PROJECT SUMMARY Better understanding is needed regarding the mechanism of HIV pathogenesis to the developing brain in individuals receiving longstanding antiretroviral therapy (ART). Despite the use of ART, brain abnormalities occur in people living with HIV, especially among individuals with perinatally-acquired HIV (pHIV) where abnormalities are frequently prevalent. Myelin water imaging (MWI) is generally regarded as the most rigorous approach for noninvasive, in-vivo measurement of myelin content. Noninvasive neuroimaging tools can assess the effectiveness of ART in preserving brain health and possibly lead to improvements in therapy. During the past three decades, it has been demonstrated that one-dimensional (1D) MR Spectroscopy (MRS) enables the study of only selected cerebral metabolites due to limited spectral dispersion even with 3 Tesla MRI scanners. Recently, our group, using the home-developed two-dimensional (2D) localized correlated spectroscopy (L- COSY) sequence combined with the prior-knowledge fitting (ProFit) algorithm showed that several cerebral metabolites can be quantified non-invasively in the prefrontal dorsolateral white matter region of perinatally HIV- infected youth and healthy children including novel metabolites such as glutathione (GSH), aspartate (Asp) and scyllo-inositol (sI). However, there were limitations due to the requirement of a 27 ml voxel and longer acquisition times. Hence, a novel five-dimensional (5D) echo-planar J-resolved spectroscopic imaging (EP-JRESI) sequence was recently implemented by our group where two spectroscopic dimensions were combined with three spatial dimensions to study the cerebral metabolite changes in pediatric HIV, with findings reported recently (5R21NS086449-02). However, a total duration of approximately 25 minutes of scan time was necessary. Using a modified rosette trajectory that densely samples both central and peripheral k-space, further acceleration and robustness to motion can be accomplished in MRSI and MRI as compared to other non- cartesian trajectories like radial, which will minimize patient discomfort by significantly reducing the scan time. Hence, the proposed study will test the following hypotheses: 1) The accelerated 5D rosette trajectories-based J-resolved Spectroscopic Imaging (ROSE-JRESI) and MWI with compressed sensing (CS)- based reconstruction will shorten the total acquisition duration, improving its clinical applicability while the 5D ROSE-JRESI data will also offer improved spatial resolution. 2) In the brains of pHIV young adults, decreased axonal myelination is present even in virally suppressed individuals correlating with worse neurocognitive performance (gross motor impairment) and altered metabolites. We propose two specific aims: 1) To optimize 5D ROSE-JRESI and 3D MWI on a 3T MRI scanner, and further optimize the CS-based reconstruction of the 5D MRSI and 3D MWI data using home developed MATLAB codes; 2a) To acquire multi-voxel 2D J-resolved...