Topological organization of whole-brain white matter in HIV infection

Infection with human immunodeficiency virus (HIV) is associated with neuroimaging alterations. However, little is known about the topological organization of whole-brain networks and the corresponding association with cognition. As such, we examined structural whole-brain white matter connectivity patterns and cognitive performance in 29 HIV+ young adults (mean age = 25.9) with limited or no HIV treatment history. HIV+ participants and demographically similar HIV− controls (n = 16) residing in South Africa underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural network models were constructed using diffusion MRI-based multifiber tractography and T(1)-weighted MRI-based regional gray matter segmentation. Global network measures included whole-brain structural integration, connection strength, and structural segregation. Cognition was measured using a neuropsychological global deficit score (GDS) as well as individual cognitive domains. Results revealed that HIV+ participants exhibited significant disruptions to whole-brain networks, characterized by weaker structural integration (characteristic path length and efficiency), connection strength, and structural segregation (clustering coefficient) than HIV− controls (p < 0.05). GDSs and performance on learning/recall tasks were negatively correlated with the clustering coefficient (p < 0.05) in HIV+ participants. Results from this study indicate disruption to brain network integrity in treatment-limited HIV+ young adults with corresponding abnormalities in cognitive performance

Interventions for neurocognitive dysfunction

Purpose of review: To evaluate current barriers to HIV cure strategies and interventions for neurocognitive dysfunction with a particular focus on recent advancements over the last three years. Recent findings: Optimal anti-retroviral therapy (ART) poses challenges to minimise neurotoxicity, whilst ensuring blood brain barrier penetration and minimising the risk of cerebrovascular disease. CSF biomarkers, BCL11B and neurofilament light chain may be implicated with a neuroinflammatory cascade leading to cognitive impairment. Diagnostic imaging with diffusion tensor imaging as well as resting-state fMRI show promise in future diagnosis and monitoring of HAND. Summary: The introduction of ART has resulted in a dramatic decline in HIV-associated dementia. Despite this reduction, milder forms of HIV-associated neurocognitive disorder (HAND) are still prevalent and are clinically significant. The central nervous system (CNS) has been recognised as a probable reservoir and sanctuary for HIV, representing a significant barrier to management interventions

The relationship between neurocognitive disorders, prospective memory impairment and white matter damage in clade C HIV-positive subjects

Includes bibliographical references.AIMS: To examine the relationship between prospective memory, cognitive function and Diffusion tensor imaging (DTI)/ White matter integrity of human immunodeficiency virus (HIV) positive individuals in the Western Cape. We hypothesize that: 1. Individuals infected with HIV will exhibit significantly poorer microstructural integrity of the white matter than HIV negative individuals, as determined by in vivo diffusion tensor imaging. We expect that values of fractional anisotropy (FA) - a measure of directional water diffusion- in the frontal white matter will be significantly lower among HIV patients compared to controls 2. Lower FA measured in the frontal white matter will correlate significantly with impaired performance on tests of prospective memor

Early microstructural white matter changes in patients with HIV: A diffusion tensor imaging study

Background: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). Methods: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. Results: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. Conclusion: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients

Effect of human immunodeficiency virus on the brain: a review

CITATION: Cilliers, K. & Muller, C. J. F. 2021. Effect of human immunodeficiency virus on the brain: A review. The Anatomical Record, 304:1389– 1399. doi:10.1002/ar.24573The original publication is available at https://anatomypubs.onlinelibrary.wiley.com/journal/19328494Thirty million people are infected with human immunodeficiency virus (HIV) worldwide, and HIV-associated neurocognitive disorder (HAND) is one of the most common comorbidities of HIV. However, the effect of HIV on the brain has not been fully investigated. This article aimed to review the changes to the brain due to HIV in terms of atrophy, diffusion changes, and hyperintensities. Studies have observed significant atrophy in subcortical gray matter, as well as in cortical white and gray matter. Moreover, the ventricles enlarge, and the sulci widen. Although HIV causes changes to the white and gray matter of the brain, few diffusion tensor imaging studies have investigated the changes to gray matter integrity. White and gray matter hyperintensities have frequently been observed in HIV-positive individuals, with the subcortical gray matter (caudate nucleus and putamen) and periventricular white matter frequently affected. In conclusion, subcortical gray matter is the first brain region to be affected and is affected most severely. Additionally, this review highlights the gaps in the literature, since the effect of HIV on the brain is not fully known. Future studies should continue to investigate the effect of HIV on the brain in different stages of the disease, and alternate therapies should be developed since highly active antiretroviral therapy is currently ineffective at treating HAND.https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/ar.24573Publisher’s versio

White Matter Deficits Assessed by Diffusion Tensor Imaging and Cognitive Dysfunction in Psychostimulant Users With Comorbid Human Immunodeficiency Virus Infection

Background Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function. Methods Twenty-one subjects (mean age 37.5&nbsp;±&nbsp;9.0&nbsp;years) with a history of heavy psychostimulant use and HIV infection (8.7&nbsp;±&nbsp;4.3&nbsp;years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health. Results The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p&nbsp;&lt;&nbsp;0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests. Conclusions White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required

Diagnostic significance of the determination of myelin basic protein in cerebrospinal fluid in HIV-associated neurological diseases.

