Antiretroviral Non-Adherence is Associated With a Retrieval Profile of Deficits in Verbal Episodic Memory.

HIV-associated deficits in verbal episodic memory are commonly associated with antiretroviral non-adherence; however, the specific aspects of memory functioning (e.g., encoding, consolidation, or retrieval) that underlie this established relationship are not well understood. This study evaluated verbal memory profiles of 202 HIV+ participants who underwent a 30-day electronic monitoring of antiretroviral adherence. At the group level, non-adherence was significantly associated with lower scores on immediate and delayed passage recall and word list learning. Retention and recognition of passages and word lists were not related to adherence. Participants were then classified as having either a normal verbal memory profile, a "subcortical" retrieval profile (i.e., impaired free recall with relatively spared recognition), or a "cortical" encoding profile (e.g., cued recall intrusions) based on the Massman et al. ( 1990 ) algorithm for the California Verbal Learning Test. HIV+ participants with a classic retrieval deficit had significantly greater odds of being non-adherent than participants with a normal or encoding profile. These findings suggest that adherence to prescribed antiretroviral regimens may be particularly vulnerable to disruption in HIV+ individuals due to deficits in the complex process of efficiently accessing verbal episodic information with minimal cues. A stronger relationship between non-adherence and passage (vs. word list) recall was also found and may reflect the importance of contextual features in remembering to take medications. Targeted interventions for enhancing and supporting episodic memory retrieval processes may improve antiretroviral adherence and overall health outcomes among persons living with HIV

Increases in a Pro-inflammatory Chemokine, MCP-1, Are Related to Decreases in Memory Over Time

Objective: To determine the longitudinal relationship between monocyte chemotactic protein 1 (MCP-1)/CCL2 and memory function in older adults.Methods: We examined longitudinal plasma MCP-1/CCL2 levels and a longitudinal verbal memory measure (CVLT-II 20’ recall) in a sample of 399 asymptomatic older adults (mean age = 72.1). Total visits ranged from 1 to 8, with an average time of 2.1 years between each visit, yielding 932 total observations. In order to isolate change over time, we decomposed MCP-1/CCL2 into subject-specific means and longitudinal deviations from the mean. The decomposed MCP-1/CCL2 variables were entered as predictors in linear mixed effects models, with age at baseline, sex, and education entered as covariates and recall as the longitudinal outcome. In follow-up analyses, we controlled for global cognition and APOE genotype, as well as baseline vascular risk factors. We also examined the specificity of findings by examining the longitudinal association between the MCP-1/CCL2 variables and non-memory cognitive tests.Results: Within-subject increases in MCP-1/CCL2 levels were associated with decreases in delayed recall (t = −2.65; p = 0.01) over time. Results were independent of global cognitive function and APOE status (t = −2.30, p = 0.02), and effects remained when controlling for baseline vascular risk factors (t = −1.92, p = 0.05). No associations were noted between within-subject increases in MCP-1/CCL2 levels and other cognitive domains.Conclusions: In an asymptomatic aging adult cohort, longitudinal increases in MCP-1/CCL2 levels were associated with longitudinal decline in memory. Results suggest that “healthy aging” is typified by early remodeling of the immune system, and that the chemokine, MCP-1/CCL2, may be associated with negative memory outcomes

“Liquid Biopsy” of White Matter Hyperintensity in Functionally Normal Elders

Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo from endothelial-derived exosomes (EDE), and comparing levels between two groups of functionally normal elders with and without WMH. In addition, we study associations of EDE proteins with upstream and downstream factors, such as inflammation and neurodegenerative changes, respectively.Methods: Twenty six neurologically normal older adults completed general health questionnaires, neuropsychological and physical examinations, and brain MRI. WMH was visually graded with modified Fazekas score of 2 or greater used to classify 11 subjects as cases, and 15 without WMH as controls. Plasma total exosomes were precipitated and EDEs enriched by sequential immuno-precipitations. In addition, we quantified three inflammatory cytokines from plasma and imaging variables on MRI. Group means were compared, the discriminant functions of biomarkers calculated, and the association of EDE biomarkers with plasma inflammatory markers, cognition, and imaging outcomes assessed via regression modeling.Results: Plasma levels of EDE cargo proteins GLUT1, LAT1, P-GP, and NOSTRIN were significantly higher in subjects with WMH in comparison to those without. In contrast, EDE levels of the marker with low expression in brain (VCAM1) were equal between groups. The effect sizes for each of the brain-expressed cargo proteins (GLUT1, LAT1, and P-GP) were such that age-adjusted logistic regressions revealed areas under the curve (AUC) with range of 0.82–0.89, differentiating subjects with WMH from those without. VCAM1 poorly discriminated between groups (AUC:0.55). Higher levels of all brain-expressed EDE proteins were also associated with lower cognitive function, unrelated to burden of WMH. Levels of LAT1 and P-GP were significantly inversely associated with global gray matter volumes, and EDE GLUT1, LAT-1, and P-GP concentrations were significantly associated with systemic IL-6 levels.Conclusion: In a case control study of clinically normal adults with and without WMH, concentrations of EDE proteins were significantly higher in subjects with WMH in comparison to controls. This work is a first step toward in vivo dissection of molecular changes in endothelia of functionally normal subjects with radiographic evidence of age-associated white matter disease