Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Prevalence of Invasive Bacterial Infection in Hypothermic Young Infants: A Multisite Study.

OBJECTIVE: To determine the prevalence of bacteremia and meningitis (invasive bacterial infection [IBI]) in hypothermic young infants, and also to determine the prevalence of serious bacterial infections (SBI) and neonatal herpes simplex virus and to identify characteristics associated with IBI. STUDY DESIGN: We conducted a retrospective cohort study of infants ≤90 days of age who presented to 1 of 9 hospitals with historical or documented hypothermia (temperature ≤36.0°C) from September 1, 2017, to May 5, 2021. Infants were identified by billing codes or electronic medical record search of hypothermic temperatures. All charts were manually reviewed. Infants with hypothermia during birth hospitalization, and febrile infants were excluded. IBI was defined as positive blood culture and/or cerebrospinal fluid culture treated as a pathogenic organism, whereas SBI also included urinary tract infection. We used multivariable mixed-effects logistic regression to identify associations between exposure variables and IBI. RESULTS: Overall, 1098 young infants met the inclusion criteria. IBI prevalence was 2.1% (95% CI, 1.3-2.9) (bacteremia 1.8%; bacterial meningitis 0.5%). SBI prevalence was 4.4% (95% CI, 3.2-5.6), and neonatal herpes simplex virus prevalence was 1.3% (95% CI, 0.6-1.9). Significant associations were found between IBI and repeated temperature instability (OR, 4.9; 95% CI, 1.3-18.1), white blood cell count abnormalities (OR, 4.8; 95% CI, 1.8-13.1), and thrombocytopenia (OR, 5.0; 95% CI, 1.4-17.0). CONCLUSIONS: IBI prevalence in hypothermic young infants is 2.1%. Further understanding of characteristics associated with IBI can guide the development decision tools for management of hypothermic young infants.

A method describing the microdissection of trabecular meshwork tissue from Brown Norway rat eyes.

Glaucoma is often associated with elevated intraocular pressure (IOP), generally due to obstruction of aqueous humor outflow within the trabecular meshwork (TM). Despite many decades of research, the molecular cause of this obstruction remains elusive. To study IOP regulation, several in vitro models, such as perfusion of anterior segments or mechanical stretching of TM cells, have identified several IOP-responsive genes and proteins. While these studies have proved informative, they do not fully recapitulate the in vivo environment where IOP is subject to additional factors, such as circadian rhythms. Thus, rodent animal models are now commonly used to study IOP-responsive genes in vivo. Several single-cell RNAseq studies have been performed where angle tissue, containing cornea, iris, ciliary body tissue in addition to TM, is dissected. However, it is advantageous to physically separate TM from other tissues because the ratio of TM cells is relatively low compared to the other cell types. In this report, we describe a new technique for rat TM microdissection. Evaluating tissue post-dissection by histology and immunostaining clearly shows successful removal of the TM. In addition, TaqMan PCR primers targeting biomarkers of trabecular meshwork (Myoc, Mgp, Chi3l1) or ciliary body (Myh11, Des) genes showed little contamination of TM tissue by the ciliary body. Finally, pitfalls encountered during TM microdissection are discussed to enable others to successfully perform this microsurgical technique in the rat eye.

Impact of Trainee Involvement on Pediatric ERCP Procedures: Results From the Pediatric ERCP Initiative.

This study examines the role of trainee involvement with pediatric endoscopic retrograde cholangiopancreatography (ERCP) and whether it affects the procedure's success, post-procedural adverse outcomes, and duration. A secondary analysis of the Pediatric ERCP Database Initiative, an international database, was performed. Consecutive ERCPs on children <19 years of age from 18 centers were entered prospectively into the database. In total 1124 ERCPs were entered into the database, of which 320 (28%) were performed by trainees. The results showed that the presence of trainees did not impact technical success ( P = 0.65) or adverse events rates ( P = 0.43). Rates of post-ERCP pancreatitis, pain, and bleeding were similar between groups ( P > 0.05). Fewer cases involving trainees were in the top quartile (>58 minutes) of procedural time (19% vs 26%; P = 0.02). Overall, our findings indicate trainee involvement in pediatric ERCP is safe.

