Serum brain-derived neurotrophic factor, nerve growth factor and ...

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The aim of this study is to measure serum levels of neurotropic factor (NF) in patients with dementia. Brain-derived neurotrophic factor (BDNF), nerve growth ...
Acta Neurol Belg (2012) 112:255–260 DOI 10.1007/s13760-012-0101-6

ORIGINAL ARTICLE

Serum brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 levels in dementia Dildar Konukoglu • Gu¨lnur Andican • Sinem Fırtına • Go¨khan Erkol • Asuman Kurt

Received: 8 October 2011 / Accepted: 6 June 2012 / Published online: 28 June 2012 Ó Belgian Neurological Society 2012

Abstract The aim of this study is to measure serum levels of neurotropic factor (NF) in patients with dementia. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) were determined in Alzheimer’s dementia patients without medication (AD; n: 22), Alzheimer’s dementia patients receiving cholinesterase inhibitor (CEI) treatment (AD ? CEI; n: 32) and vascular dementia patients receiving CEI treatment (VaD ? CEI; n: 27) and the age-matched control group (n: 20). NGF levels were detected to be significantly higher in the control group than in AD group (P \ 0.001). BDNF and NT-3 levels in AD group were not significantly different from control group’s levels. NGF levels in AD ? CEI group were significantly higher than in AD group (P \ 0.05). There was also no significant difference in serum neurotrophic factor levels between AD ? CEI and VaD ? CEI group. A positive correlation between BDNF and Mini Mental State Examination (MMSE) scores (r: 0.422, P \ 0.01) in AD group and a negative correlation between BDNF and MMSE scores in the AD ? CEI group (r: -0.357, P \ 0.005) were obtained. In conclusion, our results suggest that while serum NGF levels are associated with the presence of dementia, serum BDNF levels may be associated with the severity of Alzheimer’s dementia.

D. Konukoglu (&) Atako¨y Konakları, D2-1, Daire 10, Bakırko¨y, Istanbul, Turkey e-mail: [email protected] D. Konukoglu  G. Andican  S. Fırtına  A. Kurt Department of Biochemistry, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey G. Erkol Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

However, future studies are required to determine the importance of NFs. Keywords Alzheimer’s disease  Brain-derived neurotrophic factor  Dementia  Neurotropic factor  Nerve growth factor  Neurotrophin-3

Introduction Dementia is a progressive syndrome of many causes, affecting different areas of central nervous system. It is characterized by impairment in multiple cognitive domains followed by disability to maintain daily activities and behavioral disturbances. Dementia may be classified as primary and secondary. Primary dementias, including Alzheimer’s disease are usually neurodegenerative in nature. A dementia, occurring during the course of a systemic, neurological or psychiatric disease is classified as secondary dementia [1]. The basic mechanism of Alzheimer’s disease is a progressive loss of brain cells; the main cause of which is still unclear. The contributory factors in the development of the disease may be specified as follows: genetic factors, the role of abnormal proteins, autoimmune reactions, toxic reactions, head traumas, viruses, and deficiency of essential elements and impairment of cerebral blood flow. Some of the factors implicated in the pathogenesis of Alzheimer’s disease are based on the association of neuron degeneration with oxidative stress and inflammation [2, 3]. The most common cause of secondary dementias is vascular dementia. The causes of vascular dementia include subsequent occlusion of medium sized or large cerebral arteries, hypertensive cerebral small vessel disease and strategic single infarcts [4, 5].

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Neurotrophins, the most well-known trophic factor of the nervous system, are a family of polypeptide growth factors that control the death and survival, growth and differentiation of neurons. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) also exert their effects not only on cell survival but also on activities such as learning, memory and behavior [6]. In vivo and in vitro studies have demonstrated that neurotrophic factors are involved in a variety of pathways stimulated by excitotoxic damage, ischemia and apoptosis-mediated traumatic brain injury [6, 7]. In the present study, we aimed to investigate serum levels of neurotrophic factor in patients with dementia.

