Publications by authors named "Justin McArthur"

200 Publications

ANA Webinars: Clinical and basic research resilience during COVID-19.

Ann Clin Transl Neurol 2021 01 15;8(1):302-304. Epub 2020 Dec 15.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1002/acn3.51230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818117PMC
January 2021

Ingrained Injustice: The ANA Responds.

Ann Neurol 2020 08 10;88(2):207-208. Epub 2020 Jul 10.

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1002/ana.25836DOI Listing
August 2020

Neurological manifestations associated with COVID-19: a review and a call for action.

J Neurol 2020 Jun 20;267(6):1573-1576. Epub 2020 May 20.

Neurology, Pathology, Medicine, and Epidemiology, Sheikh Khalifa Stroke Institute, Johns Hopkins University School of Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA.

While the epidemic of Coronavirus disease 2019 (COVID-19) continues to spread globally, more and more evidences are collected about the presence of neurological manifestations and symptoms associated with it. A systematic review has been performed of papers published until 5 April 2020. 29 papers related to neurological manifestations associated with COVID-19 were examined. The results show presence of central and peripheral nervous system manifestations related to coronavirus. Neurological manifestations, or NeuroCOVID, are part of the COVID-19 clinical picture, but questions remain regarding the frequency and severity of CNS symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of COVID-19. Further clinical, epidemiological, and basic science research is urgently needed to understand and address neurological sequalae of COVID-19. Concomitant risk factors or determinants (e.g. demographic factors, comorbidities, or available biomarkers) that may predispose a person with COVID-19 to neurological manifestations also need to be identified. The review shows that although more and more papers are reporting neurological manifestations associated with COVID-19; however, many items remain unclear and this uncertainty calls for a global action that requires close coordination and open-data sharing between hospitals, academic institutions and the fast establishment of harmonised research priorities and research consortia to face the NeuroCOVID-19 complications.
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http://dx.doi.org/10.1007/s00415-020-09896-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238392PMC
June 2020

Pivoting Research to COVID-19.

Ann Neurol 2020 09 7;88(3):464-465. Epub 2020 Jun 7.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1002/ana.25784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276728PMC
September 2020

The Path Forward: Academic Neurology Responds to COVID-19.

Ann Neurol 2020 06;87(6):789-793

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1002/ana.25773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273020PMC
June 2020

Chronic inflammation mediates brain injury in HIV infection: relevance for cure strategies.

Curr Opin Neurol 2020 06;33(3):397-404

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Purpose Of Review: Chronic inflammation is a major component of HIV infection, the effects of which can be devastating in the central nervous system (CNS). Protecting the brain is, therefore, critical as efforts proceed to cure HIV infection by reactivating latent viral reservoirs and driving immune responses. We review the clinical presentation and pathology findings of inflammatory processes in the CNS in patients managed with ART and the drivers of these processes.

Recent Findings: Chronic inflammation is associated with increased mortality and morbidity and HIV infection increases the risk for chronic diseases, especially cognitive impairment. Latent viral reservoirs, including microglia and tissue macrophages, contribute to inflammation in the CNS. Inflammation is generated and maintained through residual viral replication, dysregulation of infected cells, continuously produced viral proteins and positive feedback loops of chronic inflammation. Novel therapeutics and lifestyle changes may help to protect the CNS from immune-mediated damage.

Summary: As therapies are developed to cure HIV, it is important to protect the CNS from additional immune-mediated damage. Adjunctive therapies to restore glial function, reduce neuroinflammation and systemic inflammation, and inhibit expression of viral proteins are needed.
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http://dx.doi.org/10.1097/WCO.0000000000000807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331798PMC
June 2020

Hindsight is 20/20.

J Hosp Med 2020 04 11;15(4):245-249. Epub 2020 Feb 11.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.12788/jhm.3358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850635PMC
April 2020

'A man is as old as his arteries' (attributed to Thomas Sydenham, the English Hippocrates).

