C International Psychogeriatric Association 2014 International Psychogeriatrics: page 1 of 8 doi:10.1017/S1041610214002622
BDNF serum levels are not related to cognitive functioning in older depressed patients and controls ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Annemiek Dols,1 Carisha S. Thesing,1 Filip Bouckaert,2 Richard C. Oude Voshaar,3 Hannie C. Comijs1 and M. L. Stek1 1
Department of Psychiatry, VU Medical Center / GGZ inGeest, Amsterdam, the Netherlands Department of Old Age Psychiatry, UPC KU Leuven, Kortenberg campus, Belgium 3 University Center of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2
ABSTRACT
Background: Depression and cognitive decline are highly prevalent in older persons and both are associated with low serum brain derived neurotrophic factor (BDNF). Mutual pathways of depression and cognitive decline in older persons may explain the overlap in symptoms and low serum BDNF. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance (global or specifically in working memory, speed of information processing, and episodic memory) compared to depressed elderly without cognitive impairment or non-depressed controls. Methods: BDNF Serum levels and cognitive functioning were examined in 378 depressed persons and 132 non-depressed controls from a large prospective study on late-life depression. The association between BDNF levels and each cognitive domain among the depressed patients was tested by four separate linear regression models adjusted for relevant covariates. An analysis of covariance (ANCOVA) was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls), when adjusted for potential confounders. Results: No significant linear association was found between BDNF and any of the four cognitive domains tested. There are no differences in BDNF levels between controls and depressed patients with or without cognitive impairment global or in specific domains after controlling for confounders. Conclusions: BDNF serum levels in this cohort of older depressed patients and controls are not related to cognitive functioning. As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable. Key words: BDNF, aged, cognition, depressed
Introduction Low serum BDNF levels are linked to depression and Alzheimer’s dementia in old age (Laske et al., 2006; Sen et al., 2008). The interpretation of serum BDNF levels in depression is complex, with serum BDNF levels being influenced by smoking status, food and alcohol intake, time of blood withdrawal, storage, age, gender, and urbanicity (Bus et al., 2011). The claim that low BDNF levels are a peripheral manifestation of depression was recently shown to be less robust than was previously assumed, possibly due to a large degree of Correspondence should be addressed to: A. Dols, De Nieuwe Valeriuskliniek GGZ inGeest, Amstelveenseweg 589, 1070 BB Amsterdam, the Netherlands. Phone: +31-20-7885-565; Fax: +31-20-7885-577. Email: [email protected]. Received 10 Jun 2014; revision requested 29 Jul 2014; revised version received 3 Nov 2014; accepted 13 Nov 2014.
heterogeneity in outcome variables, underpowered study designs, and publication bias (Molendijk et al., 2014). It is now suggested that BDNF is possibly more related to stress, lack of exercise, medication or cognitive functioning accompanying depression (Molendijk et al., 2010; Bus et al., 2011; Molendijk et al., 2014). In previous studies, low BDNF was linked to cognitive decline in healthy elderly (Erickson et al., 2010), patients with mild cognitive impairment (MCI) (Peng et al., 2005; Shimada et al., 2014) and Alzheimer’s patients (Laske et al., 2010), and was associated with brain atrophy (Laske et al., 2006; Driscoll et al., 2012). A large communitybased cohort study recently showed that dementiafree individuals with higher serum BDNF levels were less likely to develop dementia and Alzheimer’s disease after follow-up for up to ten years (Weinstein
