Relative sensitivity of magnetic resonance spectroscopy and quantitative magnetic resonance imaging to cognitive function among nondemented individuals infected with HIV

In the present study, we examined the relationships among cognitive function, magnetic resonance spectroscopy (MRS) brain metabolite indices measured in the basal ganglia, and quantitative magnetic resonance imaging (MRI) of the caudate nucleus and the putamen in the earliest stages of HIV-related cognitive involvement. Participants included 22 HIV-positive individuals and 20 HIV-negative individuals. HIV-positive individuals performed significantly more poorly than the HIV-negative individuals on several cognitive measures. In addition, the choline/creatine ratio was significantly higher and the N-acetyl aspartate/choline ratio was significantly lower among HIV patients. The caudate and putamen sizes were smaller among HIV-positive patients compared with controls; however, the differences did not reach statistical significance. Correlation analyses revealed associations between cognitive function and select MRS indices. In addition, caudate size was significantly correlated with performances on higher-order thinking tests whereas putamen size was significantly correlated with performances on motor tests. The results suggest that MRS differences are more pronounced than area size differences between seropositive and seronegative individuals in mild stages of HIV-related cognitive impairment. However, basal ganglia size remains an important contributor to cognitive status in this population. Longitudinal studies are needed to determine the evolution of these imaging correlates of HIV-cognitive impairment in HIV

Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

AbstractCognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV+ patients scanned with whole-brain MRI at 1.5T (mean age: 48.6±8.4years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4+ count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4+. Even so, brain volume measured by TBM showed no detectable association with current CD4+ count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet whether neurological injury can progress in this setting remains uncertain

Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response—particularly an interferon-inducible chemokine, IP-10—and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons

Smaller limbic structures are associated with greater immunosuppression in over 1000 HIV-infected adults across five continents: Findings from the ENIGMA-HIV Working Group

Background: Human immunodeficiency virus type-1 (HIV) infection can be controlled with combination antiretroviral therapy (cART), but neurocognitive impairment remains common even in chronic and treated HIV-infected (HIV+) cohorts. Identifying the neuroanatomical pathways associated with infection has the potential to delineate novel neuropathological processes underlying persisting deficits, yet individual neuroimaging studies have yielded inconsistent findings. The ENIGMA-HIV Working Group was established to harmonize data from diverse studies to identify the common effects of HIV-infection on brain structure. Methods: Data were pooled from 12 independent neuroHIV studies from Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1-weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72.4% on cART; 70.3% male; 41.6% with detectable viral load (dVL)), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell count) or dVL. Follow-up analyses stratified data by cART status and sex. Bonferroni correction was used to determine statistical significance. Findings: LowercurrentCD4+ count was associated with smaller hippocampal (β= 20.3 mm3 per 100 cells/mm3; p = 0.0001) and thalamic volumes (β= 29.3; p = 0.003); in the subset of participants not on cART, it was associated with smaller putamen volumes (β= 65.1; p = 0.0009). On average, a dVL was associated with smaller hippocampal (Cohen’s d = 0.24; p = 0.0003) and amygdala volumes (d = 0.18; p = 0.0058).Interpretation: In HIV+ individuals across five continents, smaller limbic volumes were consistently associated with current plasma markers. As we assessed cohorts with different inclusion/exclusion criteria and demographic distributions, these deficits may represent a generalizable brain-signature of HIV infection in the cART era. Our findings support the importance of achieving viral suppression and immune restoration for maintaining brain health. Funding: This work was supported, in part, by NIH grant U54 EB020403

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV

International audienceIMPORTANCE Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawnto date.OBJECTIVE To examine structural brain associations with the most commonly collected clinicalassessments of HIV burden (CD4+T-cell count and viral load), which are generalizable acrossdemographically and clinically diverse HIV-infected individuals worldwide.DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study established the HIV WorkingGroup within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortiumto pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and NorthAmerica. Regional and whole brain segmentations were extracted from data sets as contributingstudies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.MAIN OUTCOMES AND MEASURES Volume estimates for 8 subcortical brain regions wereextracted from T1-weighted magnetic resonance images to identify associations with blood plasmamarkers of current immunosuppression (CD4+T-cell counts) or detectable plasma viral load (dVL) inHIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.RESULTS After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5]years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+cell counts wereassociated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3per 100 cells/mm3;P< .001)and thalamic (mean [SE] β = 32.24 [8.96] mm3per 100 cells/mm3;P< .001) volumes and largerventricles (mean [SE] β = −391.50 [122.58] mm3per 100 cells/mm3;P= .001); in participants nottaking cART, however, lowercurrent CD4+cell counts were associated with smaller putamen volumes(mean [SE] β = 57.34 [18.78] mm3per 100 cells/mm3;P= .003). A dVL was associated with smallerhippocampal volumes (d= −0.17;P= .005); in participants taking cART, dVL was also associated withsmaller amygdala volumes (d= −0.23;P= .004