Elevated CRP Level Linked to Decline in Executive Function and Frontal Lobe Damage

Susan Jeffrey

April 01, 2010

April 1, 2010 — A new study shows a link between elevated levels of high-sensitivity C-reactive protein (hs-CRP), an indicator of low-grade inflammation, and decline in executive function but not other cognitive domains.

In addition, although white matter hyperintensities and measures of brain atrophy were associated with CRP levels but did not reach statistical significance in this study, the researchers found a significant link between increased hs-CRP levels and diffusion tensor imaging (DTI) indicators of microstructural disintegration of white matter in the frontal lobe — the seat of executive function.

"We thought that this might be a causal pathway, that the CRP may be causing this subtle white matter damage, which then causes executive dysfunction, but it's a still cross-sectional study, so we don't know about causality," lead author Heike Wersching, MD, from the Institute of Epidemiology and Social Medicine at the University of Münster, Germany, told Medscape Neurology.

Dr. Wersching and colleagues have already begun a longitudinal study to look at this question further, she added, including some of these participants.

Their findings are published in the March 30 issue of Neurology.

Previous Findings Inconsistent

An elevated hs-CRP level has been shown to be an independent predictor of myocardial infarction and stroke and has also been linked to Alzheimer's disease and dementia, the study authors write.

Executive function is the cognitive domain that appears to be most vulnerable to vascular damage, Dr. Wersching noted. Some studies looking at the relationship between CRP and small vessel disease that manifests as white matter intensities and lacunar infarcts have found a link, but others have not replicated these findings.

In this study, the researchers used DTI, a developing imaging technique that allows assessment of white matter microstructure, and detection of "even subtle pathologic changes in fiber integrity," the study authors write. "DTI changes correlate with clinical symptoms, histopathologic changes, and neuropsychological deficits in early stages of vascular and degenerative brain damage," they note.

In this study, Dr. Wersching and colleagues looked at the association between hs-CRP levels and cognitive function in 447 participants in the Systematic Evaluation and Alteration of Risk Factors for Cognitive Health (SEARCH) Health Study, a population-based sample of community-dwelling elderly individuals without prior stroke.

Of these, 321 also underwent high-field magnetic resonance imaging, including fluid-attenuated inversion recovery (FLAIR) sequences evaluating white matter hyperintensities, automated quantification of brain parenchyma volumes, and DTI to assess global and regional white matter integrity, quantified by fractional anisotropy (FA). All subjects also underwent cognitive assessment, including verbal memory, word fluency, and executive functions.

They found that higher levels of hs-CRP were associated with worse performance on tests of executive function, even after adjustment for age, sex, education, and cardiovascular risk factors. "It's not like these people are really cognitively impaired," Dr. Wersching emphasized, "but it's just they do worse than people who have a lower CRP."

A higher hs-CRP level was also related to reductions in global FA, as well as reduced regional FA in particular areas, including the frontal lobes, corona radiata, and the corpus callosum, particularly the genu, they write. Those areas, Dr. Wersching noted, "are very relevant for executive function."

Table. Relation of High-Sensitivity C-Reactive Protein Level to Executive Function and Imaging Results

Measure β P Value
Executive function −.095 .02
Global FA −.237 < .001
FA frontal lobes −.246 < .001
FA corona radiata −.222 < .001
FA corpus callosum −.141 .016
FA genu −.174 .004

FA = fractional anisotropy

They also found significant correlation of hs-CRP in motor regions, including the corona radiate and corticospinal tract. However, their assessment did not include a motor task, so "we cannot rule out that motor regions were affected in frontal areas as well, implying a specific effect of hs-CRP on motor fibers," the study authors note.

Recent results from trials such as Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) have shown that using anti-inflammatory drugs such as statins can lower hs-CRP levels, which is in turn associated with reduced cardiovascular events, they add (Ridker PM, et al. N Engl J Med. 2008;359:2195-2207). Lifestyle interventions, such as increased activity and reduced body weight, have also been shown to have beneficial effects on cognitive function and circulating hs-CRP levels.

"Whether lowering of CRP can also prevent cognitive decline and/or microstructural white matter alterations needs to be addressed in upcoming clinical trials," they conclude.

Assay for Brain Microvascular Disease

In an editorial accompanying the publication, Ronald J. Killiany, PhD, director of the Center for Biomedical Imaging at Boston University School of Medicine in Massachusetts, discusses and explains the new imaging techniques used in this study.

"By allowing us to visualize both pathways and pathology, DTI provides us with the ability to expand vastly our understanding of the organization and functions of white matter," he notes. "As Wersching and colleagues demonstrated, the associations between C-reactive protein levels and FA contrasted with the failure to find similar associations with white matter lesions in FLAIR images."

The findings, Dr. Killiany concludes, "offer the prospect that a combination of measurements of systemic inflammation (C-reactive protein) and sensitive imaging modalities (DTI) might someday provide an assay for brain microvascular disease and provide a means for intervention."

The study was supported by the German Research Foundation, the Volkswagen Foundation, the Marie Curie Research and Training Network (funded by the European Commission), the BMBF-Competence Network Mednet Atrial Fibrillation, BMBF-Research Consortium, and the Neuromedical Foundation Münster. Dr. Wersching has disclosed no relevant financial relationships. Disclosures for coauthors are listed in the paper. Dr. Killiany reports that he has a clinical affiliation with Essex Neurological Associates and a research affiliation with the MRI Centers of New England, serves as acting site principal investigator for the Boston University Contributions to the Alzheimer's Disease Neuroimaging Initiative, and receives research support from the National Institutes of Health.

Neurology. 2010;74:1022-1029, 1014-1015.

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