2
A. Dols et al.
et al., 2014). However, the longitudinal association between BDNF and cognitive functions is not supported by all studies among cognitively normal older adults (Driscoll et al., 2012; Nettiksimmons et al., 2014). Few studies have focused on the relationship between serum BDNF and cognitive functioning in depressed patients, and most of those that have were done in younger adults (Oral et al., 2012) or bipolar patients (Kapczinski et al., 2010). These studies showed no significant correlation between serum BDNF and overall cognitive functioning in younger adult depressed patients. Diniz et al. reported results in older patients who, following remission of depression, were randomized to donepezil or placebo treatment, in order to evaluate the effectiveness of the former in preventing depressive episode recurrence during a two-year follow-up period (Diniz et al., 2013). The results showed the same BDNF levels in older remitted depressed patients without cognitive decline or MCI and never depressed, cognitively normal controls (Diniz et al., 2013). To our knowledge, no studies have examined BDNF serum levels in older depressed patients with cognitive impairment, without diagnosed dementia. Cognitive impairment in depressed elderly is common (Korten et al., 2014) and after remission cognitive functions do not always improve to levels seen in non-depressed participants (Butters et al., 2000; Bhalla et al., 2006). Because the underlying mechanisms of cognitive impairment in late-life depression are still not well understood, it is important to explore possible mutual pathways of depression and cognitive impairment in older persons. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance with respect to working memory, speed of information processing, and episodic memory, compared to depressed elderly without cognitive impairment and non-depressed controls.
Methods Study sample The sample comprised 378 depressed persons and 132 non-depressed controls who were participating in a large prospective study on late-life depression, namely the Netherlands Study on Depression in Older Persons (NESDO; http://nesdo.amstad. nl) (Comijs et al., 2011). The participants were recruited from mental healthcare institutes (86.2% of the depressed persons) and general practices. The non-depressed persons were recruited from general practices and were included when no lifetime diagnosis of depression was present. Exclusion
criteria for both groups were a clinical diagnosis of dementia, psychotic disorder, obsessive compulsive disorder or bipolar disorder (all based on the clinical judgment of the general practitioner or an old-age psychiatrist), a Mini-Mental State Examination score (MMSE) below 18 (out of 30 points) and insufficient command of the Dutch language. The baseline assessment included written questionnaires, interviews, a medical examination, cognitive tests, and collection of blood. The ethical review boards of the participating institutes approved the study. All participants gave informed consent after being given oral and written information about the study.
Measurements Psychiatric diagnoses Depressive disorder, dysthymia and comorbid anxiety disorders according to the DSM-IVR criteria (APA, 2000) were assessed with the Composite International Diagnostic Interview (CIDI; WHO version 2.1; life-time version (Wittchen et al., 1991)). Severity of depression was measured with the Inventory of Depressive Symptoms (IDS) (Rush et al., 1996), a self-report questionnaire. Psychotropic medication used daily in the previous week was determined by inspection of the medication containers. Cognitive functioning Global cognitive functioning was assessed with the MMSE (Folstein et al., 1975). Episodic memory was assessed with the 10-Word Test, a modified version of the auditory verbal learning test (Rey, 1964). Immediate (range 0– 50) and delayed recall scores (range 0–10) were included in the analyses. Processing speed was assessed with cards I and II of the abbreviated (four-line) version of the Stroop color-word test (Stroop, 1935; Klein et al., 1997). The time a person needed to read the words or name the colors was included as a measure of processing speed. Interference control was assessed with the interference score of the abbreviated version of the Stroop color-word test. This score was calculated by the following formula: (tIII −0.5 ∗ (tI + tII)) / (0.5 ∗ (tI + tII)) (t = time in seconds) (Klein et al., 1997). Working memory was assessed with the subtest digit span from the Wechsler Adult Intelligence Scale (Wechsler, 1958). The total number of correct digits both forwards (range 0–12) and backwards
Cognition and BDNF in late-life depression
