LeukocyteCCR2Expression Is Associated with Mini-Mental State Examination Score in Older Adults

Abstract

Introduction: Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample. Methods: We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models. Results: In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta = -0.16, p = 5.1 · 10 -6 , false discovery rate (FDR; q = 0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta = -0.16, p = 5.1 · 10 -6 , q = 0.003; and beta = -0.13, p = 5.5 · 10 -5 , q = 0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype. Conclusions: We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated b-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.

Blood methylomic signatures of presymptomatic dementia in elderly subjects with type 2 diabetes mellitus

“…For example cg23630131 and cg09788352 lie downstream of KCDT7 and CLN6 respectively, with mutations in both these genes being associated with severe dementia in progressive myoclonus epilepsy (Kousi, et al, 2012) and ceroid-lipofuscinosis (Arsov, et al, 2011) respectively. Furthermore, cg01094683 lies upstream of TBC1D16 , with decreased leukocyte expression of this gene having been previously associated with lower Mini Mental State Examination (MMSE) scores (Harries, et al, 2012). Although the other identified loci have not been previously associated with dementia, they could still represent novel biomarkers.…”

Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts

“…We analysed microarray data from participants at the 9-year follow-up of the InCHIANTI study, which has been previously described (Ferrucci et al 2000; Harries et al 2012a, b; Holly et al 2013). 695 subjects aged between 30 and 104 years old with a mean age of 72.3 years (standard deviation 15.3 years).…”

Global expression profiling of cognitive level and decline in middle-aged monozygotic twins

“…With the exception of the study by Harries et al (Harries et al, 2012) where blood gene expression patterns were related to cognitive level and rate of change assessed by the Mini-Mental State Examination (MMSE) in 688 individuals with a mean age of 72.6 years at intake and 9 years of follow-up, most studies relating transcriptional changes to brain aging generally have not attempted to associate the profiles to measures of cognitive functioning during the normative cognitive aging of individuals in the middle-aged and young elderly age-groups. Consequently, in this study we therefore aimed at identifying transcriptional changes correlated with differences in cognitive ability as assessed by a battery of 6 cognitive tests representing tasks that are sensitive to normative aging.…”