B-type natriuretic peptide and severity of cognitive disorder

Study population

This study is a part of the larger population-based, multidisciplinary Kuopio 75+ health study focusing on the clinical epidemiology of diseases as well as medications and the functional capacity of elderly persons aged 75 years or older. The target population was a stratified random sample (n = 700) of all the inhabitants of the City of Kuopio in Eastern Finland who were aged 75 years or more on 1 January 1998 (N = 4518).

The cohort included 700 participants. A total of 79 persons refused to take part in the study, five could not be contacted and 15 expired before the examination could take place. The remaining 601 participants formed the final study population. They attended a structured clinical examination and an interview conducted by a geriatrician and trained nurse during the year 1998. As a part of the diagnostic process, brain imaging either by computer tomography (CT) or magnetic resonance imaging (MRI) was carried out for all participants with a suspicion of dementive illness, but no brain imaging in the medical history. Mini-Mental State Examination (MMSE) test was performed guided by an experienced nurse. Cognitive disorder was diagnosed as Alzheimer's disease, vascular dementia, dementia with Lewy bodies or dementia due to other medical conditions according to the DSM-IV criteria and the consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies 19 by an experienced neurogeriatrician (R.S.). Cognitive disorder severity staging was assessed according to the DSM-III R criteria.

A geriatrician and trained nurse interviewed and examined the participants at the outpatient clinic of the municipal hospital concerning their medical history and use of medications and recorded the medications they were currently taking. If a participant was unable to visit the study site, the nurse and geriatrician visited the home to perform the interview and examination. Medical records from the municipal health centre, home nursing service, local hospitals and the Kuopio University Hospital were also available. Baseline clinical and demographic data were also recorded. Depressive symptoms were assessed with the Zung self-rated depression scale (SDS) in Finnish 20. Diabetes was defined as a diagnosis of diabetes in the medical records or a fasting plasma glucose level of 7·0 mM or more. Other cardiovascular conditions were recorded from medical records. Systolic and diastolic blood pressures were measured twice, and the average of the measurements was recorded.

Written informed consent was obtained from the study participants or their relatives as stipulated in the Declaration of Helsinki. The study was approved by the ethics committee of the Hospital District of Northern Savo and the Kuopio University Hospital.

Laboratory analyses

The blood samples for the natriuretic peptide analysis were withdrawn with other blood samples into chilled tubes containing 1·5 mg of K2-EDTA per mL of blood after the patient had stayed in a supine position for 30 min at 8 a.m. The procedure for the BNP analysis has been described previously 18. Other laboratory analyses were carried out at the clinical laboratory of Kuopio University Hospital using standard laboratory techniques.

Statistical analyses

Baseline characteristics are given for the participants divided into four groups by their status and stage of cognitive disorder. Comparisons of baseline characteristics between the groups with no cognitive disorder and those with different stages of cognitive disorder were made with the aid of anova or the Kruskal–Wallis test for continuous variables, based on whether the distribution was Gaussian. BNP levels were highly skewed and therefore logarithmically transformed in the analysis. A further comparison of BNP levels in each cognitive disorder group was corrected by the LSD post hoc method. The chi-squared test was used for categorical data.

The impact of age, sex, creatinine clearance, systolic blood pressure, use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB), use of diuretics and history of heart failure on BNP was calculated using linear regression analysis. All of these factors are known to have an effect on blood levels of BNP 21, 22. The association between the level of cognitive disorder and BNP resembled an inverse U-shaped curve in a box plot (Fig. 1), and therefore, the relationship was evaluated with age-adjusted analysis of covariance (ancova). Using the above-listed parameters with physiological association with BNP as covariates, a further ancova model was constructed to assess how these factors impacted the relationship between BNP and the level of cognitive disorder. A comparison of the levels of BNP at different stages of cognitive disorder in each age tertile was calculated with anova (Fig. 2). P < 0·05 was considered statistically significant. All analyses were performed with SPSS (release 17.0).

Reporting of the study conforms to the STROBE statement 23.

General characteristics

A total number of 601 participants were included in this study. The general characteristics of the participants as divided into four groups by their status of cognitive disorder are presented in Table 1. Systolic and diastolic blood pressure was higher, the renal function was better, and the use of antihypertensive medication was the most common among individuals with no cognitive disorder. Those with cognitive disorder were older and had lower cholesterol and body mass index than their counterparts with no diagnosed cognitive disorder.

In univariable linear regression models, age, creatinine clearance, the use of diuretics, the use of ACE inhibitors/ARBs and a previous history of heart failure had a significant association with the level of BNP, while systolic blood pressure and sex were not significantly connected to BNP (Table 2).

