Lower brain glutamate is associated with cognitive deficits in HIV patients: A new mechanism for HIV‐associated neurocognitive disorder

Ernst, Thomas; Jiang, Caroline S.; Nakama, Helenna; Buchthal, Steven; Chang, Linda

doi:10.1002/jmri.22366

Cited by 120 publications

(103 citation statements)

References 39 publications

(59 reference statements)

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“…Similar to the utility of the NFL level as a biomarker of early subclinical injury, MRS has been shown to detect early HIV-associated neuropathogenesis before detection of conventional MRI changes [42]. In a recent study, subjects with chronic HIV infection who have cognitive deficits were shown to have reduced glutamate and NAA levels in several brain regions, most pronounced in the parietal gray matter [43]. Here, we extend that finding to PHI.…”

Section: Discussionsupporting

confidence: 56%

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Rahimy¹,

Hagberg³

et al. 2017

The Journal of Infectious Diseases

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Background. We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (Q Alb ) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART).Methods. The Q Alb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the Q Alb before and after cART initiation, using mixed-effects models, and associations between the Q Alb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance.Results. The baseline age-adjusted Q Alb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the Q Alb increased over time in 84 participants with a normal baseline Q Alb (P = .006) and decreased in 22 with a high baseline Q Alb (P = .011). The Q Alb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The Q Alb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = −0.352 and P < .001 at baseline and r = −0.387 and P = .008 longitudinally) but not with neuropsychological performance.Conclusion. The Q Alb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection.

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Section: Discussionsupporting

confidence: 56%

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Rahimy¹,

Hagberg³

et al. 2017

The Journal of Infectious Diseases

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“…The elevated MI in younger HIV subjects also suggests premature brain aging, because MI increases with normal aging. 20 Prematurely lower brain glutamate levels (possibly due to reduced reuptake and recycling of glutamate by activated astrocytes) 21 and prematurely reduced cognitive reserve were also reported in younger subjects with HAND. 22 However, in the parietal gray matter, elevated MI is found only in SN, but not HIV1, APOE e41 subjects.…”

Section: Mri and Mrsmentioning

confidence: 99%

Effects of APOE ε4, age, and HIV on glial metabolites and cognitive deficits

et al. 2014

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Objective: We aimed to evaluate the combined effects of HIV and APOE e4 allele(s) on glial metabolite levels, and on known cognitive deficits associated with either condition, across the ages. Results: Frontal white matter myo-inositol was elevated in subjects with HIV across the age span but showed age-dependent increase in seronegative subjects, especially in APOE e41 carriers. In contrast, only seronegative APOE e41 subjects showed elevated myo-inositol in parietal cortex. All APOE e41 subjects had lower total creatine in basal ganglia. While all HIV subjects showed greater cognitive deficits, HIV1 APOE e41 subjects had the poorest executive function, fluency memory, and attention/working memory. Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE e41 subjects, and worse fluency in HIV1 APOE e41 subjects. Methods Conclusions:In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE e4 on neuroinflammation. APOE e4 negatively affects energy metabolism in brain regions rich in dopaminergic synapses. The combined effects of HIV infection and APOE e4 may lead to greater cognitive deficits, especially in those with greater neuroinflammation. APOE e4 allele(s) may be a useful genetic marker to identify white and mixed-race HIV subjects at risk for cognitive decline. Neurology ® 2014;82:2213-2222 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; ARV 5 antiretroviral; cART 5 combination antiretroviral therapy; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAND 5 HIV-associated neurocognitive disorders; IL 5 interleukin; MI 5 myo-inositol; MP-RAGE 5 magnetization-prepared rapid-acquisition gradient echo; MRS 5 magnetic resonance spectroscopy; SN 5 seronegative; tCr 5 total creatine; TE 5 echo time; TR 5 repetition time.

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“…1,4,5 Low glutamate (Glu) is also reported in CHI with cognitive impairment and is thought to reflect neuronal and glial cell dysfunction. 6 Antiretroviral therapy (ART) offers limited reversibility 7,8 even for CHI on stable long-term therapy, 9 suggesting that early HIV invasion of the CNS 10,11 and accrued neuronal damage 12 may contribute to the substantial prevalence of HIV-associated neurocognitive disorders in the era of ART. 13,14 1 H-MRS studies during primary HIV infection (PHI, the first year after HIV transmission) describes inflammation with trends of elevated Cho/creatine-containing metabolites (Cr) and MI/Cr with potentially neurotoxic levels of Glx (combined glutamate and glutamine peak) 10,15 ; this corresponds with neuropathologic immune activation previously reported in PHI.…”

mentioning

confidence: 99%

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

et al. 2014

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Objective: We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS).Methods: Cerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine 1 phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter.Results: Fifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope 5 0.0012, p 5 0.005) and MI/Cr (slope 5 0.0041, p 5 0.005) in frontal white matter as well as increases in MI/Cr (slope 5 0.0041, p , 0.001) and NAA/Cr (slope 5 0.0024, p 5 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope 5 20.0038, p 5 0.031). Conclusions: Early in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participantssuggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation. Neurology ® 2014;83:1592-1600 GLOSSARY ART 5 antiretroviral therapy; CHI 5 chronic HIV infection; Cho 5 choline-containing metabolites; Cr 5 creatine-containing metabolites; Glu 5 glutamate; 1 H-MRS 5 proton magnetic resonance spectroscopy; IQR 5 interquartile range; MI 5 myoinositol; MPRAGE 5 magnetization-prepared rapid gradient echo; MR 5 magnetic resonance; NAA 5 N-acetylaspartate; PHI 5 primary HIV infection; TCA 5 tricarboxylic acid; TE 5 echo time; VOI 5 volume of interest.Proton magnetic resonance spectroscopy ( 1 H-MRS) can detect dynamic cerebral metabolite changes indicative of inflammation and neuronal injury in individuals with HIV.

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Lower brain glutamate is associated with cognitive deficits in HIV patients: A new mechanism for HIV‐associated neurocognitive disorder

Cited by 120 publications

References 39 publications

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Effects of APOE ε4, age, and HIV on glial metabolites and cognitive deficits

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

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