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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:1017-1021 (2005)
© 2005 The Gerontological Society of America

Serum C-Reactive Protein and Cognitive Function in Healthy Elderly Italian Community Dwellers

Giovanni Ravaglia1,, Paola Forti1, Fabiola Maioli1, Nicoletta Brunetti1, Mabel Martelli1, Lucia Servadei1, Luciana Bastagli1, Marisa Bianchin2 and Erminia Mariani3

1 Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy.
2 Lugo Medical District, Ravenna Local Health Unit, Italy.
3 Laboratory of Immunology and Genetics, Codivilla Putti Research Institute, Rizzoli Orthopaedic Institute, Bologna, Italy.

Address correspondence to Prof. Giovanni Ravaglia, Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy. E-mail: ravaglia{at}med.unibo.it


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. Chronic low-grade inflammation, as measured with the peripheral serum marker C-reactive protein (sCRP), may be a risk factor for dementia in elderly persons.

Methods. The relationship between sCRP and score on the Mini-Mental State Examination (MMSE), a commonly used screening cognitive measure, was investigated in 540 well functioning, healthy, and cognitively normal elders (age 73 ± 6 years). Sociodemographic status, lifestyle, health status, traditional and nontraditional cardiovascular risk factors including plasma total homocysteine (tHcy), and other peripheral blood markers of vascular inflammation (leukocyte count, serum albumin, and plasma fibrinogen) were also assessed.

Results. Risk for having sCRP in the highest decile (>0.7 mg/dl) was significantly higher in individuals with MMSE score 24–25 (odds ratio = 3.07, 95% confidence interval, 1.2–7.9) and 26–28 (odds ratio = 2.10, 95% confidence interval, 1.1–3.9) compared with those scoring above 28 (reference group). Results were unaffected by adjustment for all potential confounders. No association was found between MMSE and peripheral markers of vascular inflammation other than sCRP, but lower MMSE scores were also independently associated with hyperhomocysteinemia (plasma tHcy > 15 mmol/L).

Conclusion. In healthy, cognitively normal elderly community dwellers, increased sCRP levels are associated with concurrent cognitive impairment as measured by MMSE. The association is independent of sociodemographic status, lifestyle, health status, and traditional and nontraditional cardiovascular risk factors including hyperhomocysteinemia. Results support the hypothesis that chronic low-grade inflammation may be involved in age-related cognitive impairment.

CHRONIC low-grade inflammation may play a causal role in age-related cognitive impairment (1). Proinflammatory cytokines and acute-phase reactants are increased in the brain and peripheral blood of patients with Alzheimer's disease (AD) (2). Moreover, chronic vascular inflammation is an acknowledged key pathogenetic process of atherosclerosis (3). Cerebrovascular disease is the second cause of age-related dementia after AD, and degenerative and vascular damage often coexist in the brain of older patients with dementia (4).

Serum C-reactive protein (sCRP), an acute-phase reactant, is a sensitive marker of systemic inflammation (3). The highly sensitive assays now available for sCRP can evidentiate inflammation well below 5–10 mg/L, a range previously considered normal (5). Apart from short-term, major sCRP increases due to acute systemic inflammatory disorders, long-term circulating sCRP concentrations show a similar year-to-year consistency (6), and even slight increases in the upper normal range appear to have predictive value for vascular disease (7,8).

Both in middle-aged (9) and elderly (10,11) nondemented individuals, increased baseline sCRP levels are consistently associated with increased risk of cognitive impairment at follow-up. Available studies, however, disagree as to whether, in cognitively normal elderly individuals, increased sCRP are (10) or are not (11) associated with poorer cognitive performance at baseline. Clarification of this issue may be of importance in view of the possible use of sCRP as an early predictor of cognitive impairment. Indeed, it is known that persons in the preclinical stage of dementia, even if still scoring in the normal range at cognitive testing, perform worse than do age- and education-matched dementia-free counterparts (12). Because increased sCRP is also associated with increased risk of mortality and disability (13), a lack of relationship between sCRP levels and baseline cognitive function would suggest that increased sCRP may help in identifying individuals at higher risk for negative health outcomes, but have no utility for early and specific identification of subgroups at risk for dementia.

In the current study, baseline data from cognitively normal elderly participants in an Italian study of brain aging (14) were used to estimate the association between sCRP levels and performance on the Mini-Mental State Examination (MMSE), a widely used screening measure of cognitive function (15). We also examined whether sociodemographic status, lifestyle, health status, traditional and nontraditional cardiovascular risk factors, and other peripheral markers of vascular inflammation modified this association.


