Multimodal neuroimaging of fatigability development.

Fatigability refers to the inability of the neuromuscular system to generate enough force to produce movements to meet task challenges. Fatigability has a central and a peripheral component linked via the neuromuscular system, but how these two components interact as fatigue develops lacks a complete understanding. The effects of fatigability are experienced in healthy humans but also accompany various disorders, often exacerbating their symptoms.

Machine learning predicts distinct biotypes of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is universally fatal and has no cure. Heterogeneity of clinical presentation, disease onset, and proposed pathological mechanisms are key reasons why developing impactful therapies for ALS has been challenging. Here we analyzed data from two postmortem cohorts: one with bulk transcriptomes from 297 ALS patients and a separate cohort of single cell transcriptomes from 23 ALS patients.

Prevalence and severity of neurologic symptoms in Long-COVID and the role of pre-existing conditions, hospitalization, and mental health.

Background: Long-COVID refers to ongoing, relapsing, or new symptoms present 30 or more days after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This study examined the prevalence and severity of neurologic symptoms at greater than 1 month following acute SARS-CoV-2 infection and the influence of pre-existing neurologic and psychiatric conditions, current depression and anxiety status, and hospitalization on the presence and severity of these symptoms.

Methods: This prospective cohort study recruited primarily self-referred Long-COVID participants with confirmed SARS-CoV-2 infection.

A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 () causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).

Mutations in , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis.

3D organoids containing endothelial and neural cells generation by serial inductions of differentiation on human iPSC-derived embryoid bodies.

3D brain organoids have been widely used as a tool to study human brain development and disorders. Although endothelial cells play important roles in the brain development and pathogenesis in neurological disorders, most 3D brain organoids lack inherent endothelial cells and need either the addition of endothelial cells or to be transplanted to animals to reconstitute such vascular structures, likely missing the developmental interactions of endothelial cells and other cells in the human brain. In order to reconstitute a 3D organoid mimicking the in vivo neural and endothelial cells development, we cultured iPSC-derived embryoid bodies in sequentially applied endothelial and neuronal induction media along with Matrigel embedding.

Serotonergic and Dopaminergic Function in Neuropsychiatrically Asymptomatic People With HIV on Antiretroviral Therapy.

Objective: People with HIV (PWH) on antiretroviral therapy (ART) still experience neurocognitive dysfunction and accelerated brain volume loss. To assess whether the serotonergic and dopaminergic systems are affected, we used [C]DASB positron emission tomography (PET) to assess presynaptic serotonergic function and [F]FDOPA PET to measure presynaptic dopaminergic reserve in neurocognitively and psychiatrically asymptomatic PWH on ART, compared to seronegative controls (SCs).

Methods: We compared [C]DASB binding (BP) (n = 17 PWH/19 SCs) and [F]FDOPA influx constant (K) (n = 20 PWH/19 SCs) of PWH and SCs.

Post-exertional malaise in Long COVID: subjective reporting versus objective assessment.

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor.

Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models.

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI).

Expression of HIV envelope protein in the human central nervous system.

Objective/design: The HIV envelope glycoprotein gp120 contributes to neuronal damage that could lead to HIV-mediated neurocognitive disorder. However, it is debated whether gp120 could promote direct neurotoxicity to synapses as it may not be present in the central nervous system of people with HIV (PWH) on antiretroviral therapy (ART). This study sought to establish whether gp120 is expressed in the human central nervous system in the pre-ART and post-ART era.

Characterization of novel human endogenous retrovirus structures on chromosomes 6 and 7.

Human endogenous retroviruses (HERV) represent nearly 8% of the human genome. Of these, HERV-K subtype HML-2 is a transposable element that plays a critical role in embryonic development and in the pathogenesis of several diseases. Quantification and characterization of these multiple HML-2 insertions in the human chromosome has been challenging due to their size, sequence homology with each other, and their repetitive nature.

PET imaging of HIV-1 envelope protein gp120 using F-labeled nanobodies.