Materials and methods Patients with probable Alzheimer’s dementia receiving cholinesterase inhibitor (CEI) treatment (the AD ? CEI group; 17 males and 15 females, the mean age was 74.2 ± 7.4 years, the duration of the treatment was 4.1 ± 2.5 years); patients with vascular dementia receiving CEI treatment (the VaD ? CEI group; 13 males and 14 females, the mean age was 69.2 ± 10.2 years, the duration of the treatment was 4.7 ± 2.9 years); newly diagnosed patients with probable AD without medication (the AD group; 11 females and 11 males, the mean age was 73.8 ± 7.7 years) were enrolled in this study as dementia groups. Dementia patients under the therapy were received donepezil as CEI treatment. Twenty subjects who admitted to neurology department with complaints of mild forgetfulness comprising 9 females and 11 males (mean ages were 72.1 ± 12.1 years) were chosen as a control group. All control subjects were examined psychiatric, neurological and cognitive functions to exclude any neurological disorder and cognitive impairment. None of them had psychiatric or neurological antecedents and cognitive impairment. The present study was approved by Ethics Committee of Istanbul University, Cerrahpas¸ a School of Medicine. In accordance with the Declaration of Helsinki, all subjects or their caregivers were advised about the procedure and signed the informed consent prior to participation in the study. The major exclusion criteria were the presence of diabetes mellitus, hyperlipidemia, coronary heart disease, psychiatric diseases, autoimmune diseases, cancer, acute infections and history of smoking or alcohol intake. To determine subjects meeting the exclusion criteria, we obtained clinical history and performed electrocardiogram, physical examination and biochemical and hormonal status such as blood cholesterol, fasting glucose, urea, total protein, albumin, creatinine, folic acid and B12 vitamin levels

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and thyroid functions. After physical, neurological and mental states were examined, blood samples were obtained. All subjects were examined for following dementia criteria’s; Alzheimer’s dementia were established according to NINDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorder Association) criteria[8], whereas that of VaD was made according to NINDS-AIREN (Association Internationale pour la Recherche et l’Enseignement en Neurosciences) criteria [9]. Cognitive functions were assessed by MMSE (Mini Mental State Examination) score. Computerized tomography examinations were performed to rule out other structural changes and to help vascular dementia diagnosis. According to the cognitive function, the dementia patient groups were divided into two groups: a group in early stage with dementia (MMSE score C 21; early dementia) and a group later stage with moderate to severe dementia (MMSE score \ 21; late dementia) [10]. Blood samples were drawn between 8.30 and 10.00 a.m. after a 12-h night fast from the forearm into tubes without anticoagulant and into those containing ethylenediaminetetraacetic acids as an anticoagulant. Some of the blood samples were separated for complete blood counts. The samples were centrifuged and the serum was separated. Some of the serum samples were sent to Central Laboratory for routine analysis. The remaining serum was stored at -80 °C until the analysis. The serum levels of BDNF, NT-3 and NGF were measured using an enzyme-linked immunosorbent assay kit (Promega immunoassay System, Madison, USA) according to the manufacturer’s instructions. In addition, carbonate buffer, 1 N hydrochloric acid, 1 N sodium hydroxide, Tris wash buffer and Dulbecco s Phosphate Buffered Saline buffer were prepared to be used. All samples and standards were run in duplicates, and the mean values of the duplicate samples were used for statistical analysis. The detection limits were 20 pg/mL for BDNF, 1.6 pg/mL for NT-3 and 1 pg/mL for NGF. The intra- and inter-assay analyses were performed using multiple measurements of the control sample. The intra-assay coefficients of variation were 6.0 % for BDNF, 5.9 % for NT-3 and 6.5 % for NGT. The inter-assay coefficients of variation were 11.3 % for BDNF, 7.4 % for NT-3 and 8.4 % for NGT. Plasma glucose, total cholesterol, triglyceride, highdensity lipoprotein-cholesterol, low density lipoproteincholesterol (LDL-C), urea, creatinine, total protein, and albumin levels were determined by enzymatic methods using commercial kits. Serum thyroid hormone status, vitamin B12 and folate levels were evaluated using direct chemiluminescent technology (Abbott I 2000 Analyzer, USA).

