Evaluation of a low-resource screening strategy for ophthalmic pathologies and associated neurological morbidity in an older Tanzanian HIV-positive population.

Globally, 43 million people are living with HIV, 90% in developing countries. Increasing life expectancy with combination antiretroviral therapy (cART) results in chronic complications, including HIV-associated neurocognitive disorders (HAND) and eye diseases. HAND screening is currently challenging. Our aim was to evaluate clinical utility of retinopathy as a screening measure of HAND in older cART-treated individuals in Tanzania and feasibility of smartphone-based retinal screening in this low-resource setting. A cross-sectional systematic sample aged ≥ 50-years attending routine HIV follow-up in Tanzania were comprehensively assessed for HAND by American Academy of Neurology criteria and received ophthalmic assessment including smartphone-based retinal imaging. HAND and ophthalmic assessments were independent and blinded. Diagnostic accuracy was evaluated by AUROC curves. Of 129 individuals assessed, 69.8% were visually impaired. Thirteen had retinopathy. HAND prevalence was 66.7%. Retinopathy was significantly associated with HAND but HIV-disease factors (CD4, viral load) were not. Diagnostic accuracy of retinopathy for HAND was poor (AUROC 0.545-0.617) but specificity and positive predictive value were high. We conclude that ocular pathology and HAND appear highly prevalent in this low-resource setting. Although retinal screening cannot be used alone identify HAND, prioritization of individuals with abnormal retinal screening is a potential strategy in low-resource settings.

Multimodal Medical Image Fusion Based on Multiple Latent Low-Rank Representation.

A multimodal medical image fusion algorithm based on multiple latent low-rank representation is proposed to improve imaging quality by solving fuzzy details and enhancing the display of lesions. Firstly, the proposed method decomposes the source image repeatedly using latent low-rank representation to obtain several saliency parts and one low-rank part. Secondly, the VGG-19 network identifies the low-rank part's features and generates the weight maps. Then, the fused low-rank part can be obtained by making the Hadamard product of the weight maps and the source images. Thirdly, the fused saliency parts can be obtained by selecting the max value. Finally, the fused saliency parts and low-rank part are superimposed to obtain the fused image. Experimental results show that the proposed method is superior to the traditional multimodal medical image fusion algorithms in the subjective evaluation and objective indexes.

Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.

A comprehensive data-driven analysis framework for detecting impairments in brain function networks with resting state fMRI in HIV-infected individuals on cART.

Central nervous system (CNS) sequelae continue to be common in HIV-infected individuals despite combination antiretroviral therapy (cART). These sequelae include HIV-associated neurocognitive disorder (HAND) and virologic persistence in the CNS. Resting state functional magnetic resonance imaging (rsfMRI) is a widely used tool to examine the integrity of brain function and pathology. In this study, we examined 16 HIV-positive (HIV+) subjects and 12 age, sex, and race matched HIV seronegative controls (HIV-) whole-brain high-resolution rsfMRI along with a battery of neurocognitive tests. A comprehensive data-driven analysis of rsfMRI revealed impaired functional connectivity, with very large effect sizes in executive function, language, and multisensory processing networks in HIV+ subjects. These results indicate the potential of high-resolution rsfMRI in combination with advanced data analysis techniques to yield biomarkers of neural impairment in HIV.

Early prediction of putamen imaging features in HIV-associated neurocognitive impairment syndrome.

