Facing the unthinkable: Life-threatening illness in the analyst and its impact on the analytic couple.

This article explores the impact of the analyst's life-threatening illness on the analytic couple; it is informed through two theoretical lenses - Freud's ideas about the vicissitudes of mourning, which have been elaborated on by Melanie Klein and John Steiner, and Christopher Bollas's ideas about destiny and idiom. Clinical material will focus on my on-going work with a middle-aged man who has a history of early abandonment and loss and who struggles with being able to remain separate from his objects while being in relationship with them.

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aß and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release.

Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer's disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced HMGB1 translocation and release. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of APOE4-driven gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD.

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have allowed researchers to perform in-depth analyses to uncover the pathogenic mechanisms of AD. An important consideration when studying late-onset AD is its major genetic risk factor, apolipoprotein E4 (apoE4). Although the exact mechanisms underlying apoE4 effects on AD initiation and progression are not fully understood, recent studies have revealed critical insights into the apoE4-induced deficits that occur in AD. In this review, we highlight notable studies that detail apoE4 effects on prominent AD pathologies, including amyloid-ß, tau pathology, neuroinflammation, and neural network dysfunction. We also discuss evidence that defines the physiological functions of apoE and outlines how these functions are disrupted in apoE4-related AD.

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease.

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

Survival of the Fittest: Addressing the Disparities in the Burden of Chronic Kidney Disease.

The prevalence of chronic kidney disease (CKD) is increasingly becoming recognized as a global health concern as well as a critical determinant of poor health outcomes. Decreased access to health care and low socioeconomic status (SES) worsen the adverse effects of biologic or genetic predisposition to CKD. All the studies used were retrieved using the PubMed database. The literature suggests that in developing and developed countries, lower SES is inversely proportional to CKD. It shows an inconsistent relationship between CKD and race; that is, there may or may not be a relationship between these two variables. In the United States (US), the prevalence of the early stages of CKD is similar across different racial/ethnic groups. However, the preponderance of end-stage renal disease (ESRD) is higher for minorities than their non-Hispanic white counterparts. Further investigation is required to understand the role of racial disparities and CKD as well as to understand the significant difference seen in the incidence when progressing from CKD to ESRD. It is necessary to recognize how lower SES and racial/ethnic disparity may result in the impediment of appropriate disease management. A possible approach is the use of the biopsychosocial model, which integrates biological, individual, and neighborhood factors. A practical method of providing appropriate care to these populations will require economically feasible prevention strategies as well as extending the scope of dialysis by the implementation of cheaper alternatives.

Cannabis, More Than the Euphoria: Its Therapeutic Use in Drug-Resistant Epilepsy.

A significant number of epilepsy patients are refractory to conventional antiepileptic drugs. These patients experience considerable neurocognitive impairments that impact their quality of life and ability to function independently. This need for alternative treatment has generated increased interest in cannabis use as a therapeutic option in these patients. This review seeks to analyze data presented on the pharmacology, safety, and efficacy of cannabis use in patients with drug-resistant epilepsy (DRE) and to propose any future recommendations regarding its use. PubMed was used to retrieve all published studies and articles which evaluated the use of cannabis in epilepsy. The two foremost phytocannabinoids of cannabis showing anticonvulsant properties are tetrahydrocannabinol (THC) and cannabidiol (CBD). Due to the psychoactive properties of THC, most studies focused on CBD use in these patients. The use of CBD as an adjunct resulted in decreased seizure frequency, and secondary benefits observed included improvement in mood, alertness and sleep. Adverse events (AEs) reported were drowsiness, diarrhea, increased transaminases and worsening of seizures. It can safely be concluded that there is a significant benefit in DRE patients using CBD as adjunctive therapy. However, further controlled and adequately powered studies are needed to assess the pharmacokinetics and impact of the long-term use of cannabis.

A Mother's Cry: A Race to Eliminate the Influence of Racial Disparities on Maternal Morbidity and Mortality Rates Among Black Women in America.

