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Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Alzheimer's disease (AD) involves a complex pathological process that evolves over years, and its etiology is understood as a classic example of gene-environment interaction. The notion that exposure to microbial organisms may play some role in AD pathology has been proposed and debated for decades. New evidence from model organisms and -omic studies, as well as epidemiological data from the recent COVID-19 pandemic and widespread use of vaccines, offers new insights into the “germ hypothesis” of AD. To review new evidence and identify key research questions, the Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium and workshop: “New Approaches for Understanding the Potential Role of Microbes in Alzheimer's disease.” Discussion centered around the antimicrobial protection hypothesis of amyloid accumulation, and other mechanisms by which microbes could influence AD pathology including immune cell activation, changes in blood-brain barrier, or direct neurotoxicity. This summary of proceedings reviews the content presented in the symposium and provides a summary of major topics and key questions discussed in the workshop.

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IMPORTANCE: Neuroimaging is a key step in the clinical evaluation of brain injury. Conventional magnetic resonance imaging (MRI) systems operate at high-strength magnetic fields (1.5-3 T) that require strict, access-controlled environments. Limited access to timely neuroimaging remains a key structural barrier to effectively monitor the occurrence and progression of neurological injury in intensive care settings. Recent advances in low-field MRI technology have allowed for the acquisition of clinically meaningful imaging outside of radiology suites and in the presence of ferromagnetic materials at the bedside. OBJECTIVE: To perform an assessment of brain injury in critically ill patients in intensive care unit settings, using a portable, low-field MRI device at the bedside. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, single-center cohort study of 50 patients admitted to the neuroscience or coronavirus disease 2019 (COVID-19) intensive care units at Yale New Haven Hospital in New Haven, Connecticut, from October 30, 2019, to May 20, 2020. Patients were eligible if they presented with neurological injury or alteration, no contraindications for conventional MRI, and a body habitus not exceeding the scanner’s 30-cm vertical opening. Diagnosis of COVID-19 was determined by positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction nasopharyngeal swab result. EXPOSURES: Portable MRI in an intensive care unit room. MAIN OUTCOMES AND MEASURES: Demographic, clinical, radiological, and treatment data were collected and analyzed. Brain imaging findings are described. RESULTS: Point-of-care MRI examinations were performed on 50 patients (16 women [32%]; mean [SD] age, 59 [12] years [range, 20-89 years]). Patients presented with ischemic stroke (n = 9), hemorrhagic stroke (n = 12), subarachnoid hemorrhage (n = 2), traumatic brain injury (n = 3), brain tumor (n = 4), and COVID-19 with altered mental status (n = 20). Examinations were acquired at a median of 5 (range, 0-37) days after intensive care unit admission. Diagnostic-grade T1-weighted, T2-weighted, T2 fluid-attenuated inversion recovery, and diffusion-weighted imaging sequences were obtained for 37, 48, 45, and 32 patients, respectively. Neuroimaging findings were detected in 29 of 30 patients who did not have COVID-19 (97%), and 8 of 20 patients with COVID-19 (40%) demonstrated abnormalities. There were no adverse events or complications during deployment of the portable MRI or scanning in an intensive care unit room. CONCLUSIONS AND RELEVANCE: This single-center series of patients with critical illness in an intensive care setting demonstrated the feasibility of low-field, portable MRI. These findings demonstrate the potential role of portable MRI to obtain neuroimaging in complex clinical care settings.

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IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing human coronavirus disease 2019 (COVID-19), which has now spread into a worldwide pandemic. The pulmonary manifestations of COVID-19 have been well described in the literature. Two similar human coronaviruses that cause Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV-1) are known to cause disease in the central and peripheral nervous systems. Emerging evidence suggests COVID-19 has neurologic consequences as well. OBSERVATIONS: This review serves to summarize available information regarding coronaviruses in the nervous system, identify the potential tissue targets and routes of entry of SARS-CoV-2 into the central nervous system, and describe the range of clinical neurological complications that have been reported thus far in COVID-19 and their potential pathogenesis. Viral neuroinvasion may be achieved by several routes, including transsynaptic transfer across infected neurons, entry via the olfactory nerve, infection of vascular endothelium, or leukocyte migration across the blood-brain barrier. The most common neurologic complaints in COVID-19 are anosmia, ageusia, and headache, but other diseases, such as stroke, impairment of consciousness, seizure, and encephalopathy, have also been reported. CONCLUSIONS AND RELEVANCE: Recognition and understanding of the range of neurological disorders associated with COVID-19 may lead to improved clinical outcomes and better treatment algorithms. Further neuropathological studies will be crucial to understanding the pathogenesis of the disease in the central nervous system, and longitudinal neurologic and cognitive assessment of individuals after recovery from COVID-19 will be crucial to understand the natural history of COVID-19 in the central nervous system and monitor for any long-term neurologic sequelae.

Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.

Background:Patients with ischemic stroke have worse outcome if there is concomitant coronavirus 2019 (COVID-19) infection. We hypothesize that patients with intracerebral hemorrhage (ICH) during the pandemic era had worse outcomes than ICH patients during the pre-pandemic period, and that concomitant COVID-19 in ICH patients is associated with worse outcome.Methods:We analyzed data from Get With The Guidelines® Stroke. We implemented a two-stage design: first, we compared outcomes for ICH patients pre-pandemic (admitted between March 2019 and February 2020) with outcomes for ICH patients admitted during the pandemic (from March 2020 to February 2021); second, we compared outcomes of ICH patients with and without COVID-19 infection admitted during the pandemic (from March 2020 to February 2021). We used multivariable logistic regression adjusted by age, sex, race/ethnicity, and clinical covariates for in-hospital mortality and poor functional outcome using the modified Rankin Scale (mRS) at discharge (mRS >= 4) and a for length of stay (LOS).Results:The first stage included 62,743 pre-pandemic and 64,681 intra-pandemic ICH cases 64,681. ICH patients during the pandemic had worse outcomes, including higher modified rankin scale (mRS) (OR 1.10, CI 1.06-1.14) and higher mortality (OR 1.04, CI 1.01-1.07). The second stage included 60,091 COVID-19-negative and 1,326 COVID-19-positive ICH patients. Patients with concomitant COVID-19 infection had worse outcomes, including higher LOS (RR 1.32, CI 1.25-1.39), high mRS (OR 1.68, CI 1.40-2.01), and increased mortality (OR 1.50, CI 1.33-1.71). (Table).Conclusion:When comparing pre- and intra-pandemic cases of ICH, critically ill stroke patients admitted during the pandemic had worse outcomes. When comparing COVID-19 positive and negative ICH cases that happened during the pandemic, those with the infection had worse clinical outcomes. COVID-19 infection is an independent risk factor for poor outcomes in ICH.

Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown.

We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS).

Elite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20–50copiesml) in the absence of antiretroviral therapy. Here, we examine to what extent elite controllers also control infection of the central nervous system (CNS).

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: “Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD).” Participants considered current evidence for and against the hypothesis that AD could be caused or exacerbated by infection or commensal microbes. Discussion focused on connecting microglial transcriptional states to functional states, mouse models that better mimic human immunity, the potential involvement of inflammasome signaling, metabolic alterations, self-reactive T cells, gut microbes and fungal infections, and lessons learned from Covid-19 patients with neurologic symptoms. The content presented in the symposium, and major topics raised in discussions are reviewed in this summary of the proceedings.

Background Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies.Methods Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations.Results CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD ±1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood.Conclusions Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.

Background: Creutzfeldt-Jakob disease (CJD) is a prion disease which is manifest as a sporadic, inherited, and transmissible neurodegenerative disorder. The mean age at onset of CJD is ∼60 years, and as such, many people destined to succumb undoubtedly die of other illnesses first. The delayed onset of CJD has complicated the analysis of inherited forms of the illness and led to the suggestion that mutations in the prion protein (PrP) gene are necessary but not sufficient for prion disease despite genetic linkage; indeed, an environmental factor such as a ubiquitous virus has been proposed as a second necessary factor. Materials and Methods: To examine what appeared to be incomplete penetrance, we applied a life-table analysis to clinical and pedigree data from a cluster population of Libyan Jews in which the E200K mutation is prevalent. The study population included 42 affected and 44 unaffected members of 13 Libyan Jewish families, all of whom possessed the E200K mutation. Results: The calculated value using life table analysis is 0.77 at age 70 which increases to 0.89 if a mutation carrier survives to age 80 and 0.96 if age 80 is surpassed. Conclusions: These data argue that the E200K mutation alone is sufficient to cause prion disease and does so in an age-dependent manner.

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.

A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI).

Single-cell transcriptome analysis by HIV-1 SortSeq identifies HIV-1–driven aberrant host gene transcription as a mechanism of HIV-1 persistence.