Retinal capillary oximetry with visible light optical coherence tomography.

Assessing oxygen saturation (sO2) remains challenging but is nonetheless necessary for understanding retinal metabolism. We and others previously achieved oximetry on major retinal vessels and measured the total retinal oxygen metabolic rate in rats using visible-light optical coherence tomography. Here we extend oximetry measurements to capillaries and investigate all three retinal vascular plexuses by amplifying and extracting the spectroscopic signal from each capillary segment under the guidance of optical coherence tomography (OCT) angiography. Using this approach, we measured capillary sO2 in the retinal circulation in rats, demonstrated reproducibility of the results, validated the measurements in superficial capillaries with known perfusion pathways, and determined sO2 responses to hypoxia and hyperoxia in the different retinal capillary beds. OCT capillary oximetry has the potential to provide new insights into the retinal circulation in the normal eye as well as in retinal vascular diseases.

Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research.

The recently developed new genome-editing technologies, such as the CRISPR/Cas system, have opened the door for generating genetically modified nonhuman primate (NHP) models for basic neuroscience and brain disorders research. The complex circuit formation and experience-dependent refinement of the human brain are very difficult to model in vitro, and thus require use of in vivo whole-animal models. For many neurodevelopmental and psychiatric disorders, abnormal circuit formation and refinement might be at the center of their pathophysiology. Importantly, many of the critical circuits and regional cell populations implicated in higher human cognitive function and in many psychiatric disorders are not present in lower mammalian brains, while these analogous areas are replicated in NHP brains. Indeed, neuropsychiatric disorders represent a tremendous health and economic burden globally. The emerging field of genetically modified NHP models has the potential to transform our study of higher brain function and dramatically facilitate the development of effective treatment for human brain disorders. In this paper, we discuss the importance of developing such models, the infrastructure and training needed to maximize the impact of such models, and ethical standards required for using these models.

Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse.

Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER α and ER ß, there are membrane-bound ER α, ER ß, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction.

Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection.

BACKGROUND: Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). METHODS: We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. RESULTS: RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. CONCLUSIONS: Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.

Venous Thromboembolism among Noncritically Ill Hospitalized Children: Key Considerations for the Pediatric Hospital Medicine Specialist.

Venous thromboembolism (VTE) is a leading cause of morbidity and preventable harm among noncritically ill hospitalized children. Several clinical factors relevant to the noncritically ill hospitalized child significantly increase the risk of VTE including the presence of central venous catheters, systemic inflammation, and prolonged immobilization. Although risk mitigation strategies have been described, the diagnosis, treatment, and prevention of VTE require standardization of institutional practices combined with multidisciplinary collaboration among pediatric hospitalists, hematologists, and other care providers. In this narrative review, we summarize the epidemiology of VTE, risk models identifying high-risk conditions associated with VTE, and prevention and treatment strategies. We further describe successful quality improvement efforts implementing institutional VTE risk stratification and thromboprophylaxis procedures. Finally, we highlight unique challenges facing pediatric hospital medicine specialists in the era of the COVID-19 pandemic, including caring for adults admitted to pediatric hospital units, and describe future research opportunities for VTE in the noncritically ill hospitalized child.

Wide-field sensorless adaptive optics swept-source optical coherence tomographic angiography in rodents.

In this study, we present a sensorless adaptive optics swept-source optical coherence tomographic angiography (sAO-SS-OCTA) imaging system for mice. Real-time graphics processing unit (GPU)-based OCTA image acquisition and processing software were applied to guide wavefront correction using a deformable mirror based on signal strength index (SSI) from both OCT and OCTA images. High-resolution OCTA images with aberrations corrected and contrast enhanced were successfully acquired. Fifty-degree field of view high-resolution montaged OCTA images were also acquired.

Bayesian parameter estimation for automatic annotation of gene functions using observational data and phylogenetic trees.