(range 0–10) was used; a higher score indicates better performance. Brain derived neurotrophic factor Fifty millilitres of blood were withdrawn by the interviewer into vacuum tubes between 07.30 and 09.30 after an overnight fast. Following blood collection, serum was separated within one hour and stored at –80 °C until it was assayed. BDNF protein levels were measured using the Emax ImmunoAssay system from Promega according to the manufacturer’s protocol (Madison, WI, USA), in one laboratory (Maastricht University) by one technician who was blind to diagnoses. The intraand inter-assay coefficients of variation were found to be within 3% and 9%, respectively. In the present sample, serum BDNF levels were normally distributed (skewness = 0.71; kurtosis = 0.61). Statistical analysis Differences in demographics and clinical characteristics between depressed and non-depressed older adults were compared by using χ2 analysis for dichotomous variables, Student’s t-tests for normally distributed variables and Mann–Whitney U tests for non-normally distributed variables. The scores on the Stroop task were transformed (1/(Stroop card I), 1/(Stroop card II), LN(Stroop interference score)) to obtain a near-normal distribution. To observe whether the separate cognitive tasks covered the separate cognitive domains, an exploratory factor analysis was performed on the seven cognitive measures (immediate recall, delayed recall, Stroop I, Stroop II, interference Stroop, digit span forwards, and digit span backwards) (Korten et al., 2014). We used oblique rotation (promax) because the final factors were expected to be intercorrelated. Factors were extracted on the basis of high primary loadings on one factor, lower loadings on the other factors, differences between factor loadings at least 0.20, eigenvalues (>0.7) (Jolliffe, 1972), observation of the scree plot and interpretability of the factors. Z-scores from the separate cognitive tasks (except for the MMSE) were calculated, and the mean z-scores of the cognitive tasks representing one cognitive domain were computed (Korten et al., 2014). Participants were excluded when one of the tasks representing one domain was missing. Cognitive impairment was defined as a z-score more than 1.5 SD below the mean. The z-scores showed normal distribution. First, we examined the association between BDNF levels (ng/ml) and total cognition and each cognitive domain (memory, speed, working memory, and interference) among all patients by
3
five separate linear regression analyses adjusted for relevant confounders. We also investigated whether the interaction between BDNF level (ng/ml) and depression status (yes/no) influences this association. Subsequently, ANCOVA was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls). Next, correlations between the potential confounders and the outcome and independent variables were computed. When the potential confounders correlated with both the outcome and the independent variables and when they changed the strength association between BDNF and cognition by more than 10% in one of the models, we considered them confounders in all analyses. All analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 20.0 (Inc. Chicago). Potential confounders Potential confounders were socio-demographics, sampling variables, season of blood withdrawal according to the equinox (dummies for autumn, winter and spring, with summer as the reference category), lifestyle variables, depression characteristics (symptoms, age at onset, any type of antidepressant) and physical diseases. Sociodemographic characteristics included age, gender, and educational level (years of education). Fasting blood withdrawal (yes/no) and duration of serum storage (over three years or not) were the sampling variables. As lifestyle characteristics, we included smoking, use of alcohol, body mass index (BMI), and physical activity. Smoking was defined as currently smoking (yes/no). The use of alcohol was assessed with the Alcohol Use Disorder Identification Test (AUDIT; Saunders et al., 1993). Physical activity in the past week was assessed with the short form (eight items) of the International Physical Activities Questionnaire (IPAQ; Craig et al., 2003). Psychometric properties of the short version of the IPAQ are acceptable. The number of chronic diseases was assessed with previously used self-report questions about the presence of the following chronic diseases or disease events: cardiac disease (including myocardial infarction), peripheral atherosclerosis, stroke, diabetes mellitus, COPD (asthma, chronic bronchitis or pulmonary emphysema), arthritis (rheumatoid arthritis or osteoarthritis), and cancer. The accuracy of self-reports of these diseases was shown to be adequate and independent of cognitive impairment compared to data obtained from general practitioners (Kriegsman et al., 1996).
4
A. Dols et al.
Variables were included as confounders when they were correlated with both the dependent and the independent variables and when they changed the strength association between BDNF and cognition by more than 10%.
separate cognitive domains, memory, processing speed, working memory, and interference. The results showed no differences in BDNF levels between controls and depressed patients with or without cognitive impairment in the specific domains.