BACKGROUND: To explore the correlation between the volume of putamen and brain cognitive impairment in patients with HIV and to predict the feasibility of early-stage HIV brain cognitive impairment through radiomics. METHOD: Retrospective selection of 90 patients with HIV infection, including 36 asymptomatic neurocognitive impairment (ANI) patients and 54 pre-clinical ANI patients in Beijing YouAn Hospital. All patients received comprehensive neuropsychological assessment and MRI scanning. 3D Slicer software was used to acquire volume of interest (VOI) and radiomics features. Clinical variables and volume of putamen were compared between patients with ANI and pre-clinical ANI. The Kruskal Wallis test was used to analysis multiple comparisons between groups. The relationship between cognitive scores and VOI was compared using linear regression. For radiomics, principal component analysis (PCA) was used to reduce model overfitting and calculations and then a support vector machine (SVM) was used to build a binary classification model. For model performance evaluation, we used an accuracy, sensitivity, specificity and receiver operating characteristic curve (ROC). RESULT: There were no significant differences in clinical variables between ANI group and pre-clinical-ANI group (P>0.05). The volume of bilateral putamen was significantly different between AHI group and pre-clinical group (P<0.05), but there was only a trend in the left putamen between ANI-treatment group and pre-clinical treatment group(P = 0.063). Reduced cognitive scores in Verbal Fluency, Attention/Working Memory, Executive Functioning, memory and Speed of Information Processing were negatively correlated with the increased VOI (P<0.05), but the correlation was relatively low. In diagnosing the ANI from pre-clinical ANI, the mean area under the ROC curves (AUC) were 0.85 ± 0.22, the mean sensitivity and specificity were 63.12 ± 5.51 and 94.25% ± 3.08%. CONCLUSION: The volumes of putamen in patients with ANI may be larger than patients with pre-clinical ANI, the change of the volume of the putamen may have a certain process; there is a relationship between putamen and cognitive impairment, but the exact mechanism is unclear. Radiomics may be a useful tool for predicting early stage HAND in patients with HIV.

Machine learning prediction of neurocognitive impairment among people with HIV using clinical and multimodal magnetic resonance imaging data.

Diagnosis of HIV-associated neurocognitive impairment (NCI) continues to be a clinical challenge. The purpose of this study was to develop a prediction model for NCI among people with HIV using clinical- and magnetic resonance imaging (MRI)-derived features. The sample included 101 adults with chronic HIV disease. NCI was determined using a standardized neuropsychological testing battery comprised of seven domains. MRI features included gray matter volume from high-resolution anatomical scans and white matter integrity from diffusion-weighted imaging. Clinical features included demographics, substance use, and routine laboratory tests. Least Absolute Shrinkage and Selection Operator Logistic regression was used to perform variable selection on MRI features. These features were subsequently used to train a support vector machine (SVM) to predict NCI. Three different classification tasks were performed: one used only clinical features; a second used only selected MRI features; a third used both clinical and selected MRI features. Model performance was evaluated by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity with a tenfold cross-validation. The SVM classifier that combined selected MRI with clinical features outperformed the model using clinical features or MRI features alone (AUC: 0.83 vs. 0.62 vs. 0.79; accuracy: 0.80 vs. 0.65 vs. 0.72; sensitivity: 0.86 vs. 0.85 vs. 0.86; specificity: 0.71 vs. 0.37 vs. 0.52). Our results provide preliminary evidence that combining clinical and MRI features can increase accuracy in predicting NCI and could be developed as a potential tool for NCI diagnosis in HIV clinical practice.

Hypothermia - an unusual initial presentation of human immunodeficiency virus infection.

We report an unusual case of human immunodeficiency virus (HIV) infection initially presenting with hypothermia and bradycardia associated with an HIV encephalitis. Searches reveal only five reported cases of spontaneous episodic hypothermia in the context of HIV infection. In our case, magnetic resonance imaging revealed the presence of a persistent cavum septum pellucidum (CSP), an anatomical and functional neuro-developmental abnormality, as well as changes compatible with an HIV encephalitis. Episodic hypothermia can occur in association with agenesis of the corpus callosum, known as Shapiro's syndrome, and the presence of a persistent CSP in our case suggests it may have contributed to the clinical presentation.

Brain amyloid in virally suppressed HIV-associated neurocognitive disorder.

OBJECTIVE: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. METHODS: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%. RESULTS: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. CONCLUSIONS: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.

Movement disorder in a patient with Human Immunodeficiency Virus on an anti-retroviral therapy: A Case Report.

Human Immunodeficiency Virus associated neurocognitive dysfunction can present as a case of movement disorder in a patient with prolonged antiretroviral therapy. Diagnosis was made after ruling out space occupying lesions, nutritional deficiencies and infectious causes through brain imaging and cerebrospinal fluid analysis. With multidisciplinary care and change of antiretroviral therapy to drugs with higher cerebrospinal fluid penetration, symptoms of the patient improved over a span of six months. Delayed neurological damage due to Human Immunodeficiency Virus can present with isolated cerebellar symptoms.

CD8 + T-lymphocyte Encephalitis: A Systematic Review.

The increase of CD8 + T lymphocytes in the perivascular spaces of patients with HIV encephalopathy has been reported in some studies. CD8 + T lymphocyte encephalitis was first described in 2013 and then a few other similar cases were published. We proposed to analyze the clinical, MR imaging, and histopathology findings of CD8 + T lymphocyte encephalitis. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyzes protocol using the PubMed, Scopus, Lilacs, and IBECS databases up to February 3, 2018. Seven articles were included, two case series and five case reports. A total of 19 individuals were evaluated. MRI showed alterations in the white matter signal in all cases. Histopathology showed a predominance of CD8 + T lymphocytes. The findings described so far may resemble the inflammatory immune reconstitution syndrome. New studies on the subject are needed in an attempt to characterize the differences between these two entities.

Detecting cognitive impairment in HIV-infected individuals using mutual connectivity analysis of resting state functional MRI.

It is estimated that more than 50% of the individuals affected with Human Immunodeficiency Virus (HIV) present deficits in multiple cognitive domains, collectively known as HIV-associated neurocognitive disorder (HAND). Early stages of brain injury may be clinically silent but potentially measurable via neuroimaging. A total of 40 subjects (20 HIV positive and 20 age-matched controls) volunteered for the study. All subjects underwent a standard battery of neuropsychological tests used for the clinical diagnosis of HAND. Fourteen HIV+ and five healthy subjects showed signs of neurological impairment. Connectivity was computed using mutual connectivity analysis (MCA) with generalized radial basis function neural network, a framework for quantifying non-linear connectivity as well as conventional correlation from 160 regional time-series that were extracted based on the Dosenbach (DOS) atlas. We subsequently applied graph theoretic as well as network analysis approaches for characterizing the connectivity matrices obtained and localizing between-group differences. We focused on trying to detect cognitive impairment using the subset of 29 (14 subjects with HAND and 15 cognitively normal controls) subjects. For the global analysis, significant differences (p < 0.05) were seen in the variance in degree, modularity and Smallworldness. Regional analysis revealed changes occurring mainly in portions of the lateral occipital cortex and the cingulate cortex. Furthermore, using Network Based Statistics (NBS), we uncovered an affected sub-network of 19 nodes comprising predominantly of regions of the default mode network. Similar analysis using the conventional correlation method revealed no significant results at a global scale, while regional analysis shows some differences spread across resting state networks. These results suggest that there is a subtle reorganization occurring in the topology of brain networks in HAND, which can be captured using improved connectivity analysis.

Iron-regulatory genes are associated with Neuroimaging measures in HIV infection.

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs. <0.5), virus detectability in plasma, and comorbidity levels were also performed. Of 27 variants (in 12 iron-regulatory genes) associated with neuroimaging measures after correction for the 37 haplotype blocks represented, 3 variants survived additional correction for the 21 neuroimaging measures evaluated and demonstrated biologically plausible associations. SLC11A1 rs7576974_T was significantly associated with higher frontal gray matter N-acetylaspartate (p = 3.62e-5). Among individuals with detectable plasma virus, TFRC rs17091382_A was associated with smaller subcortical gray matter volume (p = 3.23e-5), and CP rs4974389_A (p = 3.52e-5) was associated with higher basal ganglia Choline in persons with mild comorbidities. Two other strong associations were observed for variants in SLC40A1 and ACO2 but were not robust due to low minor-allele frequencies in the study sample. Variants in iron metabolism and transport genes are associated with structural and metabolite neuroimaging measures in HIV-seropositive adults, regardless of virus suppression on antiretroviral therapy. These variants may confer susceptibility to HIV-related brain injury and NCI. Further studies are needed to determine the specificity of these findings to HIV infection and explore potential underlying mechanisms.