Racial/ethnic disparities in maternal care exist, even as medicine continues to progress on several aspects, medical care continues to fail countless women each year, particularly minority women and women of color. Black and American Indian/Alaska Native women experienced exponentially more pregnancy-related deaths. Recognizing factors that underlie disparities in pregnancy-related deaths and implementing preventive approaches to resolve them may mitigate racial/ethnic disparities in pregnancy-related mortality. Future research on these disparities should focus on strategies for reducing racial/ethnic inequalities in pregnancy-related deaths, including improving access to high-quality preconception, maternity, and postpartum care for minority women, multi-ethnic education for physicians and healthcare providers in a bid to eliminate implicit biases, adequate funding, and improvement of healthcare facilities in minority areas, education of healthcare providers on variation in the incidence of some certain conditions in different ethnic groups so that care is patient-centered and culturally appropriate. All of these can be enforced through the community, healthcare facility, patient, family, physician, and system-level collaboration.

In Vivo Chimeric Alzheimer's Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons.

Despite its clear impact on Alzheimer's disease (AD) risk, apolipoprotein (apo) E4's contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aß from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

Alzheimer's Gone Viral: Could Herpes Simplex Virus Type-1 Be Stealing Your Memories?

Alzheimer's disease (AD) is one of the principal causes of disability and morbidity. It is one of the most expensive illnesses. Despite this, there are no significant data regarding its etiology and optimal treatment. This review concentrates on the viral hypothesis of AD. After a comprehensive PubMed literature search, we analyzed the studies associating herpes simplex virus type-1 (HSV1) infection to AD from the previous 10 years. Molecular mechanisms whereby HSV1 induces AD-related pathophysiology, including neuronal production and accumulation of amyloid-beta (amyloid-ß), abnormal phosphorylation of tau proteins, impaired calcium homeostasis, and autophagy, are addressed. The virus also imitates the disease in other ways, showing increased neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Serological studies correlate HSV1 infection with AD and cognitive impairment. A causal link between HSV1 and AD raises the concept of a simple, efficient, and preventive treatment alternative. Anti-viral agents impede brain degeneration by preventing HSV1 spread and its replication, decreasing hyperphosphorylated tau and amyloid-ß; thus providing an efficacious treatment for AD. We also mention brown algae, intravenous immunoglobulin (IVIG), and a synthetic drug, BAY57-1293, with anti-viral properties, as options for treating AD. We want to recommend future researchers to look for more affordable, non-invasive, and swifter techniques to identify HSV1 in the brain and assist in the early detection and prevention of AD.

Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.

Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. To uncover such pathways, here we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation monitored by FRET. Our screens uncovered that knockdown of several components of the endosomal sorting complexes required for transport (ESCRT) machinery, including charged multivesicular body protein 6 (CHMP6), or CHMP2A in combination with CHMP2B (whose gene is linked to familial FTD), promote propagation of tau aggregation. We found that knocking down the genes encoding these proteins also causes damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation in neurodegenerative diseases.

Correction to: Burden of caregivers of adult patients with schizophrenia in a predominantly African ancestry population.

In the original publication, the co-author name Kelly-Marie Chen was misspelled and Shenae Miller was missed in the author group. The correct author group has been provided in this correction.

A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure.

Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.

Burden of caregivers of adult patients with schizophrenia in a predominantly African ancestry population.

PURPOSE: There is relative inattention to caregiving burden in black populations in developing economies. This study seeks to assess the level of perceived burden and social determinants of burden of care in caregivers of adult patients with schizophrenia. METHODS: In this cross-sectional study, 115 dyads of patients with schizophrenia caregivers attending public mental health clinics were consecutively recruited. Burden of care was evaluated using the 22-item Zarit Burden Scale (maximum score, 88). Multiple linear regression model explored factors associated with caregiver burden. RESULTS: Caregivers were predominantly females (75.7 %) and were on average 50.8 ± 15.0 years. Most patients with schizophrenia were males (65.2 %) and were on average 43.6 ± 17.2 years old. Caregivers showed on average, mild-to-moderate burden (score, 30.0 ± 14.7; median, 28.0). There was tendency for caregivers of patients who were parents or spouses to have higher levels of burden. In multivariable analyses, higher burden of caregiving was associated with patient's inability to perform self-care (B ± SE, 5.12 ± 1.40; p = 0.0001), closer kinship and higher numbers of psychotic episodes in previous year. The length of caregiving relationship was inversely related. CONCLUSIONS: Poorer functioning and demographic factors were important determinants of caregiver burden. Community mental health services should include self-care interventions in rehabilitation programs in Jamaica.