Gene function annotation is important for a variety of downstream analyses of genetic data. But experimental characterization of function remains costly and slow, making computational prediction an important endeavor. Phylogenetic approaches to prediction have been developed, but implementation of a practical Bayesian framework for parameter estimation remains an outstanding challenge. We have developed a computationally efficient model of evolution of gene annotations using phylogenies based on a Bayesian framework using Markov Chain Monte Carlo for parameter estimation. Unlike previous approaches, our method is able to estimate parameters over many different phylogenetic trees and functions. The resulting parameters agree with biological intuition, such as the increased probability of function change following gene duplication. The method performs well on leave-one-out cross-validation, and we further validated some of the predictions in the experimental scientific literature.

Use of Polyvinyl Alcohol-Porcine Small Intestine Submucosa Stent in the Prevention of Anastomotic Leaks in the Porcine Colon.

INTRODUCTION: Gastrointestinal anastomoses are performed millions of times per year worldwide. The major complication they share is anastomotic leak. We describe the development and initial safety/efficacy of a novel luminal stent which aims to address this clinical issue. MATERIALS AND METHODS: The stent was created out of two materials, a polyvinyl alcohol core and outer layer of acellular porcine small intestine submucosa. Ten healthy pigs underwent laparotomy, a portion of the colon was transected, and the stent was placed within the colonic lumen at the site of resection. Pigs were sacrificed at the end of postoperative week 2, and postoperative week 4. A portion of the descending colon was resected, and tissue samples from the anastomosis, intentional defect scar, and normal bowel overlying the stent were sent for histopathologic examination. RESULTS: All ten animals survived the study. None developed any clinical signs of obstruction, infection, leakage, fistula, wound complications, or bleeding. No evidence of colonic leak or luminal stenosis/stricture was noted. CONCLUSIONS: The results of this study show that a polyvinyl alcohol/acellular porcine small intestine submucosa stent sewn underneath a colonic anastomosis with a 2 cm intentional defect will result in no anastomotic complications. There were also no complications from placing this stent in any pigs. Additional studies with a control group should be conducted to see if this same stent can be built in different diameters, lengths, and configurations to prevent leaks in other organs. These encouraging results will hopefully lead to decreased leaks and the need for temporary ostomies in humans.

High-flow nasal cannula and bilevel positive airway pressure for pediatric status asthmaticus: a single center, retrospective descriptive and comparative cohort study.

INTRODUCTION: We aimed to describe patient characteristics and clinical outcomes for children hospitalized for status asthmaticus (SA) receiving high-flow nasal cannula (HFNC) or bilevel positive airway pressure (BiPAP). METHODS: We performed a single center, retrospective cohort study among 39 children admitted for SA aged 5-17 years from January 2016 to May 2019 to a quaternary pediatric intensive care unit (PICU). Cohorts were defined by BiPAP versus HFNC exposure and assessed to determine if differences existed in demographics, anthropometrics, comorbidities, asthma severity indices, historical factors, duration of noninvasive ventilation, and asthma-related clinical outcomes (i.e. length of stay, mechanical ventilation rates, exposure to concurrent sedatives/anxiolysis, and rate of adjunctive therapy exposure). RESULTS: Thirty-three percent (n = 13) received HFNC (33%) and 67% (n = 26) BiPAP. Children receiving BiPAP had greater age (10.9 ± 3.7 vs. 6.8 ± 2.2 years, P < 0.01), asthma severity (proportion with severe NHLBI classification: 38% vs. 0%, P < 0.01; median pediatric asthma severity score: 13[12,14] vs. 10[9,12], P < 0.01), previous PICU admissions (62% vs. 15%, P = 0.01), frequency of prescribed anxiolysis/sedation (42% vs. 8%, P = 0.02), and median duration of continuous albuterol (1.7[1,3.1] vs. 0.9[0.7,1.6] days, P = 0.03) compared to those on HFNC. Those on HFNC more commonly were treated comorbid bacterial pneumonia (69% vs. 19%, P < 0.01). No differences in NIV duration, mortality, mechanical ventilation rates, or LOS were observed. CONCLUSIONS: Our data suggest a trial of BiPAP or HFNC appears well tolerated in children with SA. Prospective trials are needed to establish modality superiority and identify patient or clinical characteristics that prompt use of HFNC over BiPAP.

Heliox for Pediatric Critical Asthma: A Multicenter, Retrospective, Registry-Based Descriptive Study.