Longitudinal brain atrophy patterns and neuropsychological performance in older adults with HIV-associated neurocognitive disorder compared with early Alzheimer's disease.

Older HIV-infected patients are at risk for both HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease. We investigated neuroimaging and neuropsychological performance of 61 virally suppressed older adults with HAND (mean (SD) age 64.3 (3.9) years), 53 demographically matched individuals with mild cognitive impairment of the Alzheimer's type (MCI-AD; 65.0 [4.8]), and 89 healthy controls (65.0 [4.3]) cross-sectionally and over 20 months. At the baseline, both disease groups exhibited lower volumes in multiple cortical and subcortical regions compared with controls. Hippocampal volume differentiated MCI-AD from HAND. Cognitively, MCI-AD performed worse on memory and language compared with HAND. Adjusted longitudinal models revealed greater diffuse brain atrophy in MCI-AD compared with controls, whereas HAND showed greater atrophy in frontal gray matter and cerebellum compared with controls. Comparing HAND with MCI-AD showed similar atrophy rates in all brain regions explored, with no significant findings. MCI-AD exhibited more pronounced language decline compared with HAND. These findings reveal the need for further work on unique cognitive phenotypes and neuroimaging signatures of HAND compared with early AD, providing preliminary clinical insight for differential diagnosis of age-related brain dysfunction in geriatric neuroHIV.

Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. DESIGN: A cross sectional study. METHODS: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. RESULTS: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. CONCLUSION: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

A multivoxel pattern analysis framework with mutual connectivity analysis investigating changes in resting state connectivity in patients with HIV associated neurocognitve disorder.

Functional MRI (fMRI) quantifies brain activity non-invasively by measuring the blood oxygen level dependent (BOLD) response to neuronal activity. It was recently demonstrated, on realistic fMRI simulations, that nonlinear connectivity approaches, such as Mutual Connectivity Analysis with Local Models (MCA-LM), are better suited for extracting connectivity measures than conventional techniques of cross-correlating time-series pairs. In this work, we investigate the application of MCA-LM in extracting meaningful connectivity measures aiding in distinguishing healthy controls from individuals presenting with symptoms of HIV Associated Neurocognitive Disorder (HAND), which occurs as a result of HIV infection of the central nervous system. The pairwise connectivity measures provide a high-dimensional representation of connectivity profiles for subjects and are used as features for classification. We adopt feature selection (FS) techniques reducing the number of redundant and noisy features, while also controlling the complexity of the classifiers. We investigate three FS techniques: 1) Kendall's τ, 2) Information Gain Attribute selection 3) ReliefF and two classifiers:1) AdaBoost and 2) Random Forests. Our results demonstrate that MCA-LM consistently outperforms correlation in terms of Area under the Receiver Operating Characteristic Curve and accuracy. Improved performance with MCA-LM suggests that such a nonlinear approach is better at capturing meaningful connectivity relationships between brain regions. This demonstrates potential for developing novel neuroimaging-derived biomarkers for HAND. Furthermore, FS helps identify connections between anatomical regions that are affected by HAND. In this work, we show that the regions of the basal ganglia and frontal cortex, which are known to be affected by HAND according to current literature, are identified as most discriminative.

Clinical and neuroimaging correlates of cognition in HIV.