   METHODS
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 Methods
Results
 Discussion
 References
 
Participants
Data are from the Conselice Study of Brain Aging, an Italian single-center population-based study of cognitive performance in older persons. Details on study design and data collection have been published elsewhere (14).

Briefly, between May 1999 and May 2000, 1016 (75%) of the 1353 individuals aged 65 years and older residing in the Italian municipality of Conselice, province of Ravenna, Emilia-Romagna region, underwent the following procedures: 1) a standardized medical interview, 2) an extensive physical examination, and 3) venous blood drawing. The Italian version of the MMSE (16) was administered to all participants. Because more than 80% of all participants had five or fewer years of schooling, for identification of persons without cognitive impairment, we chose the usual MMSE cutoff score of 24/30, which in the elderly Italian population ensures good sensitivity (100%) and specificity (87%) in dementia detection (16).

The study was approved by the Institutional Review Board of the Department of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna. Written informed consent was obtained from all participants.

Of the 857 community-dwelling participants scoring ≥24 on the MMSE, 264 were excluded because of clinical conditions associated with major elevation of sCRP levels (infections, cancer, inflammatory diseases, thromboembolic events or surgery in the preceding 6 months, endocrine diseases other than diabetes mellitus, current liver or kidney disease, congestive heart failure, or symptomatic osteoarthrosis with functional impairment). Another 44 persons were excluded because of conditions suspect for cognitive impairment [epilepsy, major psychiatric illnesses or use of psychotropic drugs, major sensory–motor impairments affecting neuropsychological testing, low scores on pathological clock drawing test (17), or dependency in the activities of daily living (18)]. Data on sCRP were missing for three individuals, and another six were excluded as outliers [>3 standard deviations (SD) of the distribution of log-transformed sCRP, corresponding to >3 mg/dl]. This left us with 540 participants (276 men and 264 women) aged from 65 to 91 years (mean ± SD, 73.5 ± 6.2 years). The study sample did not differ in age, sex, and education from the population of origin.

Covariates
Sociodemographic variables included: age, sex, years of formal education (categorized as ≤3 vs >3 years of education), and income (categorized as <6200 {euro}/year vs ≥6200 {euro}/year). Lifestyle variables included smoking status (never and ex-smokers vs current smokers), physical activity (classified as sedentary vs active lifestyle, defined as performing at least moderate physical activity for ≥4 hours/week), and consumption of wine and liquors (classified according to the number of drinks per day). Measures of general health status included: edentulism, use of anti-inflammatory drugs or statins, and number of comorbid chronic conditions including diabetes mellitus, ischemic cardiovascular disease (history of coronary heart disease or acute myocardial infarction), peripheral arterial disease, cerebrovascular disease (history of stroke or transient ischemic attack), chronic pulmonary disease, and peptic ulcer. Diagnoses were based on medical history as provided by the patient and confirmed by his or her general practitioner. Whenever available, previous medical records were reviewed. Traditional and nontraditional vascular risk factors included body mass index (BMI, calculated as weight in kilograms divided by the square of the height in meters), hypertension (defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medication), serum total cholesterol, and plasma total homocysteine (tHcy). Peripheral blood markers of vascular inflammation other than sCRP included leukocyte count, serum albumin, and plasma fibrinogen (6,19).

Laboratory
Venous blood samples were taken between 7:30 AM and 9:00 AM, after an overnight fast and within a week from the medical interview. Samples were put on ice and processed within 1 hour. To measure sCRP, we used the N-high sensitivity CRP assay with latex-enhanced immunonephelometric assay on a BN II analyzer (Dade Behring, Milan, Italy). The assay has a detection limit of 0.175 mg/dl and intra- and interassay coefficients of variation <3%. According to this assay, 97% of healthy adult individuals have sCRP levels <0.5 mg/dl.

Leukocyte count was performed on the automated WBC-Differential System SE 9500 (Sysmex Europe GMBH, Hamburg, Germany). Serum total cholesterol and albumin were measured by enzymatic assay (Roche Diagnostics, Monza, Italy) on a HITACHI 917 System autoanalyzer (Boehringer Mannheim, Mannheim, Germany). Plasma fibrinogen was measured by the Clauss method on a STA-SYSTEM analyzer (American Bioproducts Company, Parsippany, NJ). Blood samples for plasma tHcy determination were collected in EDTA tubes and placed in a refrigerator (4°C) for 15–30 minutes. Plasma was separated within 1–3 hours, and samples were stored at –20°C. Plasma tHcy was measured by the fully automatized IMx assay (Abbott Laboratories, Abbott Park, IL) as previously described (20).