Results Sample characteristics Of the 510 participants, 32 were excluded from the analysis because their BDNF levels were missing, and 3 non-depressed controls were excluded because they were using an antidepressant, which would have confounded the control group. BDNF levels were therefore available from 475 participants (93.1%), i.e. 117 non-depressed controls and 358 depressed patients. The excluded participants (n = 35) did not differ from included participants with respect to age (70.6 (7.8) vs. 70.6 (7.3); t = 0.016, df = 508, p = 0.99), gender (25 (73.5%) vs. 30.6 (64.3%) females; χ2 = 0.82, df = 1, p = 0.37), educational level (11.4 (3.6) vs. 10.9 (3.6) years; t = 0.79, df = 508, p = 0.43) and severity of depressive symptoms based on the IDS sum score (24.1 (13.9) vs. 24.4 (15.3); t = − 0.11, df = 500, p = 0.91). Table 1 presents the demographic and clinical characteristics of the study population by depression status (n = 475). Cognitive functioning and BDNF serum levels We first tested the linear association between BDNF level (ng/ml, independent variable) and cognition (total cognition and the four cognitive domains as the dependent variables) in five different multivariate linear regression models (Table 2). After establishing whether various variables were confounders, we included them in the models (age, education, depression diagnosis (yes/no), use of SSRI (yes/no), and season of blood withdrawal, with summer as the reference category). No significant associations were found between BDNF level (ng/ml) and total cognition or any of the four cognitive domains tested for both the depressed patients and the controls. We subsequently tested the interaction terms between BDNF levels (ng/ml) and depression diagnosis (yes/no) in the fully adjusted models. None of them was significant, suggesting that the outcomes were the same in the depressed and the non-depressed group. Next, the ANCOVAs adjusted for relevant covariates showed no differences in BDNF levels between controls and depressed patients with or without cognitive impairment (based on total z-score) (Table 3). The same ANCOVAs were conducted with cognitive functioning based on the
Discussion Contrary to findings in healthy elderly and Alzheimer’s patients, we did not find BDNF serum levels to be different in depressed older patients with or without cognitive impairment. However, the relationship between BDNF and cognitive functions is not supported by all studies among older adults (Ziegenhorn et al., 2007; Driscoll et al., 2012; Nettiksimmons et al., 2014). Given that BDNF serum levels in the elderly have not been extensively studied, discrepancies between studies may reflect methodological differences with respect to, for instance, sampling variables. Taken together with our previous finding that BDNF serum levels are not associated with depression or depressive symptom severity in this cohort of older depressed patients (van der Meij et al., 2014), alternative explanations are warranted. BDNF serum levels in depressed patients generally range from 9.5 to 27.7 μg/ml (Sen et al., 2008), whereas we report a mean BDNF serum level of 7.74 ng/ml in depressed older patients, indicating that BDNF serum levels may be substantially lower in the elderly. Previous studies among older persons have shown BDNF levels ranging from 0.016 to 23.02 ng/ml (Ziegenhorn et al., 2007; Bus et al., 2011; Diniz et al., 2013). Diniz et al. reported a decline in BDNF levels in a sample consisting of older remitted depressed patients with or without cognitive impairment and controls after two years of follow-up, suggesting that aging is an important factor in the decline of BDNF levels (Diniz et al., 2013). As BDNF serum levels decline with age, the impact of BDNF on depression and cognitive symptoms may be limited and a considerable decrease may only be observable in older patients with an advanced stage of cognitive decline or severe depression, for example in dementia patients (Laske et al., 2006) and in bipolar depression (Kapczinski et al., 2010). As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable. Lower BDNF serum levels have been associated with age-related white matter atrophy (Driscoll et al., 2012) and agerelated decline in hippocampal volume (Erickson et al., 2010), but not with cognitive functioning in
Cognition and BDNF in late-life depression
5
Table 1. Characteristics of study sample CONTROLS
DEPRESSED PARTICIPANTS
(N = 117)
(N = 358)
STATISTICS T
or χ2 or U
DF
P VALUE
............................................................................................................................................................................................................................................................................................................................
