Serum MMP-3/TIMP-1 ratio is a potential diagnostic marker for HIV-associated neurocognitive disorders

Persistent central nervous system (CNS) inflammation and chronic immune activation contribute to HIV-1-associated neurocognitive disorders (HAND). Imbalances in the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in HAND pathogenesis. We hypothesized that MMP levels would be higher in the HAND group than in the other groups. This study assessed MMPs and TIMPs in the cerebrospinal fluid (CSF) and serum of people with HIV (PWH, n=68) and people without HIV (PWoH, n=19) categorized by neurocognitive performance using the Global Deficit Score (GDS) and HAND classification. Biomarker levels were compared using linear regression adjusted for plasma HIV RNA suppression and nadir CD4. The Benjamini-Hochberg method was used for multiple testing adjustment, and Spearman method (ρ) for correlation. Serum MMP-3/TIMP-1 ratio levels were elevated in the group with GDS >0.5 versus GDS <0.5 [0.048 (0.029; 0.068) versus 0.028 (0.018; 0.049), Cohen's d 0.811 (0.274, 1.348), p BH-adjusted 0.036]. Working memory deficit was weakly correlated with MMP-2, MMP-9, TIMP-1, MMP-9/TIMP-1, and MMP-2/TIMP-2 in CSF (ρ 0.277-0.383), there was no correlation of these biomarkers in serum. The area under the receiver operating characteristic curve of MMP-3/TIMP-1 ratio for HAND diagnosis was 0.67, sensitivity was 64% (46%-79%), and specificity was 67% (45%-84%). Conclusion: Serum MMP-3/TIMP-1 ratio is a promising diagnostic biomarker of HAND, potentially eliminating the need for lumbar puncture and CSF collection.