AIDS 2020 03;34(4):637-639

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1097/QAD.0000000000002414DOI Listing
March 2020

Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy.

AIDS 2019 12;33 Suppl 2:S145-S157

Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda.

Objective: The aim of this study was to measure the protein concentration and biological activity of HIV-1 Tat in cerebrospinal fluid (CSF) of individuals on suppressive antiretroviral therapy (ART).

Design: CSF was collected from 68 HIV-positive individuals on ART with plasma viral load less than 40 copies/ml, and from 25 HIV-negative healthy controls. Duration of HIV infection ranged from 4 to more than 30 years.

Methods: Tat levels in CSF were evaluated by an ELISA. Tat protein and viral RNA were quantified from exosomes isolated from CSF, followed by western blot or quantitative reverse transcription PCR, respectively. Functional activity of Tat was assessed using an LTR transactivation assay.

Results: Tat protein was detected in 36.8% of CSF samples from HIV-positive patients. CSF Tat concentration increased in four out of five individuals after initiation of therapy, indicating that Tat was not inhibited by ART. Similarly, exosomes from 34.4% of CSF samples were strongly positive for Tat protein and/or TAR RNA. Exosomal Tat retained transactivation activity in a CEM-LTR reporter assay in 66.7% of samples assayed, which indicates that over half of the Tat present in CSF is functional. Presence of Tat in CSF was highly associated with previous abuse of psychostimulants (cocaine or amphetamines; P = 0.01) and worse performance in the psychomotor speed (P = 0.04) and information processing (P = 0.02) cognitive domains.

Conclusion: Tat and TAR are produced in the central nervous system despite adequate ART and are packaged into CSF exosomes. Tat remains biologically active within this compartment. These studies suggest that Tat may be a quantifiable marker of the viral reservoir and highlight a need for new therapies that directly inhibit Tat.
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http://dx.doi.org/10.1097/QAD.0000000000002268DOI Listing
December 2019

Brachial plexitis: an unusual presentation in sickle cell disease.

J Community Hosp Intern Med Perspect 2019 1;9(5):437-439. Epub 2019 Nov 1.

Internal medicine resident, Dow University Of Health Sciences, Karachi, Pakistan.

Brachial plexitis is defined as an inflammation of the brachial plexus. There are two entities of the disease: idiopathic, which is generally considered to be immune-mediated, and genetic. The disease manifests as the acute onset shoulder pain, weakness of the involving arm ± sensory loss. Brachial plexitis is also known as Parsonage-Turner syndrome and hereditary neuralgic amyotrophy. Diagnosis is made with the help of history, physical exam, and imaging. Conservative management is the mainstay of treatment. There has not been any proven treatment for the condition though some cases have been treated empirically with steroids. We present a case of 61-year-old woman with sickle cell anemia who presented with right upper extremity weakness and MRI findings of brachial plexitis.
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http://dx.doi.org/10.1080/20009666.2019.1659665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830239PMC
November 2019

Distinguishing cognitive impairment from HIV-associated neurocognitive disorder versus substance use?

AIDS 2019 10;33(12):1943-1944

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1097/QAD.0000000000002292DOI Listing
October 2019

Clinician-rated measures for distal symmetrical axonal polyneuropathy: ACTTION systematic review.

Neurology 2019 08 18;93(8):346-360. Epub 2019 Jul 18.

From the University of Rochester (J.S.G., J.L., J.C., N.W., D.N.H., S.M.S., R.H.D.), NY; Harvard Medical School (C.H.G., M.C., R.F.), Boston, MA; LORA Group, LLC (L.B.), Royal Oak, MD; University of Milano-Bicocca (G.C.), Monza, Italy; Johns Hopkins University (J.C.M.); University of Maryland and Veterans Administration Maryland Health Care System (J.W.R.), Baltimore, MD; Virginia Commonwealth University (A.G.S.), Richmond; and University of Washington (D.C.T.), Seattle.