This study investigated whether HIV-positive participants, stable on combined antiretroviral therapy (cART), showed cognitive impairments relative to HIV-negative controls; and whether clinical and neuroimaging factors correlated with cognitive function in the HIV-positive participants. One hundred and twenty-six white men who have sex with men, of whom 78 were HIV-positive and stable on cART and 48 were HIV negative, were recruited to this cross-sectional study. The median age of HIV-positive participants in this study was 47. They underwent clinical and neuropsychological evaluation and magnetic resonance imaging of the brain, including diffusion tensor imaging (DTI). Cognitive scores for both groups were compared, and regression models were run to explore the influence of clinical, psychiatric, lifestyle, and neuroimaging variables on cognition. The prevalence of neurocognitive impairment, using the multivariate normative comparison criteria, was 28% in HIV-positive participants and 5% in HIV-negative participants. After covarying for age, years of education, and non-English speaking background, there were significant differences between the HIV group and the controls across four cognitive domains. The HIV group showed significantly higher mean diffusivity (MD) and lower fractional anisotropy (FA) than the control group on DTI. Although anxiety levels were clinically low, anxiety and DTI measures were the only variables to show significant correlations with cognitive function. In the HIV group, poorer cognitive performance was associated with higher MD and lower FA on DTI and higher (albeit clinically mild) levels of anxiety. Our findings suggest that white matter changes and subtle anxiety levels contribute independently to cognitive impairment in HIV.

CROI 2019: neurologic complications of HIV disease.

Investigators reported many new neuroHIV research findings at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI). These findings included confirmation that HIV-associated neurocognitive disorder (HAND) remains common with an increasingly recognized role for comorbidities (eg, obesity) and neurodegenerative conditions (eg, Alzheimer's disease), especially as persons living with HIV (PLWH) advance into their seventh decade of life and beyond. HAND is increasingly recognized as a heterogeneous disorder that differs between individuals (eg, by sex) in the trajectory of specific neurocognitive abilities (eg, executive functioning). A more recent focus at this year's conference was toxicity of combination antiretroviral therapy: neurocognitive performance and neuroimaging data from several studies were presented but did not consistently support that integrase strand transfer inhibitors are associated with worse neurologic outcomes. Neuroimaging studies found that white matter changes reflect a combination of the effects of HIV and comorbidities (including cerebrovascular small vessel disease) and best correlate with blood markers of inflammation. The pathogenesis of HIV in the central nervous system (CNS) was the focus of a plenary lecture and numerous presentations on HIV compartmentalization in the CNS and cerebrospinal fluid viral escape. Novel findings were also presented on associations between HIV-associated neurologic complications and glycomics, neuron-derived exosomes, and DNA methylation in monocytes. This summary will review findings from CROI and identify new research and clinical opportunities.

Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND).

PURPOSE OF REVIEW: The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. RECENT FINDINGS: In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.

Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm.

In this review, we propose that vascular cognitive impairment (VCI), with relevance for the global HIV population, is fundamentally and clinically linked to the persistence of mild forms of HIV-associated neurocognitive disorders (HAND) in ageing people living with HIV infection (PLWH). After placing our review within the context of the general literature on HIV and ageing, we review non-VCI risks for dementia in ageing PLWH. We then present the recently updated VCI nomenclature and show that the neuropsychological and neuroimaging phenotypes of VCI and HAND are largely overlapping, suggesting that further research is needed to accurately distinguish them. We further link VCI and HAND at the mechanistic level by advancing the innovative proposal that the neuro-vascular unit (NVU) may represent the primary target of HIV-related brain injury in treated HIV infection. To this, we add the fundamental impact of mild and major VCI on the NVU. Importantly, we show that the potential contribution of vascular damage to overall brain damage in ageing PLWH is probably much higher than currently estimated because of methodological limitations, and because this research is only emerging. Finally, because all VCI risk factors are more prevalent, premature, and sometimes accelerated in the HIV population at large, we conclude that the probable total burden of VCI in the global HIV population is higher than in the general population and would need to be compared to chronic conditions such as type I diabetes and multiple sclerosis to account for the disease chronicity and lifelong treatment effects. Therefore, this review is also a call to action. Indeed, it is fully established that this amount of VCI burden is a major risk factor for dementia at aged 60+.