48 patients aged from 21 to 54 years, infected with human immunodeficiency virus (HIV) and presence of diseases of the central nervous system (CNS) were examined. CNS diseases included cerebral tuberculosis, viral encephalitis (caused by Epstein-Barr Virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV)), encephalitis of unspecified etiology, cerebral toxoplasmosis, fungal meningitis. 29 (60.4%) of the patients were discharged from the hospital with a clinical improvement, and 19 (39.6%) of the patients died as a result of CNS disease. Significant differences in the content of the myelin basic protein (MBP) in the cerebrospinal fluid (CSF), depending on the outcome of the disease, were determined. The Median of MBP in deceased patients was 2.9 times higher than in the survived patients - 4.00 (1.90-7.70) ng/ml vs. 1.40 (0.99-2.00) ng/ml (p=0.002 U). An inverse correlation between the content of MBP in the CSF and the time from the determination of the HIV status to the manifestation of neurologic symptoms (rs=-0.30, p&lt;0.05) was found. According to the results of the ROC analysis, the high risk of unfavorable course of HIV-associated CNS diseases is predicted when the concentration of MBP in the cerebrospinal fluid increases by more than 2 ng/ml (68.4% sensitivity, 75.9% specificity, 72.9% accuracy). The highest level of this protein was observed in patients with fungal lesions of the central nervous system (6.6 (1.9-7.8) ng/ml), and the lowest MBP level – in the group of patients with unspecified encephalitis (0.99 (0.9-1.1) ng/ml), which correlated to more favorable outcomes of the disease. The MBP in cerebrospinal fluid can be an important diagnostic and prognostic marker of HIV-associated neurological diseases

Diagnostic significance of the determination of myelin basic protein in cerebrospinal fluid in HIV-associated neurological diseases.

48 patients aged from 21 to 54 years, infected with human immunodeficiency virus (HIV) and presence of diseases of the central nervous system (CNS) were examined. CNS diseases included cerebral tuberculosis, viral encephalitis (caused by Epstein-Barr Virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV)), encephalitis of unspecified etiology, cerebral toxoplasmosis, fungal meningitis. 29 (60.4%) of the patients were discharged from the hospital with a clinical improvement, and 19 (39.6%) of the patients died as a result of CNS disease. Significant differences in the content of the myelin basic protein (MBP) in the cerebrospinal fluid (CSF), depending on the outcome of the disease, were determined. The Median of MBP in deceased patients was 2.9 times higher than in the survived patients - 4.00 (1.90-7.70) ng/ml vs. 1.40 (0.99-2.00) ng/ml (p=0.002 U). An inverse correlation between the content of MBP in the CSF and the time from the determination of the HIV status to the manifestation of neurologic symptoms (rs=-0.30, p<0.05) was found. According to the results of the ROC analysis, the high risk of unfavorable course of HIV-associated CNS diseases is predicted when the concentration of MBP in the cerebrospinal fluid increases by more than 2 ng/ml (68.4% sensitivity, 75.9% specificity, 72.9% accuracy). The highest level of this protein was observed in patients with fungal lesions of the central nervous system (6.6 (1.9-7.8) ng/ml), and the lowest MBP level – in the group of patients with unspecified encephalitis (0.99 (0.9-1.1) ng/ml), which correlated to more favorable outcomes of the disease. The MBP in cerebrospinal fluid can be an important diagnostic and prognostic marker of HIV-associated neurological diseases

Діагностична значущість визначення основного білка мієліну в спинномозковій рідині при ВІЛ-асоційованих неврологічних захворюваннях