Socio-demographics Age (years) Mean (SD) Female sex n (%)
69.91 (7.02) 68 (58.1)
70.74 (7.39) 237 (66.2)
t = −1.07 χ2 = 2.17
473 1
0.287 0.141
Educational levels Mean (years) (SD)
12.56 (3.46)
10.37 (3.44)
t = 5.98
473
BDNF serum levels are not related to cognitive functioning in older depressed patients and controls ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Annemiek Dols,1 Carisha S. Thesing,1 Filip Bouckaert,2 Richard C. Oude Voshaar,3 Hannie C. Comijs1 and M. L. Stek1 1
Department of Psychiatry, VU Medical Center / GGZ inGeest, Amsterdam, the Netherlands Department of Old Age Psychiatry, UPC KU Leuven, Kortenberg campus, Belgium 3 University Center of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2
ABSTRACT
Background: Depression and cognitive decline are highly prevalent in older persons and both are associated with low serum brain derived neurotrophic factor (BDNF). Mutual pathways of depression and cognitive decline in older persons may explain the overlap in symptoms and low serum BDNF. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance (global or specifically in working memory, speed of information processing, and episodic memory) compared to depressed elderly without cognitive impairment or non-depressed controls. Methods: BDNF Serum levels and cognitive functioning were examined in 378 depressed persons and 132 non-depressed controls from a large prospective study on late-life depression. The association between BDNF levels and each cognitive domain among the depressed patients was tested by four separate linear regression models adjusted for relevant covariates. An analysis of covariance (ANCOVA) was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls), when adjusted for potential confounders. Results: No significant linear association was found between BDNF and any of the four cognitive domains tested. There are no differences in BDNF levels between controls and depressed patients with or without cognitive impairment global or in specific domains after controlling for confounders. Conclusions: BDNF serum levels in this cohort of older depressed patients and controls are not related to cognitive functioning. As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable. Key words: BDNF, aged, cognition, depressed
Introduction Low serum BDNF levels are linked to depression and Alzheimer’s dementia in old age (Laske et al., 2006; Sen et al., 2008). The interpretation of serum BDNF levels in depression is complex, with serum BDNF levels being influenced by smoking status, food and alcohol intake, time of blood withdrawal, storage, age, gender, and urbanicity (Bus et al., 2011). The claim that low BDNF levels are a peripheral manifestation of depression was recently shown to be less robust than was previously assumed, possibly due to a large degree of Correspondence should be addressed to: A. Dols, De Nieuwe Valeriuskliniek GGZ inGeest, Amstelveenseweg 589, 1070 BB Amsterdam, the Netherlands. Phone: +31-20-7885-565; Fax: +31-20-7885-577. Email: [email protected]. Received 10 Jun 2014; revision requested 29 Jul 2014; revised version received 3 Nov 2014; accepted 13 Nov 2014.
heterogeneity in outcome variables, underpowered study designs, and publication bias (Molendijk et al., 2014). It is now suggested that BDNF is possibly more related to stress, lack of exercise, medication or cognitive functioning accompanying depression (Molendijk et al., 2010; Bus et al., 2011; Molendijk et al., 2014). In previous studies, low BDNF was linked to cognitive decline in healthy elderly (Erickson et al., 2010), patients with mild cognitive impairment (MCI) (Peng et al., 2005; Shimada et al., 2014) and Alzheimer’s patients (Laske et al., 2010), and was associated with brain atrophy (Laske et al., 2006; Driscoll et al., 2012). A large communitybased cohort study recently showed that dementiafree individuals with higher serum BDNF levels were less likely to develop dementia and Alzheimer’s disease after follow-up for up to ten years (Weinstein