The impact of the level of cognitive disorder on BNP is presented in Fig. 1. The association between the level of cognitive disorder and BNP resembled an inverse U-shaped curve, with participants suffering from mild cognitive disorder having higher levels of BNP in comparison to cognitively intact participants or counterparts with a more severe cognitive disorder (anova P = 0·077). In the post hoc LSD analysis, the levels of BNP were significantly higher in mild cognitive disorder compared with severe cognitive disorder (P = 0·012). In the same analysis, the levels of BNP showed a tendency towards being higher in mild cognitive disorder than in cognitively intact participants (P = 0·050). Other comparisons of the levels of BNP between the groups were not statistically significant.

In the age-adjusted ancova, the association between the level of cognitive disorder and the levels of BNP was significant (P = 0·02). We created a further multivariable ancova model where factors known to have a connection with BNP – age, sex, the use of ACE inhibitors or diuretics as well as creatinine clearance, mean systolic blood pressure and the history of heart failure – were included as covariates. In this model, BNP was no longer associated with the stage of cognitive disorder (P = 0·254).

The study population was divided into age group tertiles for further analysis: 75–78 years (n = 235), 79–82 years (n = 175) and 83 years or older (n = 191). The levels of BNP for each age tertile divided by their status of cognitive disorder are presented in Fig. 2. The levels of BNP resembled a U-shaped curve, being highest in the youngest and middle-age tertiles of the groups with mild cognitive disorder (anova P = 0·494 and P = 0·219, respectively). This U-shape tendency was lost in the oldest age tertile where the highest levels of BNP were detected among the cognitively intact participants (P = 0·047).

Blood pressure and cognitive disorder

In an older population, low diastolic blood pressure is related to an increased risk of developing a cognitive disorder 31, and the presence of cognitive disorder has been associated with low blood pressure 8. In the present study, the individuals included in the groups with any level of cognitive disorder had significantly lower systolic and diastolic blood pressure when compared to their cognitively intact counterparts.

Natriuretic peptides and cognition

Natriuretic peptides are secreted from the heart muscle cells in response to cardiovascular stress, and clinically, they are used in the diagnosis and follow-up of heart failure 21. The association between elevated levels of blood natriuretic peptides and both cognitive dysfunction and cognitive disorder has been demonstrated in several studies 2, 4, 24, 25, 32. In a study performed on the present older general population, BNP was shown to be superior to traditional cardiovascular risk factors in its predictive value for future cognitive disorder 3. In one study, elevated MR-proANP predicted the conversion of mild cognitive impairment (MCI) into AD in patients aged < 72 years, but not among older individuals 1. In our recent study, we demonstrated that the association between BNP and cognitive disorder was age dependent: the relationship was valid only among those under 79 years of age 18.

Older people often have an impaired ability to sense thirst 5, and chronic dehydration is common among the elderly, especially among cognitively impaired individuals 6. In a study with 890 patients suffering from the final phase of dementia, cachexia and dehydration were the immediate cause of death in 35·2% of all deaths occurred 33. Dehydration decreases the filling pressures and stretch of the left ventricle, which in turn attenuates the secretion of natriuretic peptides 21 and could partly explain why the individuals with a progressed cognitive disorder in our material had a decrease in their BNP levels. Also, history of heart failure was more frequent among subjects with mild or moderate cognitive disorder than in those cognitively intact or with severe cognitive disorder. This may also explain lower levels of BNP among those with severe cognitive disorder.

BNP is excreted from the body through the kidneys, and renal dysfunction is known to elevate the levels of natriuretic peptides 21. Dehydration, related to cognitive disorder, may explain, at least partly, the lowered creatinine clearance. In addition, creatinine clearance is known to decrease with ageing even without diagnosed renal disease 34, 35. In the present study, participants with cognitive disorder were older than the cognitively intact subjects, which may, for its part, explain the lowered creatinine clearance in those with a diagnosed cognitive disorder.

Study limitations, strengths and conclusions

As a study limitation, the number of participants in the subgroups was low, which decreased the power to detect significant differences in blood BNP levels between the groups. However, the total number of participants with a diagnosed cognitive disorder was superior to earlier studies on natriuretic peptides and cognitive dysfunction 2, 24, 25, 32, 36. The participants of the study were over 75 years of age, which is the clinically most relevant age group. The extrapolation of the results to other age groups or other ethnic groups besides Caucasians should be carried out with caution. The strengths of our study include the population-based approach and extensive characterization of the study population. The diagnoses and classification of cognitive disorders were carried out by an experienced geriatrician (R.S.), and brain imaging by CT or MRI was used routinely.

In conclusion, the previously reported elevation of natriuretic peptides among individuals with a diagnosed cognitive disorder occurs only in individuals with milder stages of the disorder. Comorbidities and behavioural changes connected to progressed cognitive disorder are the probable causes of the decrease in BNP levels that occurs in a more progressed cognitive disorder.