Диагностическая значимость определения основного белка миелина в спинномозговой жидкости при ВИЧ-ассоциированных неврологических заболеваниях. Литвин Е.Ю. Обследовано 48 пациентов от 21 до 54 лет, инфицированных вирусом иммунодефицита человека (ВИЧ) и наличием заболеваний центральной нервной системы, которые включали церебральний туберкулез, вирусные энцефалиты (вызванные вирусом Эпштейна-Барр (EBV), цитомегаловирусом (CMV) и вирусом простого герпеса (HSV)), энцефалиты неуточненной этиологии, церебральный токсоплазмоз, грибковые менингиты. 29 (60,4%) пациентов были выписаны из больницы с клиническим улучшением состояния, а 19 (39,6%) пациентов умерли в результате заболевания центральной нервной системы (ЦНС). Определены существенные различия содержания основного белка миелина (ОБМ) в спинномозговой жидкости в зависимости от исхода заболевания. Медиана основного белка миелина у умерших пациентов была в 2,9 раза выше, чем у выживших - 4,00 (1,90-7,70) нг/мл против 1,40 (0,99-2,00) нг/мл (р=0,002 U). Выявлена обратная корреляция между содержанием ОБМ в ликворе и временем от определения ВИЧ-статуса до манифестации неврологических симптомов (rs=-0,30; p<0,05). По результатам ROC-анализа, высокий риск неблагоприятного течения ВИЧ-ассоциированных заболеваний ЦНС прогнозируется при повышении концентрации ОБМ в спинномозговой жидкости более 2 нг/мл (чувствительность теста 68,4%, специфичность - 75,9%, точность - 72,9%). Наиболее высокое содержание этого белка наблюдалось у пациентов с грибковыми поражениями ЦНС (6,6 (1,9-7,8) нг/мл), а наименьший показатель ОБМ - в группе пациентов с неуточненными энцефалитами (0,99 (0,9-1,1) нг/мл), что соответствовало большему количеству благоприятных исходов заболевания. Основной белок миелина в спинномозговой жидкости может быть важным диагностическим и прогностическим маркером ВИЧ-ассоциированных неврологических заболеваний. 48 patients aged from 21 to 54 years, infected with human immunodeficiency virus (HIV) and presence of diseases of the central nervous system (CNS) were examined. CNS diseases included cerebral tuberculosis, viral encephalitis (caused by Epstein-Barr Virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV)), encephalitis of unspecified etiology, cerebral toxoplasmosis, fungal meningitis. 29 (60.4%) of the patients were discharged from the hospital with a clinical improvement, and 19 (39.6%) of the patients died as a result of CNS disease. Significant differences in the content of the myelin basic protein (MBP) in the cerebrospinal fluid (CSF), depending on the outcome of the disease, were determined. The Median of MBP in deceased patients was 2.9 times higher than in the survived patients - 4.00 (1.90-7.70) ng/ml vs. 1.40 (0.99-2.00) ng/ml (p=0.002 U). An inverse correlation between the content of MBP in the CSF and the time from the determination of the HIV status to the manifestation of neurologic symptoms (rs=-0.30, p<0.05) was found. According to the results of the ROC analysis, the high risk of unfavorable course of HIV-associated CNS diseases is predicted when the concentration of MBP in the cerebrospinal fluid increases by more than 2 ng/ml (68.4% sensitivity, 75.9% specificity, 72.9% accuracy). The highest level of this protein was observed in patients with fungal lesions of the central nervous system (6.6 (1.9-7.8) ng/ml), and the lowest MBP level – in the group of patients with unspecified encephalitis (0.99 (0.9-1.1) ng/ml), which correlated to more favorable outcomes of the disease. The MBP in cerebrospinal fluid can be an important diagnostic and prognostic marker of HIV-associated neurological diseases

HIV-associated structural brain changes as related to cognition

Nearly half of all HIV-positive individuals present with some form of HIV-associated neurocognitive disorder (HAND). The experiments described in this thesis examined the structural changes that occur in the brain as a result of HIV infection. While previous work has established that HIV targets the basal ganglia and fronto-striatal systems and impacts cortical and white matter pathways, it was unknown whether these changes occur in the absence of HAND. The studies described here focused on cognitively asymptomatic HIV+ individuals (CAHIV+) without HAND as determined by widely accepted neuropsychological performance guidelines. Experiment 1 utilized diffusion tensor imaging (DTI) to examine HIV-associated alterations in white matter (WM) fractional anisotropy (FA) in the absence of HAND in 23 HIV+ individuals and 17 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would show lower FA values than HIV- in the corpus callosum, frontotemporal, and parietal regions of interest (ROIs). CAHIV+ individuals demonstrated higher FA in the frontotemporal region and posterior corpus callosum, but lower FA in parietal WM relative to HIV- individuals. Experiment 2 utilized structural MRI to compare cortical thickness in 22 CAHIV+ individuals and 19 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would have thinner frontal, temporal, and parietal regions than HIV- participants. Reduced cortical thickness measures were identified in the cingulate and superior temporal gyri, with increased cortical thickness measures in the inferior occipital gyrus, for HIV+ participants compared to HIV-. Experiment 3 examined the relationship between the structural alterations identified in Experiments 1 and 2, neuropsychological performance on tests sensitive to HAND identification, and immunological characteristics in 30 HIV+ participants and 28 HIV- control participants. As hypothesized, regional FA values, cortical thickness, and viral load were related to neuropsychological composite scores for CAHIV+, but not HIV-. Together, results from these three studies suggest that regional FA and cortical alterations identified in CAHIV+ patients may contribute to the cognitive deficits often seen in later stages of HIV disease