Distal symmetrical axonal polyneuropathy (DSP) is due to injury to peripheral sensory, motor, and autonomic nerve fibers, resulting in distal predominant sensory loss, pain, and gait instability. DSP occurs as a complication of multiple medical conditions including diabetes or HIV, or following exposure to various toxins such as chemotherapy. It affects at least 10% of the United States population. Few treatments for DSP are approved by regulatory agencies. Reliable and responsive outcome measures are integral to developing new DSP treatments. Multiple clinician-rated measures that incorporate neuropathy signs exist, however, it is not clear which of these measures performs best for various DSP phenotypes. This systematic review summarizes the content of 18 published measures of DSP identified using PubMed and from personal archives of the authors. The relative percentage of scoring dedicated to motor, reflex, large and small fiber sensory, and autonomic domains varied considerably among measures. The most common neurologic examination items included in the scales were (1) vibration perception (n = 18, 100%), (2) reflexes (n = 16, 89%), (3) pinprick perception (n = 14, 78%), (4) muscle strength (n = 11, 61%), (5) touch-pressure perception (n = 9, 50%), and (6) joint position perception (n = 8, 44%). This review can be used to inform decisions regarding which of the available clinician-rated sign outcome measures would be most appropriate for use in a particular DSP population, based on the domains most affected by that neuropathy or on the domains most likely to be affected by a particular experimental therapy.
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http://dx.doi.org/10.1212/WNL.0000000000007974DOI Listing
August 2019

Acute myocardial infarction associated with initial alemtuzumab infusion cycle in relapsing-remitting multiple sclerosis.

Mult Scler Relat Disord 2019 Sep 18;34:100-102. Epub 2019 Jun 18.

Johns Hopkins University School of Medicine, Department of Neurology, Medicine, Epidemiology, and Pathology, Johns Hopkins Department of Neurology, Pathology Building, Room 509, 600 N. Wolfe Street, Baltimore, MD 21287, United States. Electronic address:

Alemtuzumab is an anti-CD52 monoclonal antibody used for the treatment of lymphoproliferative disorders and relapsing-remitting multiple sclerosis. We report a 30-year-old woman with relapsing-remitting multiple sclerosis who developed a type 2 non-ST elevated myocardial infarction (NSTEMI) during her first alemtuzumab infusion cycle. While acute coronary syndrome has been described with alemtuzumab in the treatment of lymphoma, alemtuzumab-associated cardiac ischemia in multiple sclerosis is uncommon and can occur in patients without cardiovascular risk factors.
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http://dx.doi.org/10.1016/j.msard.2019.06.022DOI Listing
September 2019

Correlates of HIV RNA concentrations in cerebrospinal fluid during antiretroviral therapy: a longitudinal cohort study.

Lancet HIV 2019 07 14;6(7):e456-e462. Epub 2019 Jun 14.

Department of Psychiatry, University of California San Diego, San Diego, CA, USA; Department of Medicine, University of California San Diego, San Diego, CA, USA. Electronic address:

Background: Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort.

Methods: We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres-in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates.

Findings: At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12-84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log copy per mL, 95% CI 11·3 to 28·8; p<0·0001), increased CSF leucocyte count (2·01 per 5 cells per μL, 1·61 to 2·39; p<0·0001), decreased CD4 cell count (0·53 per 5 square-root cells per μL, 0·35 to 0·79; p=0·0025), decreased CNS penetration-effectiveness value (0·71 per unit, 0·56 to 0·92; p=0·0078), increased CD8 cell count (1·51 per 5 square-root cells, 1·11 to 2·06; p=0·0089), and protease inhibitor use (3·26, 1·04 to 10·23; p=0·039; model R=0·22, p<0·0001). Analyses of continuous HIV RNA concentration in CSF that accounted for censoring below the lower limit of quantification had similar findings, although increased HIV RNA concentrations in CSF were also associated with black ethnicity (change in log HIV RNA concentration in CSF 0·205, 0·0367 to 0·3733; p=0·017), increased total protein in CSF (0·0025, -0·0002 to 0·0052; p=0·069), and the presence of addictive-drug metabolites in urine (0·103, -0·013 to 0·219; p=0·081).

Interpretation: The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs.

Funding: The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
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http://dx.doi.org/10.1016/S2352-3018(19)30143-2DOI Listing
July 2019

Cognitive Trajectory Phenotypes in Human Immunodeficiency Virus-Infected Patients.

J Acquir Immune Defic Syndr 2019 09;82(1):61-70

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: The presentation of cognitive impairments in HIV-infected individuals has transformed since the introduction of antiretroviral therapies. Although the overall prevalence of cognitive impairments has not changed considerably, frank dementia is now infrequent, and milder forms of cognitive impairments predominate. Mechanistic insights to the underlying causes of these residual cognitive impairments have been elusive, in part due to the heterogenous etiology of cognitive dysfunction in this population. Here, we sought to categorize longitudinal change in HIV-infected patients based on the performance in specific cognitive domains.

Design: This study consisted of 193 participants from the CHARTER cohort with detailed demographic, clinical, and neuropsychological testing data obtained from 2 study visits interspersed by ∼6 months. Cognitive testing assessed executive function, learning and delayed recall, working memory, verbal fluency, speed of information processing, and motor skills. Change scores were calculated for each domain between the 2 study visits. Dimension reduction and clustering was accomplished by principal component analysis of change scores and k-means clustering to identify cognitive domains that group together and groups of subjects with similar patterns of change.

Results: We identified 4 distinct cognitive change phenotypes that included declines in: (1) verbal fluency, (2) executive function (3) learning and recall, and (4) motor function, with approximately equal numbers of participants in each phenotype.

Conclusions: Each of the 4 cognitive change phenotypes identify deficits that imply perturbations in specific neural networks. Future studies will need to validate if cognitive change phenotypes are associated with alterations in associated neural pathways.
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http://dx.doi.org/10.1097/QAI.0000000000002093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692206PMC
September 2019

Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice.

AIDS 2019 05;33(6):973-984

Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Objective: Almost half of HIV-positive people on antiretroviral therapy have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal insulin therapy improves cognition in Alzheimer's disease and diabetes. Here we tested intranasal insulin therapy in a model of HIV-NCI in EcoHIV-infected conventional mice.

Design And Methods: Insulin pharmacokinetics following intranasal administration to mice was determined by ELISA. Mice were inoculated with EcoHIV to cause NCI; 23 days or 3 months after infection they were treated daily for 9 days with intranasal insulin (2.4 IU/mouse) and examined for NCI in behavioral tests and HIV burdens by quantitative PCR. Some animals were tested for hippocampal neuronal integrity by immunostaining and expression of neuronal function-related genes by real time-quantitative PCR. The effect of insulin treatment discontinuation on cognition and neuropathology was also examined.

Results: Intranasal insulin administration to mice resulted in μIU/ml levels of insulin in cerebrospinal fluid with a half-life of about 2 h, resembling pharmacokinetic parameters of patients receiving 40 IU. Intranasal insulin treatment starting 23 days or 3 months after infection completely reversed NCI in mice. Murine NCI correlated with reductions in hippocampal dendritic arbors and downregulation of neuronal function genes; intranasal insulin reversed these changes coincident with restoration of cognitive acuity, but they returned within 24 h of treatment cessation. Intranasal insulin treatment reduced brain HIV DNA when started 23 but not 90 days after infection.

Conclusion: Our preclinical studies support the use of intranasal insulin administration for treatment of HIV-NCI and suggest that some dendritic injury in this condition is reversible.
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http://dx.doi.org/10.1097/QAD.0000000000002150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457131PMC
May 2019

Solitary sclerosis presenting as isolated spontaneous paroxysmal dysarthria.

eNeurologicalSci 2019 Mar 11;14:98-100. Epub 2019 Jan 11.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.

