Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Abstract

Objective: HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition.Methods: Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson's correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores.Results: HIV significantly interacted with METH (p<.001) such that compared to HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d=0.96; HIV-/METH+: d=0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d=0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r=−0.19), learning (r=−0.23), and delayed recall (r=−0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH-groups (i.e., HIV-/METH-and HIV+/ METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (i.e., HIV-/METH+, HIV+/METH+).

Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure

“…In HIV-1 Tg rats, therefore, the preponderance of dendritic spines on distal dendrites, which extend into layer I, supports alterations in neurotransmitter innervation and synaptic connectivity. Indeed, neurotransmitter systems, including the dopamine (for review, [ 77 ]), norepinephrine (e.g., [ 78 ]) and serotonin (e.g., [ 79 , 80 ]) systems, are dysregulated by HIV-1 viral protein exposure. Furthermore, the magnitude of the rightward shift in the distribution of dendritic spines along the apical dendrite progresses with age in HIV-1 Tg animals, supporting an age-related loss in neurotransmitter innervation and synaptic connectivity.…”

Through the Looking-Glass: Psychoneuroimmunology and the Microbiome-Gut-Brain Axis in the Modern Antiretroviral Therapy Era

“…Another study with 4000 PWH from the Strategies for Management of Antiretroviral Therapy study revealed cross-sectional inverse associations between heart rate variability with soluble markers of inflammation and coagulation (140). Bearing in mind that stimulants act primarily by altering the function of catecholamines, stimulants and HIV are independently associated with higher NE in cerebrospinal fluid and dysregulated systemic metabolism of tyrosine (an essential amino acid precursor for catecholamines) (141,142). Alterations in catecholamines could partially explain associations of stimulant use with greater immune activation, inflammation, HIV proviral DNA in immune cells, and immune exhaustion in PWH who are virally suppressed or undetectable (142)(143)(144)(145)(146).…”

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

“…In addition, sleep disturbances may be an underlying neurobiological mechanism of depression. While one study found the highest prevalence of lifetime major depression disorder in HIV+/METH+ individuals [ 142 ], the other study established that METH use was a more important determinant of depression than HIV-1 status [ 143 ]. In mouse studies, brain-specific Tat expression led not only to reward deficits, a core symptom of depression, but also to increasing METH-induced reward sensitivity [ 144 , 145 ].…”