Statistical Methods
Variables are presented as mean ± SD or number and percentage except for sCRP and plasma tHcy. Because of their highly skewed distribution, these variables were analyzed both as normalized, log-transformed continuous variables [data reported as geometric mean and 95% confidence interval (CI)] and categorical variables. Because no standard cutoff exists for sCRP, on the basis of previous reports of inflammatory markers (21) and preliminary analyses, sCRP was dichotomized as being either >0.7 mg/dl or ≤0.7 mg/dl, corresponding to the highest decile. Hyperhomocysteinemia was defined according to the standard plasma tHcy threshold of 15 µmol/L (22).

Participants were categorized into three groups according to MMSE score (24–25, 26–28, and >28), and group differences were evaluated using analysis of variance (Tukey's test for all pairwise multiple comparisons) or chi-square. The association between sCRP and the other inflammatory markers was tested by the Pearson coefficient.

Crude and multivariable-adjusted odds ratios (ORs) for the highest decile of sCRP by MMSE group were determined by logistic regression, taking individuals with MMSE score above 28 as the reference category. The final multivariable-adjusted model included as covariates only the variables significantly contributing to the model (p <.05 for the likelihood ratio test comparing the models with and without the variable) (23).

In agreement with previous reports (10,11,19,24), the final logistic model included adjustment for age, education, sex, plasma fibrinogen, leukocyte count, serum albumin, BMI, number of comorbid diseases, and edentulism.

Statistical analyses were performed with SYSTAT10 (SPSS Inc., Chicago, IL). All tests were two-tailed, and a p value less than.050 was considered significant.


   RESULTS
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 Abstract
 Methods
 Results
Discussion
 References
 
The population characteristics by MMSE score group are shown in Table 1. MMSE scores ranged from 24 to 30 (median 29) and, as expected, individuals with lower MMSE scores were older, less educated, had a lower socioeconomic status and a poorer health status than individuals with higher MMSE scores. Levels of sCRP ranged from 0.18 to 2.2 mg/dl with an overall median of 0.30 mg/dl, which is close to the detection limit of the assay. Mean sCRP did not significantly differ by MMSE group, but the number of individuals in the highest decile of sCRP distribution was significantly higher for both MMSE score 24–25 (OR = 3.07, 95% CI, 1.2–7.9) and 26–28 (OR = 2.10, 95% CI, 1.1–3.9) compared with the reference group (MMSE score >28). As previously reported from a larger sample of the same population (20), plasma tHcy and prevalence of hyperhomocysteinemia had an inverse association with MMSE score. None of the other study variables differed among MMSE groups, except for use of statins, which was highest among participants with an MMSE score above 28. The Pearson correlations between sCRP and the other inflammatory markers were r = 0.153 (p <.001) for leukocyte count, r = –169 (p <.001) for serum albumin, and r = 0.442 (p <.001) for fibrinogen. No significant association was found for plasma tHcy (r = 0.051, p =.233).


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  		Table 1. Population Characteristics According to Mini-Mental State Examination (MMSE) Score.

 
As shown in Figure 1A, after multivariable adjustment the inverse association between the highest decile of sCRP and MMSE score maintained statistical significance. Multivariable adjustment for sCRP and all its significant covariates did not affect the inverse association between risk of hyperhomocysteinemia and MMSE score (Figure 1B). Risk estimates for both sCRP and hyperhomocysteinemia by MMSE score were unaffected by additional adjustment for other known major determinants of plasma homocysteine in older age such as serum creatinine, serum folate, and vitamin B12 (25) (data not shown).



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  		Figure 1. Multivariable-adjusted odds ratios (ORs) for the highest decile (>0.7 mg/dl) of serum C-reactive protein (A) and for hyperhomocysteinemia (plasma total homocysteine > 15 µmol/L) (B) according to Mini-Mental State Examination score

 
Unfortunately, the number of participants with high levels of both sCRP and plasma tHcy was too small (17, 3% of the overall sample) for a reliable estimate of their risk of having lower MMSE scores with respect to participants with only one or none of the markers.