BACKGROUND: In cases of critical asthma (CA), heliox may be applied as an adjunctive rescue therapy to avoid invasive mechanical ventilation (MV), improve deposition of aerosolized medications, and enhance laminar airflow through obstructed airways. Using the Pediatric Health Information System (PHIS) registry, we evaluate heliox prescribing and explored for differences in MV rates and hospital length of stay (LOS) among children with and without heliox exposure. METHODS: We performed a retrospective cohort study using PHIS data from 42 pediatric intensive care units among children 5-17 years of age admitted for CA from 2010 through 2019. Primary outcomes were heliox prescribing rates and trends. Secondary outcomes were invasive MV rates and LOS assessed in a subgroup of children receiving ≥ 1 adjunctive intervention(s). RESULTS: Of the 19,780 studied, heliox was prescribed in 12.5% and linearly declined from 16.1% in 2010 to 5.6% in 2019. The overall MV rate was 12.8% and was lower in subjects receiving heliox alone (4.9%) compared to heliox plus alternative adjunctive therapies [31.2%] or children receiving non-heliox adjunctive therapies [22.1%], P < .01). Accounting for MV, no difference in LOS was observed. In exploratory adjusted models, MV free hospitalization was associated with heliox-only exposure (OR: 0.33, 95% CI: 0.17-0.63, P < .01) and exposure to multiple adjunctive therapies was associated with MV (OR: 2.48, 95% CI: 1.56-3.94, P < .01). CONCLUSIONS: In this multicenter retrospective study from 42 children's hospitals, heliox prescribing for CA declined over the last decade. Subjects receiving multiple adjunctive therapies more commonly required invasive MV perhaps indicating a greater severity of illness. At this time, prospective trials needed to identify the role of heliox for pediatric CA.

Oligomeric Aß in the monkey brain impacts synaptic integrity and induces accelerated cortical aging.

As the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and Alzheimer's disease (AD) has increased and is projected to cost more than $290 billion in the United States in 2019. Despite significant investment in research over the last decades, there is no effective treatment to prevent or delay AD progression. There is a translational gap in AD research, with promising drugs based on work in rodent models failing in clinical trials. Aging is the leading risk factor for developing AD and understanding neurobiological changes that affect synaptic integrity with aging will help clarify why the aged brain is vulnerable to AD. We describe here the development of a rhesus monkey model of AD using soluble oligomers of the amyloid beta (Aß) peptide (AßOs). AßOs infused into the monkey brain target a specific population of spines in the prefrontal cortex, induce neuroinflammation, and increase AD biomarkers in the cerebrospinal fluid to similar levels observed in patients with AD. Importantly, AßOs lead to similar dendritic spine loss to that observed in normal aging in monkeys, but so far without detection of amyloid plaques or tau pathology. Understanding the basis of synaptic impairment is the most effective route to early intervention and prevention or postponement of age-related cognitive decline and transition to AD. These initial findings support the use of monkeys as a platform to understand age-related vulnerabilities of the primate brain and may help develop effective disease-modifying therapies for treatment of AD and related dementias.

Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.

Towards developing a rhesus monkey model of early Alzheimer's disease focusing on women's health.

Alzheimer's disease (AD) is the most common cause of elderly dementia, affecting nearly 50 million people worldwide, with two-thirds of the cases in the USA in women. Despite considerable investment, this prevalence is expected to increase further in the coming decades, based on the projected demographics of the population. Currently, most of the preclinical AD studies rely on transgenic mice carrying mutations associated with the early onset familiar form of AD, although the vast majority of cases are sporadic. A prevailing current hypothesis is that the cascade of events leading to AD starts with the accumulation of small soluble oligomers of the Aß peptide (AßOs) that target and disrupt synapses. Taking advantage of the high translational power of rhesus monkeys due to their physiological and genetic similarities to humans, we recently developed a female rhesus monkey model of early AD pathogenesis based on exogenous administration AßOs. Here we review and discuss how soluble oligomers of Aß can target vulnerable spines in the neocortex and hippocampus of female middle-aged monkeys and induce neuroinflammatory responses, similar to what is known to occur in the human brain. Developing a rhesus monkey model of early AD focusing on women's health is critical for the understanding of how hormonal changes during menopause transition affect brain health and ultimately may contribute to AD neurodegeneration.