Radiolabeled antibodies against the HIV-1 envelope protein, gp120, have been previously tested in animal models and in people with HIV (PWH). Nanobodies offer advantages over antibodies, including smaller size and faster clearance, which allow labeling with fluorine-18. In this study, three nanobodies (J3, 3E3, B9) chosen based on their binding properties to the conserved CD4-binding site of gp120 were labeled with fluorine-18 and used for PET imaging in mice bearing wild-type (WT) and/or gp120-expressing (Env+) tumors.

Derivation of a Human Brain Organoid with Microglia Development.

Three-dimensional (3D) brain organoid cultures derived from induced pluripotent stem cells (iPSC) provide an important alternative in vitro tool for studying human brain development and pathogenesis of neurological diseases. However, the lack of incorporation of microglia in the human brain organoids is still a major hurdle for 3D models of neuroinflammation. Current approaches include either the incorporation of fully differentiated microglia into mature brain organoids or the induction of microglial differentiation from the early stage of iPSC-derived embryoid bodies (EBs).

Building a growing genomic repository for maternal and fetal health through the PING Consortium.

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Of note, prenatal Zika infection can cause a spectrum of neurodevelopmental disorders, including congenital Zika syndrome.

Reemerging Infectious Diseases and Neuroimmunologic Complications.

During the past decade (and beyond), neurologists have become aware of the emergence, persistence, and consequences of some familiar and new infections affecting the nervous system. Even among the familiar CNS infections, such as herpes virus, polyoma virus/JC, influenza, arbovirus, and hepatitis, challenges remain in developing effective antiviral treatments and treatments of postinfection sequelae. With the changing environment and increased global travel, arthropod vectors that mediate zoonotic disease transmission have spread unfamiliar viruses such as West Nile virus, dengue, chikungunya, equine encephalitis, and Zika, among others.

Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma.

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI).

Cardiovascular Disease, Brain Glucose Metabolism, and Neurocognitive Decline in People With Human Immunodeficiency Virus.

Background: Cardiovascular disease (CVD) and neuroinflammation are thought to exacerbate neurocognitive dysfunction in treated people with human immunodeficiency virus (PWH). Here, we longitudinally measured brain glucose metabolism as a measure of neuronal integrity in treated PWH using [F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in correlation with atherosclerotic cardiovascular disease (ASCVD) scores, cerebrospinal fluid (CSF) neuroinflammatory markers, neurocognitive outcomes, and other clinical and laboratory variables (CLVs).

Methods: Well-controlled PWH (n = 36) underwent baseline and follow-up FDG PET/CT obtained 3.

Persistent Autonomic and Immunologic Abnormalities in Neurologic Post-Acute Sequelae of SARS-CoV2 Infection.

Objectives: After acute coronavirus disease-2019 (COVID-19), people often experience fatigue, "brain fog," or other central neurologic symptoms (neuro-post-acute SARS-CoV2, or "Neuro-PASC"). In this observational study we evaluated whether abnormalities noted on initial evaluation persist after at least another year.

Methods: Neuro-PASC research participants who had undergone comprehensive inpatient testing at the NIH Clinical Center returned after at least 1 year for follow-up assessments including symptoms rating scales, MRI, lumbar puncture for tests of the CSF, physiologic recordings during the Valsalva maneuver and head-up tilting (with serial plasma catechols and cardiac Doppler ultrasound during the tilting), blood volume measurement, skin biopsies to examine sympathetic innervation, and blood sampling for neuroendocrine and immunologic measures.

Endogenous retroviruses are dysregulated in ALS.

Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood. We examined bulk RNA-seq data from almost 2,000 ALS and unaffected control samples derived from the cortex and spinal cord.

Building a growing genomic data repository for maternal and fetal health through the PING Consortium.

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Discordant outcomes among dizygotic twins could be explained by genetic susceptibly or protection.

HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes.

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals.

TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis.

Neurological manifestations of nontuberculous mycobacteria in adults: case series and review of the literature.

Introduction: Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature.

Materials And Methods: Between January 1995 and December 2020, six cases were identified.

Antiretroviral Drug Repositioning for Glioblastoma.

Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear.