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1.
J Pediatr ; 237: 298-301.e1, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34216632

ABSTRACT

We evaluated neurologic complications following noncongenital Zika virus infection in 11 children who presented with central nervous system signs. Zika virus RNA was detected by real-time reverse transcription-polymerase chain reaction in cerebrospinal fluid. Approximately one-quarter of patients required antiepileptic medication in follow-up, and 2 children progressed to learning difficulties or developmental delay.


Subject(s)
Developmental Disabilities/virology , Learning Disabilities/virology , Nervous System Diseases/virology , Zika Virus Infection/complications , Anticonvulsants/therapeutic use , Brazil , Child , Child, Preschool , Developmental Disabilities/diagnosis , Electroencephalography , Female , Hospitalization , Humans , Infant , Learning Disabilities/diagnosis , Male , Nervous System Diseases/diagnosis , Prospective Studies , Real-Time Polymerase Chain Reaction , Zika Virus/isolation & purification , Zika Virus Infection/diagnosis , Zika Virus Infection/psychology
2.
J Clin Exp Neuropsychol ; 36(8): 806-17, 2014.
Article in English | MEDLINE | ID: mdl-25111120

ABSTRACT

INTRODUCTION: It is unclear whether or to what degree literacy, aging, and other neurologic abnormalities relate to cognitive deficits among people living with HIV/AIDS in the combined antiretroviral therapy (CART) era. The primary aim of this study was to simultaneously examine the association of age, HIV-associated motor abnormalities, major depressive disorder, and reading level with information processing speed, learning, memory, and executive functions, and to determine whether processing speed mediated any of the relationships between cognitive and noncognitive variables. METHOD: Participants were 186 racially and ethnically diverse men and women living with HIV/AIDS who underwent comprehensive neurological, neuropsychological, and medical evaluations. Structural equation modeling was utilized to assess the extent to which information processing speed mediated the relationship between age, motor abnormalities, major depressive disorder, and reading level with other cognitive abilities. RESULTS: Age, motor dysfunction, reading level, and current major depressive disorder were all significantly associated with information processing speed. Information processing speed fully mediated the effects of age on learning, memory, and executive functioning and partially mediated the effect of major depressive disorder on learning and memory. The effect of motor dysfunction on learning and memory was fully mediated by processing speed. CONCLUSIONS: These findings provide support for information processing speed as a primary deficit, which may account, at least in part, for many of the other cognitive abnormalities recognized in complex HIV/AIDS populations. The association of age and information processing speed may account for HIV/aging synergies in the generation of CART-era cognitive abnormalities.


Subject(s)
Cognition Disorders/etiology , Executive Function/physiology , HIV Infections/complications , HIV Infections/psychology , Learning Disabilities/etiology , Memory Disorders/etiology , Adult , Age Factors , Cognition Disorders/virology , Cohort Studies , Female , Humans , Learning Disabilities/virology , Male , Memory Disorders/virology , Middle Aged , Models, Statistical , Mood Disorders/etiology , Movement Disorders/etiology , Neurologic Examination , Neuropsychological Tests , Psychiatric Status Rating Scales
3.
Proc Natl Acad Sci U S A ; 110(22): 9112-7, 2013 May 28.
Article in English | MEDLINE | ID: mdl-23650398

ABSTRACT

Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain--such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem--of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.


Subject(s)
Brain/metabolism , Learning Disabilities/etiology , RNA, Viral/metabolism , Respiratory Syncytial Virus Infections/complications , Respiratory Syncytial Virus Infections/immunology , Viral Proteins/metabolism , Animals , Brain/pathology , Learning Disabilities/prevention & control , Learning Disabilities/virology , Long-Term Potentiation/physiology , Maze Learning/physiology , Mice , Mice, Inbred BALB C , Mycobacterium bovis/immunology , Rats , Rats, Sprague-Dawley , Respiratory Syncytial Virus Infections/metabolism , T-Lymphocytes/immunology , Viral Vaccines/immunology
4.
Int J Infect Dis ; 17(10): e862-7, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23562357

ABSTRACT

OBJECTIVES: We aimed to characterize neurological outcomes and determine the prevalence of HIV encephalopathy in a cohort of HIV-infected children in Jamaica. METHODS: Data for 287 HIV-infected children presenting between 2002 and 2008 were reviewed and neurological outcomes characterized. A nested case-control study was conducted between July and September 2009 used 15 randomly selected encephalopathic HIV-infected children aged 7-10 years and 15 matched controls (non-encephalopathic HIV-infected). Their neurocognitive functions were evaluated using clinical assessment and standardized tests for intelligence, short term memory (visuo-spatial and auditory), selective attention, and fine motor and coordination functions. Outcomes were compared using Fisher's exact test and the Mann-Whitney U-test. RESULTS: Sixty-seven (23.3%) children were encephalopathic. The median age at diagnosis of HIV encephalopathy was 1.6 years (interquartile range (IQR) 1.1-3.4 years). Predominant abnormalities were delayed milestones (59, 88.1%), hyperreflexia (59, 86.5%), spasticity (50, 74.6%), microcephaly (42, 61.7%), and quadriparesis (21, 31.3%). The median age of tested children was 8.7 years (IQR 7.6-10.8 years) in the encephalopathic group and 9 years (IQR 7.4-10.7 years) in the non-encephalopathic group. Encephalopathic children performed worse in all domains of neurocognitive function (p<0.05). CONCLUSIONS: A high prevalence of HIV encephalopathy was noted, and significant neurocognitive dysfunction identified in encephalopathic children. Optimized management through the early identification of neurological impairment and implementation of appropriate interventions is recommended to improve quality of life.


Subject(s)
AIDS Dementia Complex/psychology , Cognition Disorders/virology , Developing Countries , AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/epidemiology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Case-Control Studies , Child , Child, Preschool , Cognition Disorders/epidemiology , Humans , Infant , Jamaica/epidemiology , Learning Disabilities/epidemiology , Learning Disabilities/virology , Memory Disorders/epidemiology , Memory Disorders/virology , Microcephaly/epidemiology , Microcephaly/virology , Prevalence , Quality of Life , Reflex, Abnormal
5.
Behav Brain Res ; 229(1): 48-56, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22197678

ABSTRACT

HIV-Tat protein has been implicated in the pathogenesis of HIV-1 neurological complications (i.e., neuroAIDS), but direct demonstrations of the effects of Tat on behavior are limited. GT-tg mice with a doxycycline (Dox)-inducible and brain-selective tat gene coding for Tat protein were used to test the hypothesis that the activity of Tat in brain is sufficient to impair learning and memory processes. Western blot analysis of GT-tg mouse brains demonstrated an increase in Tat antibody labeling that seemed to be dependent on the dose and duration of Dox pretreatment. Dox-treated GT-tg mice tested in the Barnes maze demonstrated longer latencies to find an escape hole and displayed deficits in probe trial performance versus uninduced GT-tg littermates, suggesting Tat-induced impairments of spatial learning and memory. Reversal learning was also impaired in Tat-induced mice. Tat-induced mice additionally demonstrated long-lasting (up to one month) deficiencies in novel object recognition learning and memory performance. Furthermore, novel object recognition impairment was dependent on the dose and duration of Dox exposure, suggesting that Tat exposure progressively mediated deficits. These experiments provide evidence that Tat protein expression is sufficient to mediate cognitive abnormalities seen in HIV-infected individuals. Moreover, the genetically engineered GT-tg mouse may be useful for improving our understanding of the neurological underpinnings of neuroAIDS-related behaviors.


Subject(s)
Gene Expression Regulation, Viral/genetics , Gene Products, tat/genetics , HIV-1/genetics , Learning Disabilities/etiology , Memory Disorders/etiology , Analysis of Variance , Animals , Disease Models, Animal , Doxycycline/therapeutic use , Exploratory Behavior/drug effects , Gene Expression Regulation, Viral/drug effects , Gene Products, tat/metabolism , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , HIV-1/metabolism , HIV-1/pathogenicity , Learning Disabilities/drug therapy , Learning Disabilities/virology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/drug therapy , Memory Disorders/virology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Recognition, Psychology/drug effects , Time Factors
6.
Int J Neurosci ; 119(10): 1779-803, 2009.
Article in English | MEDLINE | ID: mdl-19922386

ABSTRACT

OBJECTIVE: To examine the hypothesis of subcortical pathologic impairment in HIV/AIDS. METHOD: The study included 22 HIV+, 22 HIV- controls, 22 learning disordered (LD) HIV-, and 22 depressive HIV-. The groups were compared on eight WMS-III Indices. RESULTS: Analyses revealed significantly lower scores (p < .05) in HIV+ on visual immediate memory, immediate memory, visual delayed memory, auditory delayed memory, working memory, and general memory. For all cases, HIV+ participants scored below the control group only. CONCLUSIONS: WMS-III indices discriminated HIV+ participants from normal comparisons. Inability to find differences between HIV+ and depressive and LD groups reflects the isolation of the subcortical effect to the HIV+ group.


Subject(s)
Depression/complications , HIV Infections/complications , Memory Disorders/complications , Memory Disorders/diagnosis , Adult , Analysis of Variance , Depression/virology , Female , Humans , Intelligence , Learning Disabilities/physiopathology , Learning Disabilities/virology , Male , Memory Disorders/virology , Middle Aged , Neuropsychological Tests , Psychiatric Status Rating Scales , Reproducibility of Results
7.
Neurology ; 72(19): 1661-8, 2009 May 12.
Article in English | MEDLINE | ID: mdl-19433739

ABSTRACT

OBJECTIVE: Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIV+ men, though HIV+ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women. METHODS: Participants included 54 HIV+ and 12 HIV- women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Women's Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task. RESULTS: HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIV+ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory. CONCLUSIONS: Verbal episodic memory deficits are evident in HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.


Subject(s)
AIDS Dementia Complex/physiopathology , HIV Seropositivity/complications , Hippocampus/pathology , Hippocampus/physiopathology , Memory Disorders/physiopathology , AIDS Dementia Complex/diagnosis , Adult , Brain Mapping , Cohort Studies , Disease Progression , Female , Functional Laterality/physiology , Hippocampus/virology , Humans , Language Disorders/diagnosis , Language Disorders/physiopathology , Language Disorders/virology , Learning Disabilities/diagnosis , Learning Disabilities/physiopathology , Learning Disabilities/virology , Magnetic Resonance Imaging , Memory Disorders/diagnosis , Memory Disorders/virology , Middle Aged , Neuropsychological Tests , Parahippocampal Gyrus/pathology , Parahippocampal Gyrus/physiopathology , Parahippocampal Gyrus/virology , Sex Factors , Viral Load
8.
J Neurovirol ; 15(1): 14-24, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19085205

ABSTRACT

Human immunodeficiency virus (HIV)-associated dementia (HAD) encompasses a spectrum of cognitive and motor deficits resulting from the progression of central nervous system abnormalities caused by the HIV-1 virus. With the advent of highly active antiretroviral therapy (HAART), these deficits have become milder, but more prevalent as the population of HIV-positive individuals ages. Mild impairment in cognition has also been identified in asymptomatic HIV-1 patients. The noninfectious HIV-1 transgenic (Tg) rat recently developed to study the pathogenesis of acquired immunodeficiency syndrome (AIDS) may also be useful for the study of the early and chronic effects of HIV-1 on learning and cognition. In a previous study, we demonstrated that HIV-1Tg rats show a deficit in learning how to swim to a hidden platform in a modified water maze task compared to normal and transgenic controls. In the present study, we replicate this result and demonstrate that HIV-1Tg rats also show a significant deficit in reversal learning and new strategy learning. These results indicate that the HIV-1Tg rat is a promising model in which to study the neuropathogenic mechanisms that can cause cognitive deficits in patients with HAD as well as asymptomatic HIV-positive individuals.


Subject(s)
HIV Infections/psychology , HIV-1 , Learning Disabilities/psychology , Learning Disabilities/virology , Learning , Spatial Behavior , AIDS Dementia Complex/physiopathology , AIDS Dementia Complex/psychology , Animals , Cognition , Disease Models, Animal , HIV Infections/physiopathology , Learning Disabilities/physiopathology , Rats , Rats, Transgenic
9.
Neurobiol Dis ; 24(2): 266-73, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16919964

ABSTRACT

Picornaviruses are a socioeconomically important family of viruses that includes the rhinoviruses and enteroviruses. Many of these viruses, including the "common cold" Coxsackie virus A21, maintain neurovirulent potential and may induce hippocampal injury. The behavioral implications of this injury have not been adequately explored. Using C57BL/6J mice infected with Theiler's murine encephalomyelitis virus, we examined the formation of spatial memories using the Morris water maze test. Virus-infected mice had greater search error compared to sham-infected animals during the location of a hidden platform and were unable to discriminate the location of the training quadrant during the final probe trial. Furthermore, sham-infected mice were place responders whereas virus-infected mice were cue responders, indicating a lack of spatial memory formation in infected animals. Importantly, the degree of memory impairment was correlated to the extent of hippocampal injury. This suggests that picornavirus infection of the human CNS may also result in at least some degree of neurologic deficit. An important implication of such subclinical virus-induced neurologic deficit is that the injury may accumulate over the lifetime of the individual, eventually leading to the manifestation of clinical cognitive or memory deficits.