Paroxysmal dysarthria and ataxia (PDA) is a rare syndrome characterized by brief, stereotyped episodes of slurred speech, clumsiness with extremities, or vertigo. It is usually observed in young patients suffering from multiple sclerosis with numerous lesions. PDA is challenging to identify in those presenting with atypical patterns. Here, a non-ataxic variant of PDA in an otherwise neurologically healthy elderly man is presented who had a single midbrain lesion. A broad diagnostic workup illustrates the challenges of identifying PDA. Teaching points emphasize the significance of the midbrain lesion and response to anti-epileptic medication.
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http://dx.doi.org/10.1016/j.ensci.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382995PMC
March 2019

Impaired insulin sensitivity is associated with worsening cognition in HIV-infected patients.

Neurology 2019 03 20;92(12):e1344-e1353. Epub 2019 Feb 20.

From the Departments of Neurology (S.S.K., S.C., L.H.R., N.S., J.C.M., N.J.H.) and Psychiatry (N.J.H.), Johns Hopkins University School of Medicine, Baltimore, MD; HIV Neurobehavioral Research Program and Department of Psychiatry (S.L., T.M., I.G., D.F.), School of Medicine, University of California, San Diego, La Jolla; Department of Epidemiology (J.B.M., L.P.J., G.D.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (V.S.), Division of Infectious Diseases, and Department of Surgery (V.S.), Division of Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL; University of Texas Health Sciences Center (J.E.L.), Houston; Infectious Disease and Microbiology (G.R.), University of Pittsburg, PA; and Turku Centre for Biotechnology (A.M.D.), Turku University, Finland.

Objective: To determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals.

Methods: We conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition.

Results: Patients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition.

Conclusions: These findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy-treated HIV-infected patients.
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http://dx.doi.org/10.1212/WNL.0000000000007125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511093PMC
March 2019

Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2018 11 22;34(11):942-949. Epub 2018 Aug 22.

9 Icahn School of Medicine of Mount Sinai , New York, New York.

Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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http://dx.doi.org/10.1089/AID.2018.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421985PMC
November 2018

Advanced Pediatric Neurosonography Techniques: Contrast-Enhanced Ultrasonography, Elastography, and Beyond.

J Neuroimaging 2018 03 27;28(2):150-157. Epub 2017 Dec 27.

Division of Pediatric Radiology and Pediatric Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD.

Recent technical advances in neurosonography continue broadening the diagnostic utility, sensitivity, and specificity of ultrasound for detecting intracranial abnormalities bed side. The clinical and functional applications of neurosonography have significantly expanded since the 1980s when transcranial Doppler sonography first allowed anatomic and hemodynamic delineation of the intracranial vessels through the thin temporal skull. In the past few years, contrast-enhanced ultrasonography, elastography, 3D/4D reconstruction tools, and high-resolution microvessel imaging techniques have further enhanced the diagnostic significance of neurosonography. Given these advances, a thorough familiarity with these new techniques and devices is crucial for a successful clinical application allowing improved patient care. It is essential that future neurosonography studies compare these advanced techniques against the current "gold standard" computed tomography and magnetic resonance imaging to assure the accuracy of their diagnostic potential. This review will provide a comprehensive update on currently available advanced neurosonography techniques.
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http://dx.doi.org/10.1111/jon.12492DOI Listing
March 2018

Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse.

ACS Chem Neurosci 2018 04 4;9(4):809-816. Epub 2018 Jan 4.

Department of Medicine , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.

Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUC = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUC = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUC = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUC = 354 h·μIU/mL), amounting to a ∼ 2000-fold increase in the AUC ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.
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http://dx.doi.org/10.1021/acschemneuro.7b00434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906198PMC
April 2018

Paroxetine and fluconazole therapy for HIV-associated neurocognitive impairment: results from a double-blind, placebo-controlled trial.