2
A. Dols et al.
et al., 2014). However, the longitudinal association between BDNF and cognitive functions is not supported by all studies among cognitively normal older adults (Driscoll et al., 2012; Nettiksimmons et al., 2014). Few studies have focused on the relationship between serum BDNF and cognitive functioning in depressed patients, and most of those that have were done in younger adults (Oral et al., 2012) or bipolar patients (Kapczinski et al., 2010). These studies showed no significant correlation between serum BDNF and overall cognitive functioning in younger adult depressed patients. Diniz et al. reported results in older patients who, following remission of depression, were randomized to donepezil or placebo treatment, in order to evaluate the effectiveness of the former in preventing depressive episode recurrence during a two-year follow-up period (Diniz et al., 2013). The results showed the same BDNF levels in older remitted depressed patients without cognitive decline or MCI and never depressed, cognitively normal controls (Diniz et al., 2013). To our knowledge, no studies have examined BDNF serum levels in older depressed patients with cognitive impairment, without diagnosed dementia. Cognitive impairment in depressed elderly is common (Korten et al., 2014) and after remission cognitive functions do not always improve to levels seen in non-depressed participants (Butters et al., 2000; Bhalla et al., 2006). Because the underlying mechanisms of cognitive impairment in late-life depression are still not well understood, it is important to explore possible mutual pathways of depression and cognitive impairment in older persons. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance with respect to working memory, speed of information processing, and episodic memory, compared to depressed elderly without cognitive impairment and non-depressed controls.
Methods Study sample The sample comprised 378 depressed persons and 132 non-depressed controls who were participating in a large prospective study on late-life depression, namely the Netherlands Study on Depression in Older Persons (NESDO; http://nesdo.amstad. nl) (Comijs et al., 2011). The participants were recruited from mental healthcare institutes (86.2% of the depressed persons) and general practices. The non-depressed persons were recruited from general practices and were included when no lifetime diagnosis of depression was present. Exclusion
criteria for both groups were a clinical diagnosis of dementia, psychotic disorder, obsessive compulsive disorder or bipolar disorder (all based on the clinical judgment of the general practitioner or an old-age psychiatrist), a Mini-Mental State Examination score (MMSE) below 18 (out of 30 points) and insufficient command of the Dutch language. The baseline assessment included written questionnaires, interviews, a medical examination, cognitive tests, and collection of blood. The ethical review boards of the participating institutes approved the study. All participants gave informed consent after being given oral and written information about the study.
Measurements Psychiatric diagnoses Depressive disorder, dysthymia and comorbid anxiety disorders according to the DSM-IVR criteria (APA, 2000) were assessed with the Composite International Diagnostic Interview (CIDI; WHO version 2.1; life-time version (Wittchen et al., 1991)). Severity of depression was measured with the Inventory of Depressive Symptoms (IDS) (Rush et al., 1996), a self-report questionnaire. Psychotropic medication used daily in the previous week was determined by inspection of the medication containers. Cognitive functioning Global cognitive functioning was assessed with the MMSE (Folstein et al., 1975). Episodic memory was assessed with the 10-Word Test, a modified version of the auditory verbal learning test (Rey, 1964). Immediate (range 0– 50) and delayed recall scores (range 0–10) were included in the analyses. Processing speed was assessed with cards I and II of the abbreviated (four-line) version of the Stroop color-word test (Stroop, 1935; Klein et al., 1997). The time a person needed to read the words or name the colors was included as a measure of processing speed. Interference control was assessed with the interference score of the abbreviated version of the Stroop color-word test. This score was calculated by the following formula: (tIII −0.5 ∗ (tI + tII)) / (0.5 ∗ (tI + tII)) (t = time in seconds) (Klein et al., 1997). Working memory was assessed with the subtest digit span from the Wechsler Adult Intelligence Scale (Wechsler, 1958). The total number of correct digits both forwards (range 0–12) and backwards
Cognition and BDNF in late-life depression
