HIV-associated neurocognitive disorders (HAND) remain prevalent in people with HIV (PWH) despite effective antiretroviral therapy, suggesting that persistent immune activation contributes to ongoing neurological dysfunction. Maladaptive trained immunity (TRIM), long-term innate immune reprogramming characterized by sustained inflammatory responses, metabolic rewiring, and epigenetic remodeling, has been proposed as a sustaining mechanism. We performed single-nucleus RNA-seq and ATAC-seq on post-mortem brain from PWH with HIV-associated dementia (HAD) or asymptomatic neurocognitive impairment (ANI) and compared these data with published HIV-uninfected (PWoH) datasets. In PWH versus PWoH, glia, led by microglia, showed enrichment of innate immune signaling and upregulation of inflammatory mediators including NLRP3, TLR2, and TLR4. In parallel, glia showed coordinated cholesterol remodeling, with efflux transporter and apolipoprotein upregulation alongside LDLR downregulation, and partial microglial glycolytic reprogramming (PFKFB3, HK2, PGK1 upregulation). Chromatin accessibility profiling showed concordant gains at inflammatory, cholesterol regulatory (notably RXRA and APOE), and glycolytic loci. The HAD versus ANI comparison revealed selective reorganization rather than uniform amplification, with increased lipid scavenger receptor accessibility in oligodendrocytes and reduced accessibility at cholesterol efflux and glycolytic loci. Neurons exhibited predominantly bystander epigenetic changes. Three features distinguish this pattern from chronic inflammation alone and align it with trained immunity hallmarks: concordant transcriptional and chromatin-level priming at inflammatory loci, parallel rewiring of glycolytic and cholesterol metabolism, and persistence despite long-term viral suppression. These multiomic data are consistent with maladaptive trained immunity sustaining neuroinflammation in HAND, though functional validation is required.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare autoimmune encephalopathy characterized by heterogeneous neuropsychiatric manifestations. We describe the case of a 59-year-old woman with a history of anxiety and severe alcohol use disorder who presented with acute psychosis, marked behavioral disorganization, and cognitive impairment initially attributed to alcohol withdrawal, metabolic disturbance, or primary psychiatric illness. Despite extensive evaluation, including negative infectious, toxicologic, metabolic, structural, and paraneoplastic workups, no clear etiology was identified. Additional findings, including a reactive HIV screening assay and elevated vitamin B12 levels, further complicated the diagnostic process. Thyroid studies revealed markedly elevated anti-thyroid peroxidase and anti-thyroglobulin antibodies with subclinical hypothyroidism, raising suspicion for SREAT. Following initiation of high-dose intravenous (IV) corticosteroids, the patient demonstrated rapid and marked improvement in mental status within 48 hours, supporting an immune-mediated process. Subsequent cerebrospinal fluid analysis, electroencephalography, and brain imaging remained unremarkable. This case highlights the diagnostic challenges of SREAT, particularly in patients with comorbid psychiatric and substance use disorders, and underscores the importance of considering autoimmune encephalopathy in cases of unexplained neuropsychiatric decline. Early recognition and timely immunosuppressive therapy may lead to significant clinical recovery and prevent prolonged morbidity.

HIV-1-associated neurocognitive disorders (HAND) manifest in 15% to 50% of people with HIV, impairing learning and memory and executive function. The chronic generation of HIV-1 Transactivator of transcription (Tat) likely contributes to HAND via direct neuronal toxicity and glial-mediated toxicity. This review summarizes our current understanding of how chronic Tat generation from microglia and astrocytes promote glutamate excitotoxicity.

