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

Abstract

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.

Facial emotion recognition impairments are associated with brain volume abnormalities in individuals with HIV

“…Neuroimaging studies provide evidence of accelerated aging processes in HIV+ adults (Chang et al, 2014; Holt, Kraft-Terry, & Chang, 2012; Thomas, Brier, Snyder, Vaida, & Ances, 2013), with some indication that aging may increase HIV-related neural change (Clark & Cohen, 2010; Cysique et al, 2013). In addition, studies of facial emotion recognition in non-HIV samples indicate that older adults are less accurate at recognizing fearful expressions than younger adults (Calder et al, 2003; Circelli, Clark, & Cronin-Golomb, 2013).…”

Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia

“…Although neurons exhibit activity-dependent uptake of myo-Inositol (Uldry et al, 2004), myo-Inositol is more concentrated in glial cells than neurons (Brand et al, 1993;Griffin et al, 2002), and may be critical for glial osmoregulatory functioning (Strange, 1992;Fisher et al, 2002). In neuro-inflammatory conditions, elevated myo-Inositol levels are presumed to reflect astrocyte and microglial activation (Chang et al, 2014, Kirov et al, 2013; conversely, reduced myo-Inositol levels have been interpreted as evidence of astrocyte necrosis in neuromyelitis optica (Ciccarelli et al, 2013). Several postmortem studies have found reduced density of glial cells (Ongür et al, 1998;Hamidi et al, 2004) and decreased concentration of protein markers specific to astrocytes in MDD (MiguelHidalgo et al, 2000;Miguel-Hidalgo et al, 2011;MiguelHidalgo et al, 2014), providing a histological basis for interpreting reduced myo-Inositol levels in MDD as evidence of glial dysfunction (Coupland et al, 2005;Chen et al, 2014).…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…One is ART-induced neurotoxicity, which is now known to result in part by dysregulated A[H9252]PP processing and subsequent deposition of Aβ plaques in the brain. Based on neuropathological data [11, 205], genetic screening [206, 207], and CSF markers [208], researchers have raised the possibility that AD may be becoming more common in HIV patients on cART. Although the exact mechanisms through which cART contributes to Aβ deposition in the brain are unknown, neurotoxic effects of ART drugs such as mitochondrial dysfunction [81, 91, 209], increased oxidative and ER stress [82, 92, 93, 210, 211], and neuronal damage and synaptic loss [212, 213] are now linked to altered AβPP processing and Aβ deposition in the brains of HIV patients.…”