(range 0–10) was used; a higher score indicates better performance. Brain derived neurotrophic factor Fifty millilitres of blood were withdrawn by the interviewer into vacuum tubes between 07.30 and 09.30 after an overnight fast. Following blood collection, serum was separated within one hour and stored at –80 °C until it was assayed. BDNF protein levels were measured using the Emax ImmunoAssay system from Promega according to the manufacturer’s protocol (Madison, WI, USA), in one laboratory (Maastricht University) by one technician who was blind to diagnoses. The intraand inter-assay coefficients of variation were found to be within 3% and 9%, respectively. In the present sample, serum BDNF levels were normally distributed (skewness = 0.71; kurtosis = 0.61). Statistical analysis Differences in demographics and clinical characteristics between depressed and non-depressed older adults were compared by using χ2 analysis for dichotomous variables, Student’s t-tests for normally distributed variables and Mann–Whitney U tests for non-normally distributed variables. The scores on the Stroop task were transformed (1/(Stroop card I), 1/(Stroop card II), LN(Stroop interference score)) to obtain a near-normal distribution. To observe whether the separate cognitive tasks covered the separate cognitive domains, an exploratory factor analysis was performed on the seven cognitive measures (immediate recall, delayed recall, Stroop I, Stroop II, interference Stroop, digit span forwards, and digit span backwards) (Korten et al., 2014). We used oblique rotation (promax) because the final factors were expected to be intercorrelated. Factors were extracted on the basis of high primary loadings on one factor, lower loadings on the other factors, differences between factor loadings at least 0.20, eigenvalues (>0.7) (Jolliffe, 1972), observation of the scree plot and interpretability of the factors. Z-scores from the separate cognitive tasks (except for the MMSE) were calculated, and the mean z-scores of the cognitive tasks representing one cognitive domain were computed (Korten et al., 2014). Participants were excluded when one of the tasks representing one domain was missing. Cognitive impairment was defined as a z-score more than 1.5 SD below the mean. The z-scores showed normal distribution. First, we examined the association between BDNF levels (ng/ml) and total cognition and each cognitive domain (memory, speed, working memory, and interference) among all patients by
3
five separate linear regression analyses adjusted for relevant confounders. We also investigated whether the interaction between BDNF level (ng/ml) and depression status (yes/no) influences this association. Subsequently, ANCOVA was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls). Next, correlations between the potential confounders and the outcome and independent variables were computed. When the potential confounders correlated with both the outcome and the independent variables and when they changed the strength association between BDNF and cognition by more than 10% in one of the models, we considered them confounders in all analyses. All analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 20.0 (Inc. Chicago). Potential confounders Potential confounders were socio-demographics, sampling variables, season of blood withdrawal according to the equinox (dummies for autumn, winter and spring, with summer as the reference category), lifestyle variables, depression characteristics (symptoms, age at onset, any type of antidepressant) and physical diseases. Sociodemographic characteristics included age, gender, and educational level (years of education). Fasting blood withdrawal (yes/no) and duration of serum storage (over three years or not) were the sampling variables. As lifestyle characteristics, we included smoking, use of alcohol, body mass index (BMI), and physical activity. Smoking was defined as currently smoking (yes/no). The use of alcohol was assessed with the Alcohol Use Disorder Identification Test (AUDIT; Saunders et al., 1993). Physical activity in the past week was assessed with the short form (eight items) of the International Physical Activities Questionnaire (IPAQ; Craig et al., 2003). Psychometric properties of the short version of the IPAQ are acceptable. The number of chronic diseases was assessed with previously used self-report questions about the presence of the following chronic diseases or disease events: cardiac disease (including myocardial infarction), peripheral atherosclerosis, stroke, diabetes mellitus, COPD (asthma, chronic bronchitis or pulmonary emphysema), arthritis (rheumatoid arthritis or osteoarthritis), and cancer. The accuracy of self-reports of these diseases was shown to be adequate and independent of cognitive impairment compared to data obtained from general practitioners (Kriegsman et al., 1996).
4
A. Dols et al.
Variables were included as confounders when they were correlated with both the dependent and the independent variables and when they changed the strength association between BDNF and cognition by more than 10%.
separate cognitive domains, memory, processing speed, working memory, and interference. The results showed no differences in BDNF levels between controls and depressed patients with or without cognitive impairment in the specific domains.