J Neurovirol 2018 02 23;24(1):16-27. Epub 2017 Oct 23.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2 × 2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20 mg/day, (2) fluconazole 100 mg every 12 h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change = 0.25 vs - 0.19, p = 0.049), CalCAP sequential test reaction time (mean change = 0.34 vs -0.23, p = 0.014), Trail Making Part B test performance (mean change = 0.49 vs - 0.33, p = 0.041), and FAS verbal fluency (mean change = 0.25 vs 0.02, p = 0.020) but a decline in the Letter number sequencing test (mean change = - 0.40 vs 0.26, p = 0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.
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http://dx.doi.org/10.1007/s13365-017-0587-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792316PMC
February 2018

Modifications in acute phase and complement systems predict shifts in cognitive status of HIV-infected patients.

AIDS 2017 06;31(10):1365-1378

aIntramural Research Program, National Institute on Aging, Baltimore, Maryland bDepartment of Pharmacology and Experimental Neuroscience, The University of Nebraska Medical Center, Omaha, Nebraska cDepartment of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland dDivision of Epidemiology, Department of Health Sciences Research eDepartment of Neurology College of Medicine, Mayo Clinic, Rochester, Minnesota fHIV Neurobehavioral Research Program and Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California gDepartment of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: The prevalence of HIV-associated neurocognitive disorders (HAND) has not changed considerably in the last two decades. Potent antiretroviral therapy has shifted the severity of HAND to milder phenotypes, but excess morbidity and mortality continue to be associated with HAND. Changes in numerous markers of immune function, inflammation, and cellular stress have been repeatedly associated with HAND, but the underlying systems that drive these changes have not been identified.

Method: In this study, we used systems informatics to interrogate the cerebrospinal fluid proteomic content of longitudinal samples obtained from HIV-infected adults with stably unimpaired, stably impaired, worsening, or improving neurocognitive performance.

Results And Conclusion: The patterns of change in cerebrospinal fluid protein content implicated the induction of acute phase and complement systems as important regulators of neurocognitive status. Worsening neurocognitive performance was preceded by induction of acute phase and complement systems, whereas improving neurocognitive performance was preceded by a downregulation of these systems.
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http://dx.doi.org/10.1097/QAD.0000000000001503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501712PMC
June 2017

Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment.

J Neuroinflammation 2017 03 31;14(1):72. Epub 2017 Mar 31.

Genomic Medicine Institute/Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.

Background: Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.

Methods: We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression.

Results: CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment.

Conclusions: CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.
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http://dx.doi.org/10.1186/s12974-017-0848-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374652PMC
March 2017

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations.

J Pain 2017 07 27;18(7):757-777. Epub 2017 Feb 27.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials.

Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.
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http://dx.doi.org/10.1016/j.jpain.2017.02.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484729PMC
July 2017

PML in natalizumab-treated multiple sclerosis: Modeling errors and risk miscalculations.

Neurology 2017 03 22;88(12):1110-1111. Epub 2017 Feb 22.

From the Departments of Neurology (E.M.M., J.C.M.), Epidemiology (E.M.M., J.C.M.), Pathology (J.C.M.), and Medicine (J.C.M.), Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1212/WNL.0000000000003749DOI Listing
March 2017

Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy.

J Infect Dis 2017 Jan 26;215(1):105-113. Epub 2016 Oct 26.

University of California, San Diego.

Background:  Neurocognitive disorders remain common among human immunodeficiency virus (HIV)-positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART).

Methods:  Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice.

Results:  HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4 T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months.

Conclusions:  Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4 T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.
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http://dx.doi.org/10.1093/infdis/jiw505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225254PMC
January 2017

Pearls and Pitfalls, Part 2.

Semin Neurol 2016 10 23;36(5):407-408. Epub 2016 Sep 23.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1055/s-0036-1593540DOI Listing
October 2016

Pearls and Pitfalls, Part 1.

Semin Neurol 2016 08 19;36(4):315-6. Epub 2016 Sep 19.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1055/s-0036-1586259DOI Listing
August 2016