Cognitive impairment is one of the leading causes of disability worldwide and it affects about 6.5% of the population over the age of 65. Hearing impairment is a significant health problem and a possible cause for dementia. Preventing hearing loss or at least correcting it by the use of acoustic prosthesis may reduce the onset of dementia in old age. Indeed, hearing loss has been proposed as a risk factor for dementia, even if the mechanisms that correlate the two diseases are not yet fully understood. It can accelerate existing mild cognitive impairment by increasing the cognitive burden and/or exhausting existing cognitive compensatory strategies, and it could also increase social isolation. Peripheral hearing impairments and Central Auditory Processing (CAP) dysfunction should both be evaluated. Indeed, although peripheral auditory function impairment is perhaps the primary pathological component of early age-related hearing loss (ARHL), CAP dysfunction becomes increasingly important in the later stages of ARHL. The assessment of peripheral hearing function includes self-reporting and some screening tests (such as the 10-item Hearing Handicap Inventory for the Elderly - Short Form), a first-level clinical assessment for hearing loss (such as spoken voice or finger friction tests), audiometric screening tests (portable audiometers, portable audio) and diagnostic audiometric tests (such as pure tone audiometry in a soundproof booth to test the acoustic threshold). The present article focuses on the possible connection between sensory deprivation and the development of cognitive impairment in late age. The use of hearing aids and cognitive training could help delay or prevent the onset of cognitive decline. Furthermore, the use of hearing aids can be an effective tool not only to minimize perceived disability in older individuals, but also to reduce the caregiver's burden by improving the patients' ability to communicate.

HIV-1 remains a major global health concern, exerting detrimental effects not only on the immune system but also on the central nervous system (CNS). Soon after HIV-1 infection, the virus can breach the blood-brain barrier (BBB), initiating processes that result in neuronal damage and cell death. These effects manifest clinically as a spectrum of cognitive, behavioural, and motor impairments collectively termed HIV-associated neurocognitive disorders (HAND). Among the viral proteins implicated in CNS pathology, the Trans-Activator of Transcription (Tat) protein stands out due to its pronounced neurotoxic and neurotropic characteristics. Tat is secreted by infected cells and can accumulate in the CNS, persisting even in individuals undergoing effective antiretroviral therapy (ART), thereby contributing to ongoing neurocognitive complications. Although Tat has been extensively studied since the 1980s, current literature examining its effects within the context of modern treatment regimens remains sparse. This chapter offers a comprehensive and updated review of the role of HIV-1 Tat in neuropathogenesis, drawing on research from the past 25 years to highlight its contribution to HAND and to outline potential avenues for therapeutic advancement.

Although neurons are not productively infected by HIV-1, the envelope glycoprotein gp120, detectable in cerebrospinal fluid independently of active viral replication, gains intraneuronal access via lipid raft-mediated endocytosis, macropinocytosis, and retrograde axonal transport, contributing to persistent neurobiological dysfunction within the central nervous system. Once internalized, gp120 is associated with neuronal dysfunction involving convergent pathways, including excitotoxic calcium dysregulation, mitochondrial and metabolic failure, and inflammatory and senescence-associated amplification. These pathways converge on suppression of CREB and BDNF signaling, dismantling the transcriptional and neurotrophic programs required for synaptic maintenance and cognitive resilience. Extracellular vesicle-mediated dissemination and microRNA reprogramming extend gp120-associated neurobiological effects beyond sites of receptor engagement, while gut-derived metabolites, particularly quinolinic acid, lower the excitotoxic threshold through synergistic activation of NMDA receptors. Together, these mechanisms define HAND as a network disorder in which gp120 contributes to persistent neurocognitive dysfunction beyond active viral replication, identifying convergent therapeutic nodes where combination strategies targeting excitotoxicity, mitochondrial dysfunction, and neuroinflammation offer the most promising path toward durable neuroprotection.

Cytomegalovirus (CMV) establishes lifelong latency following primary infection and can reactivate to cause severe illness in immunocompromised hosts. CMV DNAemia in non-HIV-infected, non-solid organ/bone marrow transplant (NHNT) hosts is poorly characterized, with limited clinical insights. We aim to describe the clinical presentation, prognostic indicators, and outcomes of CMV DNAemia among NHNT patients. We used the TriNetX international patient database to identify adult patients diagnosed with CMV DNAemia from 2016 until March 2023. We evaluated hospitalization, intensive care unit (ICU) level care, and all-cause mortality at 30 days and 1 year. We also completed a post-propensity score analysis comparing clinical characteristics of survivors versus non-survivors at 90 days. We identified 1123 NHNT patients with CMV DNAemia, most of whom had neoplasms (63%). Venous thromboembolism occurred in 31% of the population. The 30-day hospitalization and all-cause mortality rates were 35% and 14%, respectively. After propensity score matching and Bonferroni correction, weakness, purpura, acute respiratory failure, malnutrition, encephalopathy, and hypotension were associated with increased 90-day all-cause mortality. NHNT patients with CMV DNAemia carry a substantial morbidity and all-cause mortality. Further studies are warranted to clarify whether CMV DNAemia is a causative factor or an incidental finding in this population.

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood-brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND.

HIV-associated neurocognitive disorders (HAND) are characterized by an insidious onset and a slowly progressive course and are observed in approximately 20-50% of people living with HIV. No disease-specific laboratory tests or neuroimaging findings exist for the diagnosis of HAND, and comprehensive neuropsychological assessment is considered the ideal diagnostic approach. Although antiretroviral therapy reduces the risk of developing HAND, HIV is known to invade the central nervous system (CNS) early in the course of infection and establish a so-called "CNS reservoir." Consequently, therapeutic strategies that take the CNS reservoir into account are required.

This study examined behavioral, clinical, and hematologic factors associated with HIV-associated neurocognitive disorder (HAND) among people with HIV (PWH) using the International HIV Dementia Scale (IHDS) within a randomized clinical trial. This secondary analysis used data from the Hospital Visit as Opportunity for Prevention and Engagement for HIV-Infected Drug Users (HOPE) study, which enrolled 801 PWH who use substances from 11 U.S. hospitals. CD4 cell count, HIV-1 viral load, Global Severity Index (GSI), Global Assessment of Functioning (GAF), and Physical and Mental Component Scores (PCS, MCS) were assessed at baseline, 6 months, and 12 months. HAND was defined as an IHDS score ≤ 10. Multivariable linear and logistic regression models were used to identify baseline correlates of IHDS score and HAND, respectively. Linear mixed models were applied to evaluate the longitudinal changes in clinical outcomes. HAND prevalence was 76.3% (84.2% for females and 72.5% for males). Multivariable linear models revealed that obesity, CD4 cell counts < 200 cells/ µL, higher hemoglobin level and hematocrit, and higher GAF scores were significantly associated with IHDS score (p < 0.05). Furthermore, logistic models showed that recent alcohol use, obesity, viral suppression (≤ 200 copies/mL), hemoglobin and hematocrit levels, and GAF scores were associated with lower odds of HAND, whereas platelet count was linked to higher odds. Longitudinal analyses demonstrated significant increases in hemoglobin, hematocrit, PCS, and MCS over time, alongside decreases in platelet count and GSI. Compared with participants without HAND, those with HAND consistently exhibited lower hemoglobin, hematocrit, GAF, and GSI scores, and higher platelet counts and MCS scores across follow-up. These findings underscore the complex interplay between hematologic and mental health, substance use, and functional status in shaping neurocognitive outcomes among PWH. Targeting modifiable hematologic, behavioral, and psychosocial factors may help reduce HAND risk and improve long-term cognitive and functional outcomes. ClinicalTrials.gov ID: NCT01612169.

Pulseless electrical activity (PEA) arrest in patients with end-stage heart failure with reduced ejection fraction (HFrEF) most commonly reflects profound circulatory collapse rather than a primary arrhythmogenic event. Although post-resuscitation encephalopathy often prompts early neurologic prognostication, myocardial dysfunction and refractory shock frequently dominate outcomes in this population. We report the case of a 59-year-old woman with end-stage HFrEF, severe multivessel coronary artery disease, chronic lung disease, HIV infection, and active cocaine use who presented with acute hypoxic respiratory failure and decompensated heart failure and subsequently developed prolonged PEA arrest. Her post-arrest course was complicated by refractory cardiogenic shock, focal cerebellar infarction with delayed MRI due to hemodynamic instability and vasopressor dependence, and multisystem organ failure. Taken together, these findings underscore an important post-resuscitation diagnostic pitfall: neurologic abnormalities may coexist; however, refractory hemodynamic collapse often predominates. An integrated framework incorporating shock physiology, substance-associated cardiotoxicity, and competing neurologic injury is essential for accurate clinical assessment and informed goals-of-care discussions.