Subject(s)
Cardiovirus Infections/virology , Hippocampus/virology , Learning Disabilities/virology , Memory Disorders/virology , Neurons/virology , Picornaviridae Infections/complications , Animals , Brain Damage, Chronic/pathology , Brain Damage, Chronic/physiopathology , Brain Damage, Chronic/virology , Cardiovirus Infections/pathology , Cardiovirus Infections/physiopathology , Disease Models, Animal , Hippocampus/pathology , Hippocampus/physiopathology , Learning Disabilities/pathology , Learning Disabilities/physiopathology , Male , Maze Learning/physiology , Memory Disorders/pathology , Memory Disorders/physiopathology , Mice , Mice, Inbred C57BL , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Nerve Degeneration/virology , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Neurodegenerative Diseases/virology , Neurons/pathology , Picornaviridae Infections/genetics , Picornaviridae Infections/physiopathology , Theilovirus/physiology
10.
Hepatology ; 41(4): 801-8, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15793853

ABSTRACT

Neurocognitive morbidity has been reported in individuals with chronic hepatitis C virus (HCV) infection, but the magnitude of such dysfunction in the absence of disease-correlated factors known to affect the central nervous system (e.g., substance abuse, cirrhosis, depression, interferon treatment) and the impact of any such change on functioning is unclear. We investigated a cohort of individuals with HCV, all of whom were carefully screened to exclude relevant comorbidities, to elucidate virus-related changes in the brain using neuropsychological tests and magnetic resonance spectroscopy (MRS). A cohort of 37 patients with chronic HCV infection was culled from 300 consecutive patients presenting to a tertiary care liver clinic. A comparison group of healthy controls (n = 46) was also assessed. Of 10 neurocognitive measures evaluated, the HCV group showed marginally poorer learning efficiency compared with controls; only 13% of patients demonstrated a clinical level of impairment on this test (defined as 1.5 SD below the normative standard). Although patients reported greater levels of fatigue and symptoms of depression, these factors did not correlate with the degree of learning inefficiency. With respect to MRS, the HCV group demonstrated increased choline and reduced N-acetyl aspartate relative to controls in the central white matter. Indicators of liver disease severity did not correlate with either memory or MRS abnormalities. In conclusion, while our findings support an association between hepatitis C and indicators of central nervous system involvement in a cohort of patients carefully screened to eliminate other factors influencing neurocognitive integrity, the clinical significance of these effects is limited.


Subject(s)
Cognition Disorders/epidemiology , Cognition Disorders/virology , Hepatitis C, Chronic/complications , Nervous System Diseases/epidemiology , Nervous System Diseases/virology , Adult , Case-Control Studies , Cognition Disorders/diagnosis , Cohort Studies , Depression/virology , Fatigue/virology , Hepatitis C, Chronic/psychology , Humans , Learning Disabilities/virology , Magnetic Resonance Spectroscopy , Middle Aged , Nervous System Diseases/diagnosis , Neuropsychological Tests , Prevalence
11.
Virus Genes ; 10(3): 217-26, 1995.
Article in English | MEDLINE | ID: mdl-8560783

ABSTRACT

Two recent studies provided new evidence on the latency of HSV-1 DNA in 15.5% of olfactory bulbs and in 72.5% of trigeminal nerves from human corpses at forensic postmortems (1) and in 35% of 40 autopsied human brains (2). In the latter brains, latent HSV-1 DNA was found in the olfactory bulbs, amygdala, hippocampus, brain stem, and trigeminal ganglia. Although in these studies it is not known by which route HSV-1 entered the olfactory bulbs and brain, experimental studies in mice (3) revealed that injection of HSV-1 into the olfactory bulbs leads to virus migration into the brain amygdala and hippocampus via the olfactory nerve and locus coeruleus. If the olfactory ciliary nerve epithelium is the port of entry of HSV-1 into the olfactory bulbs and brain in humans as well, protection of the nose against HSV-1 infection may be needed to prevent virus latency in neurons in the amygdala and hippocampus (3). Infection of humans by HSV-1 was estimated to increase from 18.2% in the 0-20 year population group to 100% in persons older than 60 years (1), indicating that worldwide human populations at all ages are at risk of brain infection by the olfactory nerve route. In addition, both primary infection and reactivation of latent DNA in the brain may lead to damage of neurons in the brain involved in memory, learning, and behavior, as observed in infected, acyclovir-treated mice (3). The current introduction of a live apathogenic varicella-zoster virus (VZV) vaccine to immunize children against chickenpox (4) may suggest that the time is ripe for immunization of children and adults against HSV-1 infections, especially infections by the olfactory nerve route, to prevent potential brain damage.


Subject(s)
Brain Diseases/virology , Herpes Simplex/physiopathology , Herpesvirus 1, Human , Learning Disabilities/virology , Mental Disorders/virology , Adult , Animals , Brain Diseases/physiopathology , Child , Herpes Simplex/virology , Humans , Nasal Mucosa/virology , Olfactory Nerve/virology , Viral Vaccines , Virus Activation , Virus Latency
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