Results Sample characteristics Of the 510 participants, 32 were excluded from the analysis because their BDNF levels were missing, and 3 non-depressed controls were excluded because they were using an antidepressant, which would have confounded the control group. BDNF levels were therefore available from 475 participants (93.1%), i.e. 117 non-depressed controls and 358 depressed patients. The excluded participants (n = 35) did not differ from included participants with respect to age (70.6 (7.8) vs. 70.6 (7.3); t = 0.016, df = 508, p = 0.99), gender (25 (73.5%) vs. 30.6 (64.3%) females; χ2 = 0.82, df = 1, p = 0.37), educational level (11.4 (3.6) vs. 10.9 (3.6) years; t = 0.79, df = 508, p = 0.43) and severity of depressive symptoms based on the IDS sum score (24.1 (13.9) vs. 24.4 (15.3); t = − 0.11, df = 500, p = 0.91). Table 1 presents the demographic and clinical characteristics of the study population by depression status (n = 475). Cognitive functioning and BDNF serum levels We first tested the linear association between BDNF level (ng/ml, independent variable) and cognition (total cognition and the four cognitive domains as the dependent variables) in five different multivariate linear regression models (Table 2). After establishing whether various variables were confounders, we included them in the models (age, education, depression diagnosis (yes/no), use of SSRI (yes/no), and season of blood withdrawal, with summer as the reference category). No significant associations were found between BDNF level (ng/ml) and total cognition or any of the four cognitive domains tested for both the depressed patients and the controls. We subsequently tested the interaction terms between BDNF levels (ng/ml) and depression diagnosis (yes/no) in the fully adjusted models. None of them was significant, suggesting that the outcomes were the same in the depressed and the non-depressed group. Next, the ANCOVAs adjusted for relevant covariates showed no differences in BDNF levels between controls and depressed patients with or without cognitive impairment (based on total z-score) (Table 3). The same ANCOVAs were conducted with cognitive functioning based on the
Discussion Contrary to findings in healthy elderly and Alzheimer’s patients, we did not find BDNF serum levels to be different in depressed older patients with or without cognitive impairment. However, the relationship between BDNF and cognitive functions is not supported by all studies among older adults (Ziegenhorn et al., 2007; Driscoll et al., 2012; Nettiksimmons et al., 2014). Given that BDNF serum levels in the elderly have not been extensively studied, discrepancies between studies may reflect methodological differences with respect to, for instance, sampling variables. Taken together with our previous finding that BDNF serum levels are not associated with depression or depressive symptom severity in this cohort of older depressed patients (van der Meij et al., 2014), alternative explanations are warranted. BDNF serum levels in depressed patients generally range from 9.5 to 27.7 μg/ml (Sen et al., 2008), whereas we report a mean BDNF serum level of 7.74 ng/ml in depressed older patients, indicating that BDNF serum levels may be substantially lower in the elderly. Previous studies among older persons have shown BDNF levels ranging from 0.016 to 23.02 ng/ml (Ziegenhorn et al., 2007; Bus et al., 2011; Diniz et al., 2013). Diniz et al. reported a decline in BDNF levels in a sample consisting of older remitted depressed patients with or without cognitive impairment and controls after two years of follow-up, suggesting that aging is an important factor in the decline of BDNF levels (Diniz et al., 2013). As BDNF serum levels decline with age, the impact of BDNF on depression and cognitive symptoms may be limited and a considerable decrease may only be observable in older patients with an advanced stage of cognitive decline or severe depression, for example in dementia patients (Laske et al., 2006) and in bipolar depression (Kapczinski et al., 2010). As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable. Lower BDNF serum levels have been associated with age-related white matter atrophy (Driscoll et al., 2012) and agerelated decline in hippocampal volume (Erickson et al., 2010), but not with cognitive functioning in
Cognition and BDNF in late-life depression
5
Table 1. Characteristics of study sample CONTROLS
DEPRESSED PARTICIPANTS
(N = 117)
(N = 358)
STATISTICS T
or χ2 or U
DF
P VALUE
............................................................................................................................................................................................................................................................................................................................
Socio-demographics Age (years) Mean (SD) Female sex n (%)
69.91 (7.02) 68 (58.1)
70.74 (7.39) 237 (66.2)
t = −1.07 χ2 = 2.17
473 1
0.287 0.141
Educational levels Mean (years) (SD)
12.56 (3.46)
10.37 (3.44)
t = 5.98
473
