Early treatment discontinuation in patients with deficient mismatch repair or microsatellite instability high metastatic colorectal cancer receiving immune checkpoint inhibitors.

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.

Intraoperative FiO and risk of impaired postoperative oxygenation in lung resection: A propensity score-weighted analysis.

Study Objective: To assess whether, in a lung resection cohort with a low probability of confounding by indication, higher FiO is associated with an increased risk of impaired postoperative oxygenation - a clinical manifestation of lung injury/dysfunction.

Design: Pre-specified registry-based retrospective cohort study.

Setting: Two large academic hospitals in the United States.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant.

Randomized Control Trial Evaluating Different Modalities of Real-Time Surgical Feedback.

Introduction:: Surgical training is a constant exchange between trainers and trainees, and intraoperative surgical feedback is an integral part of learning. New technologies in robotic surgery allow for the delivery of visual aid and verbal feedback intraoperatively, but it has not yet been determined if feedback type affects the trainee learning process.

Methods:: 49 novice participants were recruited and randomized into four feedback groups: , , of verbal/visual, and no feedback ().

Basic Science and Pathogenesis.

Background: Microglia undergo varying regional dependent functional changes, which can exacerbate cognitive decline in Alzheimer's disease, but the full clinical relevance remains unclear. Ramified microglia survey the micro-environment and inert/amoeboid microglia engulf debris. A third morphological type; rod microglia, have been observed in a number of pathological conditions, but are relatively understudied.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a neurological disorder marked by progressive cognitive decline, memory deficits, and neuronal cell loss (Knopman, 2021). A brain region significantly impacted by the progression of AD is the subiculum, a structure responsible for spatial navigation, cognitive processes, and the modulation of emotional and affective behaviors within the hippocampus (Fanselow and Dong, 2010). Although subiculum cell loss has been well-established as an early indicator of AD (Carlesimo et al.

Basic Science and Pathogenesis.

Background: The ways in which diverse genetic variants interact to affect the phenotype of AD is poorly understood. The relatively consistent phenotype associated with specific mutations causing autosomal dominant AD (ADAD) provides the opportunity to study how other genetic variants contribute to disease manifestations.

Method: We performed an in-depth case study of a patient with the A431E PSEN1 mutation who had onset of progressive spastic paraplegia at age 20.

Basic Science and Pathogenesis.

Background: Cellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer's disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so-called "senescence-associated secretory phenotype" (SASP) characterized by increased secretion of pro-inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.

Method: In this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) and other dementia risk may be influenced by the immune function and associated with several white blood cell type counts. In cognitively normal Black, Hispanic, and non-Hispanic white older adults we related three white blood cell types previously associated with AD risk to tau positron emission tomography (PET) values in the medial temporal lobe (MTL), where tau accumulates early. We assessed whether amyloid positivity moderated this relationship.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aβ). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer's Disease (AD) despite the fact that synuclein pathology is present in over 50% of postmortem brains of AD patients. We are now expanding on our previous studies which showed positive therapeutic effects of downregulating α-syn in AD mice to understand the overall brain transcriptomic and mechanistic changes induced by treatment.

Basic Science and Pathogenesis.

Background: Cerebrovascular injury is a common pathological feature of a spectrum of neurological disorders, including traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), and aging. Vascular manifestations among these conditions are similar indeed, including the breakdown of the blood-brain barrier (BBB). However, whether there is a unique molecular mechanism underlying the vascular changes among these conditions remains elusive.

Basic Science and Pathogenesis.

Background: Synaptic loss predicts cognitive decline in Alzheimer's disease (AD). However, the critical disease modifying molecular mechanisms of synaptic failure remain elusive. Animal studies implicate the increased activation of cytosolic phospholipase (cPLA2) activation in synaptic loss and neuroinflammation.

Basic Science and Pathogenesis.

Background: According to data from the Alzheimer's Association, more than two-thirds of patients living with Alzheimer's disease (AD) in the United States are women. The interplay between aging and hormone depletion during menopause has been proposed as a leading cause, but the molecular underpinnings of this vulnerability are not fully understood. On the one hand, approaches that seek to supplement estrogens to rescue pre-menopausal hormonal levels have had contradictory outcomes in clinical trials.

Basic Science and Pathogenesis.

Background: Evaluating sex differences in modifiable risk factors for Alzheimer's disease could provide valuable information regarding the mechanisms by which these factors confer risk. Physical activity is a risk factor that has been shown to positively impact both telomere length, a marker of cellular age, and cognition. The goal of this study was to evaluate whether telomere length mediates the association between physical activity and cognition differently by sex.

Basic Science and Pathogenesis.

Background: Cerebrovascular disease (CVD) is a major cause of mortality in females, while two-thirds of Alzheimer's disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well-established; it is unclear if associations between APOE and CVD are sex-specific.

Basic Science and Pathogenesis.

Background: Positron emission tomography (PET) tau tracer PI-2620 frequently shows off-target meningeal binding (Figure 1). Of standard regions of interest, only lateral parietal (LP) is contaminated by this. We compare the standardized uptake value ratio (SUVR) in the LP before and after eroding the LP mask to remove meningeal contamination.

Basic Science and Pathogenesis.

Background: Identification of cell-type vulnerability in Alzheimer's Disease (AD) is critical to the clinical development of targeted treatments. Neurodegeneration of the subiculum (SUB) is an early biomarker of AD, but it is unknown if specific SUB cell-types are susceptible to AD neurodegeneration. In the 5xFAD mouse model, significant cell loss occurs within the SUB by 8 months of age.

Basic Science and Pathogenesis.

Background: Mitochondrial dysfunction is an early and prominent feature of Alzheimer's disease (AD). We have recently published that lower brain mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of AD neuropathological change and reduced cognitive performance. Here, we addressed how mtDNAcn affects cell-type specific phenotypes.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the foremost cause of global dementia, also characterized by retinal changes involving Aβ, hyperphosphorylated-tau (p-tau), neuronal degeneration, and tissue atrophy. Mitochondrial-driven reactive oxygen species (ROS) production, linked to synaptic dysfunction, is common to various neurodegenerative conditions, including AD. Despite synaptic dysfunction being an early predictor of cognitive decline in AD, its occurrence in the AD retina is unexplored.

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: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset.

Basic Science and Pathogenesis.

Background: Individuals with Down Syndrome (DS) exhibit a unique aging profile and have early-onset Alzheimer's Disease (AD) due to a triplication of the amyloid precursor protein (APP) gene on chromosome 21.

Method: Here, we present a study of a 73-year-old non-Hispanic White female with DS who underwent extensive clinical assessments for several decades. She had a cognitive and functional impairment consistent with DS and AD-like symptoms.

Basic Science and Pathogenesis.

Background: Mutations in the presenilin 1 (PSEN1) gene cause early onset autosomal dominant Alzheimer's Disease (AD), and the Jalisco mutation (A431E) is a subset found in people of Mexican descent (Yescas P, 2006). The Jalisco A431E mutation has been shown to produce distinct AD neuropathology such as cotton-wool amyloid plaques as well as motor dysfunction like spastic paraparesis (Orozco-Barajas, 2022). High levels of tau neuropathology have been observed with other PSEN1 mutations, but tau neuropathology in Jalisco patients has not been examined.

Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.