Alzheimer's disease transcriptional landscape in ex-vivo human microglia.

Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present the transcriptional landscape of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, including 63 patients representing the full spectrum of clinical and pathological severity of AD.

Lung Transplantation in Patients with Previous or Unknown Oncological Disease: Evaluation of Short- and Long-Term Outcomes.

The accurate selection of the recipient is a crucial aspect in the field of lung transplantation (LTX), especially if patients were previously affected by oncological disease. The aim of this bicentric retrospective study was to evaluate short- and long-term outcomes in patients with previous oncological disease or unknown neoplasia found on native lungs submitted to LTX, compared to a control group. A total of 433 patients were included in the analysis, 31 with malignancies (Group 1) and 402 without neoplastic disease (Group 2).

CHRNA5 links chandelier cells to severity of amyloid pathology in aging and Alzheimer's disease.

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer's Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP).

Association of cognitive reserve with the risk of dementia in the UK Biobank: role of polygenic factors.

Background: It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions.

Aims: We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia.

Method: Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia.

Healthy Lifestyle and Cognition in Older Adults With Common Neuropathologies of Dementia.

Importance: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain.

Objective: To determine the role of postmortem brain pathology, including β-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death.

Design, Setting, And Participants: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up.

Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.

Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism.

Sleep restriction alters the integration of multiple information sources in probabilistic decision-making.

The detrimental effects of sleep loss on overall decision-making have been well described. Due to the complex nature of decisions, there remains a need for studies to identify specific mechanisms of decision-making vulnerable to sleep loss. Bayesian perspectives of decision-making posit judgement formation during decision-making occurs via a process of integrating knowledge gleaned from past experiences (priors) with new information from current observations (likelihoods).

Chronic traumatic encephalopathy and aging-related tau astrogliopathy in community-dwelling older persons with and without moderate-to-severe traumatic brain injury.

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI.

Modulatory effects of estrous cycle on ingestive behaviors and energy balance in young adult C57BL/6J mice maintained on a phytoestrogen-free diet.

The estrous cycle is known to modify food, fluid, and electrolyte intake behaviors and energy homeostasis in various species, in part through fluctuations in estrogen levels. Simultaneously, commonly commercially available rodent dietary formulations greatly vary in soy protein content, and thereby the delivery of biologically active phytoestrogens. To explore the interactions among the estrous cycle, sodium, fluid, and caloric seeking behaviors, and energy homeostasis, young adult C57BL/6J female mice were maintained on a soy protein-free 2920x diet and provided water, or a choice between water and 0.

From theory to practice: translating the concept of cognitive resilience to novel therapeutic targets that maintain cognition in aging adults.

While the concept of cognitive resilience is well-established it has not been defined in a way that can be measured. This has been an impediment to studying its underlying biology and to developing instruments for its clinical assessment. This perspective highlights recent work that has quantified the expression of cortical proteins associated with cognitive resilience, thus facilitating studies of its complex underlying biology and the full range of its clinical effects in aging adults.

Impact of COVID-19 on cancer incidence, presentation, diagnosis, treatment and survival in Northern Ireland.

The COVID-19 pandemic had a major impact on cancer patients and services but has been difficult to quantify. We examined how the entire cancer pathway-from incidence, presentation, diagnosis, stage, treatment and survival-was affected in Northern Ireland during April-December 2020 compared to equivalent 2018-2019 periods using retrospective, observational cancer registry data from the Northern Ireland Cancer Registry (NICR). There were 6748 cancer cases in April-December 2020 and an average 7724 patients in April-December 2018-2019.

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program.

Background: Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results.

Objectives: We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex.

Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer's disease microglia.

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-β and tau. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases.

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the AD-BXD Mouse Population.

Alzheimer's disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel.

Trajectories of olfactory identification preceding incident mild cognitive impairment and dementia: a longitudinal study.

Background: The pattern of olfactory identification change in the early phases of dementing disorders is unclear. We aimed to assess olfactory identification trajectories preceding incident mild cognitive impairment (MCI) and dementia and explore the role of brain pathologies in these trajectories.

Methods: Within the Rush Memory and Aging Project, 1318 dementia-free older adults were followed annually for up to 11 years.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

Background: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [ ε4], and diabetes).

GABA Increases Sensory Transmission In Monkeys.

Sensory input flow is central to voluntary movements. For almost a century, GABA was believed to modulate this flow by inhibiting sensory axons in the spinal cord to sculpt neural inputs into skilled motor output. Instead, here we show that GABA can also facilitate sensory transmission in monkeys and consequently increase spinal and cortical neural responses to sensory inputs challenging our understanding of generation and perception of movement.

Big data, big consortia, and pain: UK Biobank, PAINSTORM, and DOLORisk.

Chronic pain (CP) is a common and often debilitating disorder that has major social and economic impacts. A subset of patients develop CP that significantly interferes with their activities of daily living and requires a high level of healthcare support. The challenge for treating physicians is in preventing the onset of refractory CP or effectively managing existing pain.

Trends in flame retardant levels in upholstered furniture and children's consumer products after regulatory action in California.

In 2013, California revised its upholstered furniture flammability standard TB 117-2013 to improve fire safety without the need for flame retardant (FR) chemicals. Subsequent legislation (SB 1019) required disclosure of FR content. In 2020 California expanded restriction on FR chemicals to include juvenile products and upholstered furniture (AB 2998).

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition.

Methods And Results: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)].

Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer's Disease.

Background: Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer's disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling.

Methods: Using genome sequencing data from 197 families in The NIA Alzheimer's Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.

Results: Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.

miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.

Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers.

Methods: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset.