Background: HIV infection causes neuroinflammation and immune activation (NIIA) and systemic inflammation and immune activation (SIIA), which in turn drive neurodegeneration (ND). Cross-sectionally, higher levels of NIIA biomarkers correlate with increased biomarkers of ND. A more convincing confirmation would be a longitudinal demonstration. Methods: PWH in the US multisite CHARTER Aging project were assessed at a baseline visit and after 12 years using standardized evaluations. We measured a panel of 14 biomarkers of NIIA, SIIA, and ND in plasma and CSF at two time points and calculated changes from baseline to the 12-year visit. Factor analysis yielded simplified indices of NIIA, SIIA, and ND. Results: The CSF NIIA factor analysis yielded Factor1 loading on soluble tumor necrosis factor type-2 (sTNFR-II) and neopterin, and Factor2, loading on MCP1, soluble CD14, and IL-6. The SIIA factor analysis yielded Factor1 loading on CRP, D-dimer, and Neopterin; Factor2 loading on sTNFR-II. The ND analysis yielded Factor1 loading on Phosphorylated tau (p-tau) and Aβ42; Factor2 loading on NFL. NIIA Factor1, but not Factor2, correlated with increases in CSF NFL (r = 0.370, p = 0.0002). Conclusions: Increases in NIIA and SIIA in PWH were associated with corresponding increases in ND, suggesting that reducing neuro/systemic inflammation might slow or reverse neurodegeneration.

Objective. Crocin as an important constituent of saffron has antineuropathic pain properties; however, the exact mechanism of this effect is not known. The aim of this study was whether the hypoalgesic effect of crocin can be exerted through muscarinic receptors. Materials and Methods. In the present project, 36 male Wistar rats (200 ± 20 g) were used. Animals randomly divided into six groups (sham, neuropathy, neuropathy + crocin, neuropathy + atropine 0.5 mg/kg, neuropathy + atropine 1 mg/kg, and neuropathy + atropine 1 mg/kg + crocin). Neuropathy was induced by the chronic constriction injury (CCI) method on the sciatic nerve. Crocin and atropine was administered intraperitoneally during 14 days following the 14^th day after surgery. Pain response was detected every three days, two hours after each injection and 3 days following last injection. Mechanical allodynia and thermal hyperalgesia were detected using the Von Frey filaments and plantar test device, respectively. Results. CCI significantly reduced the paw withdrawal response to mechanical and thermal stimulus ( and , respectively). Crocin therapy significantly reduced mechanical allodynia and thermal hyperalgesia induced by CCI ( ). Atropine pretreatment significantly blocked the hypoalgesic effect of crocin ( in mechanical allodynia and in thermal hyperalgesia). Fourteen days administration of atropine alone at a dose of 0.5 mg/kg but not 1 mg/kg significantly reduced CCI-induced mechanical allodynia at day 30 after surgery. Conclusion. Crocin significantly decreased CCI-induced neuropathic pain. The hypoalgesic effect of crocin was blocked by atropine pretreatment, which indicates an important role for muscarinic receptors in the effect of crocin.

Objective: Neurocognitive (NC) impairment in people with HIV (PWH) is associated with erythrocyte indices, which may serve as indicators of iron metabolism, inflammation, and related factors. Erythropoiesis requires iron, regulated by a multifaceted system of peptide hormones, including hepcidin. This study postulated that hepcidin might modify the relationship between erythrocyte indices and NC performance in PWH. Methods: Plasma hepcidin and erythrocyte indices were quantified in 88 virally-suppressed PWH who underwent comprehensive NC assessments. Global NC performance was summarized by global T-scores. Associations of global T-scores with anemia and erythrocyte indices were determined in univariable analyses. To examine the influence of hepcidin on the relationship between NC performance and erythrocyte indices, we evaluated interactions between these covariates in relation to global T-scores and then performed stratified analyses. Results: In multivariable analyses, hepcidin detectability interacted with age (p = 0.007) and mean corpuscular volume (MCV) (p = 0.031) in relation to the global T-score. Interactions between anemia and erythrocyte indices on global T-scores were significant (anemia x MCV, p = 0.008; anemia x MCH, p = 0.011). Stratified analyses identified that lower global T-scores were associated with older age (p = 0.001) and higher MCV (p = 0.0046) and mean corpuscular hemoglobin (MCH, p = 0.026) only when hepcidin was undetectable. Among the anemic, worse global T-score was associated with higher MCV (p = 0.001) and MCH (p = 0.002). Conclusion: Findings suggest that iron-related factors (hepcidin, anemia, MCV, MCH) and age influence neurocognitive health. This cross-sectional study underscores hepcidin as an effect modifier in the associations of erythrocyte indices, anemia, and age with neurocognitive function in PWH.

Background: Aging-related comorbidities such as cardiovascular disease and neurocognitive impairment are more common among people with HIV (PWH). Hypertension (HTN) has been implicated in cognitive decline, and antihypertensives with anticholinergic properties may exacerbate this decline. Our research probed the relationship between neurocognitive performance and antihypertensives in hypertensive PWH and in those without HIV (PWoH), examining whether increased antihypertensives followed the worsening in neurocognitive performance. Methods: This longitudinal analysis encompassed seven visits over five years, enrolled between 1999 and 2022. Participants were included if they reported HTN or used antihypertensives. All participants underwent comprehensive cognitive assessments, and their global cognitive performance was evaluated using summary, demographically corrected T-scores. The association between the global T-score and the number of antihypertensives was evaluated using generalized linear mixed-effects models. Summary regression-based change score (sRCS) was analyzed as an indicator of global performance over time. Results: Among 1158 hypertensive PWH (79.9% were on ART), worsening cognitive performance was associated with an increased number of antihypertensives (p = 0.012) but not in PWoH (p = 0.58). PWH had lower mean arterial pressure (MAP) than PWoH after adjusting for demographics (β = −5.05, p = 2.3 × 10⁻¹¹). In PWH, an association between mean arterial pressure (MAP) and sRCS suggested that those with cognitive improvement had lower MAP (p = 0.027). PWH taking more anticholinergics were more likely to have worse cognitive performance over time (p < 0.001). Conclusions: PWH with declining neurocognitive performance over time used increasing numbers of antihypertensives, suggesting that their providers prescribed more antihypertensives because of either treatment refractory HTN or poor adherence. Prescribers should avoid using antihypertensives with anticholinergic properties when possible.

Background: Metabolic dysfunction and neurocognitive decline share inflammatory pathways that may be amplified in people with HIV (PWH). Prior studies suggest insulin resistance correlates with cognitive decline, while gut-related metabolites, such as betaine, may be protective through metabolic regulation and anti-inflammatory effects. We investigated whether metabolic markers differentially associate with cognitive performance in PWH versus people without HIV (PWoH). Methods: We enrolled 200 participants, equally stratified by HIV and diabetes mellitus status, into four groups of 50. All completed neuropsychological testing yielded demographically corrected global T-scores (higher indicates better performance). Biomarkers included GlycA, Diabetes Risk Index (DRI), Lipoprotein Insulin Resistance Index (LP-IR), branched-chain amino acids, and betaine. Multiple linear regression examined associations between metabolic markers and T-scores, adjusting for covariates. Results: Participants had a mean age of 55.7 years (71.0% male). GlycA levels were higher in individuals with diabetes (p = 0.001). Higher DRI levels were associated with worse global T-scores (standardized β = -0.27, p = 0.009). Higher LP-IR was associated with worse cognitive performance in PWH, but not in PWoH (interaction p = 0.007). HIV moderated the association between betaine and global T-scores (interaction p = 0.01); higher betaine was associated with better cognitive performance (standardized β = 0.24, p = 0.02). Higher betaine correlated with lower LP-IR in PWH (standardized β = -0.47, p < 0.01) and lower DRI in all participants (ps < 0.05). Conclusion: Insulin resistance might play a prominent role in cognitive health in PWH than PWoH, suggesting HIV-related metabolic vulnerability is affecting brain health. Associations between betaine, which has immunomodulatory effects, and improved metabolic profiles suggest potential therapeutic targets to preserve cognitive function in PWH. These observational findings may reflect metabolic, dietary, or lifestyle-related factors and require confirmation in studies with detailed nutritional assessment.