Associations between cerebrospinal fluid N-acetyl-aspartyl-glutamate (NAAG) and cognitive function in people with HIV.

Objectives: Despite effective antiretroviral therapy, many people with HIV (PWH) experience persistent deficits in attention and working memory (WM). Identifying neurometabolic drivers of these impairments is critical for precision diagnostics and targeted interventions. N-acetylaspartylglutamate (NAAG), the most abundant brain dipeptide and endogenous agonist of metabotropic glutamate receptor 3 (mGluR3), regulates glutamatergic transmission central to these cognitive domains. While prior magnetic resonance spectroscopy (MRS) studies have associated higher NAAG with better cognition, NAAG has never been quantified in cerebrospinal fluid (CSF) of PWH or linked to cognition in this population.

Design: We tested whether CSF NAAG levels relate to domain-specific cognitive function in 28 PWH (plasma viral load <200 cp/mL).

Methods: NAAG was quantified by a sensitive and selective liquid chromatography-tandem mass spectrometric (LC/MS-MS) method. Cognition was measured using a Research Domain Criteria (RDoC)-based battery, with principal component analysis deriving domain scores. Pearson correlations and age/viral load-adjusted regressions were used to assess NAAG- cognition associations.

Results: Higher CSF NAAG was significantly associated with better spatial attention and WM (r = 0.479, P = 0.01), independent of age and viral load. In contrast, NAAG levels showed no relationship with verbal attention and WM or other domains such as verbal episodic memory and motor function.

Conclusions: This is the first study to identify a CSF-based neurometabolic marker linked to specific cognitive domains in PWH, bridging MRS findings to a scalable fluid biomarker platform. NAAG CSF measurement opens new translational pathways for early detection, risk profiling, and glutamatergic-targeted interventions in neuroHIV. Longitudinal studies will determine its prognostic and therapeutic utility.