C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In this study we examined the relationship between CRP and markers of neuronal integrity and cerebral metabolism in middle-aged adults with intact cognitive function, using proton magnetic resonance spectrocospy. We hypothesized that increased levels of circulating CRP would correlate with changes in brain metabolites indicative of early brain vulnerability. Thirty-six individuals, aged 40 to 60, underwent neuropsychological assessment, a blood draw for CRP quantification, and 1H MRS examining N-acetyl-aspartate, myo-inositol, creatine, choline, and glutamate concentrations in occipito-parietal grey matter. Independent of age, sex and education, serum CRP was significantly related to higher cerebral myo-inositol/creatine ratio ( ), a relationship which remained unchanged after adjustment for cardiovascular risk ( , CRP β = 0.322, ). Because these biomarkers are detectable in midlife they may serve as useful indicators of brain vulnerability during the preclinical period when mitigating intervention is still possible. 1. Introduction Much evidence suggests that inflammatory conditions common in midlife such as obesity, atherosclerosis, and Type II diabetes play an important role in the development of dementia [1, 2]. Longitudinal studies have indicated that low-grade systemic inflammation in middle age adds to the risk of late-life cognitive impairment over and above the risk assessment afforded by disease (e.g., hypertension and atherosclerosis) and lifestyle habits (e.g., smoking) [1, 3, 4]. In addition, increases in serum inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been shown to exacerbate cognitive decline in older adults with metabolic syndrome, a condition defined by cooccurring obesity, hypertension, dyslipidemia, and hyperglycemia [2, 5]. The long-term use of anti-inflammatory drugs (NSAIDS), on the other hand, has been associated with a reduction in dementia risk [6–8], lending further support to the idea that sustained activation of an inflammatory immune response can foster neuronal vulnerability beyond what is expected of normal aging. With increasing age, inflammatory changes are appreciable in the brain in the form of astrocyte proliferation and the presence of activated microglia [9]. However, it is still unclear in what capacity midlife inflammation initiates detectable changes in the
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