Abstract
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.
Highlights
Dysregulation of immune cascades is considered to be a core component of aging and has been linked with negative pathological outcomes
Animal studies suggest that blood-borne MCP-1/CCL2 levels are elevated in older mice and young heterochronic parabionts, are linked with age-related decline in neurogenesis, and are associated with poorer memory function (Villeda et al, 2011; Villeda and Wyss-Coray, 2013); MCP-1/CCL2 knockout mice evidence increased neurogenesis in the dentate gyrus subsequent to cranial irradiation (Lee et al, 2013)
We examined the effects of both the within-subject change in MCP-1/CCL2 levels and the average MCP-1/CCL2 levels on longitudinal memory outcomes, controlling for baseline age, sex, and education level
Summary
Dysregulation of immune cascades is considered to be a core component of aging and has been linked with negative pathological outcomes. The impact of the peripheral immune system on cognitive aging outcomes has been controversial, with higher levels of circulating inflammatory markers often being conceptualized as non-specific, downstream effects of aging with unclear significance to the central nervous system (CNS; Galasko and Montine, 2010; Galasko and Golde, 2013). That the peripheral milieu actively communicates with the CNS, such that bloodborne, circulating immune markers may accelerate the peripheral aging process (i.e., immunosenescence; Franceschi et al, 2000; Baruch et al, 2013), but may directly impact the CNS by impeding hippocampal neurogenesis (Villeda et al, 2011) and exacerbating cognitive decline (Cunningham et al, 2009; Westin et al, 2012). Animal studies suggest that blood-borne MCP-1/CCL2 levels are elevated in older mice and young heterochronic parabionts (i.e., a young mouse whose vascular system is joined with an older mouse), are linked with age-related decline in neurogenesis, and are associated with poorer memory function (Villeda et al, 2011; Villeda and Wyss-Coray, 2013); MCP-1/CCL2 knockout mice evidence increased neurogenesis in the dentate gyrus subsequent to cranial irradiation (Lee et al, 2013)
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