   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In this study of cognitively normal elderly community dwellers, increased sCRP levels were inversely associated with MMSE score. The association remained significant after adjustment for demographics, lifestyle, health status, traditional and nontraditional vascular risk factors, and other peripheral blood markers of vascular inflammation.

There are several possible reasons why no significant association was found for sCRP considered as a continuous variable, as compared with the significant findings for sCRP dichotomized at the highest decile. The distribution of sCRP was very highly skewed, with half of the values falling near the detection limit of the assay, and it is possible that our sample size was not sufficient to detect any significant difference across MMSE score groups. Alternatively, it is possible that only higher sCRP levels are, in fact, related to poor cognitive performance.

Elevation of sCRP reflects with high sensitivity the increase of the proinflammatory cytokine interleukin-6 (3), which is overexpressed in AD (1,2) and, according to findings in nondemented elderly individuals, is associated with increased risk of developing cognitive impairment (but not with baseline cognitive performance) (11,26).

Peripheral blood inflammatory markers may reflect cerebral inflammatory mechanisms related to dementia, because proinflammatory cytokines cross the blood–brain barrier and function as mediators between central and peripheral neuroendocrine and immune systems (1,2). Moreover, the association between cognitive impairment and low-grade chronic inflammation as measured by sCRP may be mediated through vascular damage (3,4).

Available data about sCRP and cognitive function in nondemented elderly individuals are scant and contrasting. In the small population of the Maastricht Aging Study (10), sCRP was associated with measures of memory both at baseline and at a 6-year follow-up. By contrast, in the larger, multiethnic population of the Health Aging, and Body Composition Study (Health ABC Study) (11), sCRP was associated with cognitive decline at a 2-year follow-up, but no differences across tertiles of sCRP were found for baseline scores of global cognitive function as measured with the Modified MMSE [an extended version of the MMSE broadening the range of scores to 0–100 (27)].

Differences in selection criteria and confounders taken into account may in part explain the different results. In the present study, a major effort was made to avoid inclusion of participants with major inflammatory conditions. Moreover, a large number of known and supposed determinants of sCRP was taken into account, including edentulism, a condition often underrated but that may lead to significant sCRP elevations in apparently healthy older individuals (24).

Apart from the hypothesis that sCRP is a marker of underlying brain inflammation, other explanations can by hypothesized for our findings. First, sCRP elevation may be an aspecific response to environmental stimuli causing brain damage. If so, however, the association of sCRP with MMSE would have been be attenuated by controlling for sociodemographic and lifestyle variables. Another possibility is that sCRP is an aspecific indicator of vascular damage (28). Results, however, were unaffected by controlling for prevalent vascular disease, traditional and nontraditional risk factors, and other peripheral blood markers of vascular inflammation. Results were also unaffected by the inverse, independent association between MMSE score and plasma tHcy previously reported in this population (20). Several lines of evidence support the view that, because of its proinflammatory (29), prothrombotic (23), and neurotoxic effects (30,31), homocysteine may be an important risk factor for both AD and vascular dementia (32).

Several limitation of this study must also be acknowledged. First, only a few participants were included in the MMSE 24–25 group, and even fewer in this group had elevated sCRP, so wide confidence intervals were found when estimating ORs. Second, the cross-sectional design of the study does not allow causal inferences. Third, measurement of interleukin-6 and other proinflammatory chemokines is at present not available for this population. Fourth, we did not measure serum markers of Chlamydia pneumoniae and Helicobacter pylori infection, which according to some authors (33), but not all (34), may be associated with variations in sCRP within the normal range. Finally, the generalizability of our findings to other populations remains to be seen.

Conclusion
Our findings support the hypothesis that sCRP levels are inversely related to MMSE score in cognitively normal elderly community dwellers. However, further data are needed to confirm the hypothesis that sCRP may be of use for early identification of individuals at risk of dementia.


   Acknowledgments
 
This study was supported by grants from the Ministero dell'Università e della Ricerca Scientifica (ex-60% fund) and from Ricerca Corrente, Istituti Ortopedici Rizzoli.

Research was facilitated by collaboration with Conselice municipal administration and the Local Health Unit of Ravenna, Emilia-Romagna region.

We also want to acknowledge with sincere gratitude the population of Conselice for their enthusiasm and participation in the study.


   Footnotes
 
Decision Editor: John E. Morley, MB, BCh

Received May 4, 2004

Accepted May 7, 2004


   References
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