In our community-based cohort, we examined a large panel of inflammatory markers in relation to brain MRI findings. Though we did not observe a significant association between the inflammatory markers and WMH/TCV, IL-6, OPG, and TNFα were modestly associated with TCBV in stepwise multivariable-adjusted models. In analyses of each inflammatory marker separately, the same markers (IL-6, OPG, and TNFα) were significantly associated with TCBV. The relations between inflammatory markers and TCBV were modified by both sex and age, such that the association was strongest among men and individuals aged 60 and older. These data are among the first to report an association between TCBV and circulating inflammatory markers in a dementia-free, community-based sample. Though the clinical magnitude of these associations was heavily influenced by age, the decrease in brain volume observed when the inflammatory marker increased from the 25th to the 75th percentile was comparable to the decrease in brain volume associated with every 1.5 years of advancing age.
Prior research has linked inflammatory markers, such as OPG,33
with AD, which is characterized in part by global cerebral atrophy. Due to the observational nature of our study, we are unable to conclude if the association between certain markers of inflammation (i.e., IL-6, OPG, and TNFα) and TCBV reflects a unique pathophysiologic insight specific to these markers or a nonspecific manifestation of inflammation. Furthermore, inflammatory cytokines, such as IL-6 and TNFα, are activated in many conditions associated with advancing age,34
and inflammatory markers purportedly contribute to the pathophysiology of cardiovascular disease.35
We acknowledge that circulating biomarkers of inflammation may not adequately represent inflammatory events at the tissue level in the CNS. Though we selected a broad panel of inflammatory markers to represent various phases of the inflammatory cascade, we did not measure all inflammatory biomarkers that previously have been related to neurologic phenotypes.
Prior research utilizing animal models has related hippocampal and entorhinal cortex atrophy to chronic neuroinflammation.36
We extend the previous work by reporting an association between inflammatory markers and TCBV in a nondemented, community-based sample, and the association was most robust among individuals over age 60 years. The finding of effect modification by age coincides with a period in the life cycle when both health risk factors and cognitive impairment are of emerging relevance. We hypothesize, but cannot examine in a cross-sectional study, that the presence of systemic inflammation accelerates age-related changes in the brain, which may either act as a susceptibility factor or possibly an associated marker for the early evolution of AD neuropathology.4
We did not find an association between biomarkers of inflammation and WMH/TCV, which contrasts with prior epidemiologic evidence.19
In an older cohort, the Rotterdam Scan Study documented that higher CRP concentrations were associated with both increased WMH cross-sectionally and WMH progression longitudinally,19
which supports the well-established association between inflammation and the atherosclerotic process.35
There are several potential explanations for our null finding, including the fact that our sample was predominantly healthy, younger, and had less WMH burden. Another reason may be the technique we employed for measuring WMH (i.e., we digitized and quantified WMH in contrast to semiquantitative estimates). A third explanation for the discrepancy is that we had adequate statistical power to detect modest associations between inflammatory markers and WMH cross-sectionally. However, we cannot exclude the possibility that the inflammatory markers had a very small association with WMH, which might have been detected in a larger dataset. Longitudinal study of our cohort may yield different relations between WMH and inflammatory markers that are more consistent with the previous findings.
Our study has a number of strengths, including the core MRI reading laboratory blinded to clinical characteristics, a large community-based cohort free from clinical dementia and stroke, simultaneous examination of 9 or 10 inflammatory biomarkers, comprehensive ascertainment of potential confounding variables, and stringent quality control procedures for measurement of both inflammatory biomarkers and brain MRI. However, the present findings must be tempered by several caveats. First, the age and racial makeup of the Framingham Offspring Study is predominantly white, of European descent, and middle-aged to elderly; the generalizability to other races, ethnicities, and age groups is unknown. The exclusion of institutionalized individuals and participants with clinical stroke and the inclusion of individuals willing to undergo MRI resulted in a generally healthy sample thereby reducing the likelihood of finding relations that may be present in the general population, which includes individuals with cognitive impairment or stroke.
Because we observed effect modification by age and sex and we present several models, our data might in part represent false positives due to multiple testing. To address multiple testing concerns we used an omnibus test (i.e., examining the markers as a group in relation to the MRI phenotypes) as the primary analysis. In addition, for the specific marker analyses ( through ), we used a p value threshold of < 0.01. We cannot exclude the possibility that only very high values of some of the markers may be related to MRI phenotypes; we did not pursue threshold analyses because we sought to limit the number of statistical tests. Nevertheless, our findings will need to be replicated in another cohort.