOE "switch mouse" (APOE4s2) uses the Cre-loxP system to allow for inducible APOE allele switching from E4 to E2.