Interbatch Reliability of Blood-Based Cytokine and Chemokine Measurements in Community-Dwelling Older Adults: A Cross-Sectional Study.

Blood-based inflammatory markers hold considerable promise for diagnosis and prognostication of age-related neurodegenerative disease, though a paucity of research has empirically tested how reliably they can be measured across different experimental runs ("batches"). We quantified the interbatch reliability of 13 cytokines and chemokines in a cross-sectional study of 92 community-dwelling older adults (mean age = 74; 48% female). Plasma aliquots from the same blood draw were parallelly processed in 2 separate batches using the same analytic platform and procedures (high-performance electrochemiluminescence by Meso Scale Discovery). Interbatch correlations (Pearson's r) ranged from small and nonsignificant (r = .13 for macrophage inflammatory protein-1 alpha [MIP-1α]) to very large (r > .90 for interferon gamma [IFNγ], interleukin-10 [IL-10], interferon gamma-induced protein 10 [IP-10], MIP-1ß, thymus and activation-regulated chemokine [TARC]) with most markers falling somewhere in between (.67 ≤ r ≤ .90 for IL-6, tumor necrosis factor alpha [TNF-α], Eotaxin, Eotaxin-3, monocyte chemoattractant protein-1 [MCP-1], MCP-4, macrophage-derived chemokine [MDC]). All markers, except for IL-6 and MCP-4, showed significant differences in absolute values between batches, with discrepancies ranging in effect size (Cohen's d) from small to moderate (0.2 ≤ |d| ≤ 0.5 for IL-10, IP-10, MDC) to large or very large (0.68 ≤ |d| ≤ 1.5 for IFNγ, TNF-α, Eotaxin, Eotaxin-3, MCP-1, MIP-1α, MIP-1ß, TARC). Relatively consistent associations with external variables of interest (age, sex, systolic blood pressure, body mass index, cognition) were observed across batches. Taken together, our results suggest heterogeneity in measurement reliability of blood-based cytokines and chemokines, with some analytes outperforming others. Future work is needed to evaluate the generalizability of these findings while identifying potential sources of batch effect measurement error.

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.

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage.

Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Aß42, phosphorylated tau [p-tau], sAßPPß) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1ß levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1ß, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aß42. Higher CSF sAßPPß levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1ß were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aß42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.

An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations.

INTRODUCTION: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. METHODS: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. RESULTS: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 ± 10.9% in plasma and -10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. DISCUSSION: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes.

INTRODUCTION: MCP-1 and eotaxin-1 are encoded on chromosome 17 and have been shown to reduce hippocampal neurogenesis in mice. We investigated whether these chemokines selectively associate with memory in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. METHODS: MCP-1 and eotaxin-1 were assayed in controls, MCI, and AD dementia patients with varying phenotypes (n = 171). A subset of 55 individuals had magnetic resonance imaging (MRI) scans available. Composite scores for cognitive variables were created, and medial temporal lobe volumes were obtained. RESULTS: An interaction was noted between MCP-1 and eotaxin-1, such that deleterious associations with memory were seen when both chemokines were elevated. These associations remained significant after adding APOE genotype and comparison (non-chromosome 17) chemokines into the model. These chemokines predicted left medial temporal lobe volume and were not related to other cognitive domains. DISCUSSION: These results suggest a potentially selective role for MCP-1 and eotaxin-1 in memory dysfunction in the context of varied MCI and AD dementia phenotypes.