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All statistical analyses were performed using the statistical analysis software package Statistical Package for the Social Sciences 11.0 for Windows. Data were expressed as mean ± standard deviation (SD) Un-paired Student’s t test and Mann–Whitney test were used for the comparison of groups. Relationships between variables were assessed with Spearman’s correlation coefficient. P \ 0.05 was considered statistically significant.

Results Table 1 presents characteristics of the study groups. Levels of serum glucose, total protein, albumin, urea and creatinine, vitamin status and results of thyroid function tests in the dementia groups were not different when compared to those in the control group. MMSE score of the control group was significantly higher than that of the dementia groups (P \ 0.0001 for each comparisons). Table 2 shows serum levels of BDNF, NGF and NT-3 in the control and dementia groups. Serum NGF levels were detected to be statistically significantly higher in the control group than in all dementia groups (for each comparisons P \ 0.0001). In the AD ? CEI group, serum NGF levels were significantly higher than in AD group (P \ 0.05). Serum BDNF and NT-3 levels in all dementia groups were not different from control group’s levels. There was also no significant difference in serum

neurotrophic factor levels between AD ? CEI and VaD ? CEI group. Patients in dementia groups were subdivided as early and late dementia according to the cognitive state. 12 patients in the AD group, 13 in the AD ? CEI and 12 in the VaD ? CEI groups were defined as having early dementia (MMSE scores were 22.7 ± 2.6, 22.8 ± 1.6 and 23.6 ± 1.2, respectively). The remaining patients were included in the late dementia group (MMSE scores were 14.8 ± 4.8 for AD, 13.1 ± 4.8 for AD ? CEI and 14.5 ± 4.9 for VaD ? CEI group). Serum NGF and NT-3 levels in patients with early and late dementia did not reach statistically significant difference in dementia groups; however, serum NGF levels in all subgroups were statistically significantly lower than in the controls (P \ 0.0001, for each). In AD group, patients with early dementia have significantly higher serum BDNF levels than in patients with late dementia (P \ 0.005). There was a significant difference in serum BDNF levels between early dementia AD group and control group (P \ 0.005). In the AD ? CEI group, serum BDNF levels in patients with late dementia were found to be statistically significantly higher than in patients with early dementia (P \ 0.05). Patients with late dementia in the AD ? CEI group have significantly higher BDNF levels than in the patients with late dementia in the AD group (P \ 0.05). BDNF levels of patients with early dementia in AD ? CEI group were found to be lower than that of patients with early dementia

Table 1 Clinical features, demographics and blood chemistry results of controls, Alzheimer dementia and vascular dementia patients (mean ± SD) Controls (n: 20)

Alzheimer dementia (n: 22)

Alzheimer dementia ? CEI (n: 32)

Vascular dementia ? CEI (n: 27)

Sex (N: female/male)

9/11

11/11

17/15

14/13

Age (years)

72.1 ± 12.1

73.8 ± 7.7

74.2 ± 7.4

69.2 ± 10.2

Mini Mental State Examination score

27.8 ± 2.6

20.7 ± 4.6a

15.9 ± 6.6a

19.6 ± 5.7a

Glucose (mg/dL)

97.2 ± 11.1

104.5 ± 24.6

107.5 ± 20.2

100.7 ± 22.5

Total cholesterol (mg/dL)

219.6 ± 54.7

210.1 ± 23.8

210.5 ± 43.7

198.8 ± 42.3

Triglyceride (mg/dl)

77.5 ± 19.8

120.7 ± 58.3

124.8 ± 58.5

100.7 ± 52.8

Total protein (g/dL)

7.45 ± 0.35

7.53 ± 0.64

7.38 ± 0.62

7.13 ± 0.72

Albumin (g/dL)

3.87 ± 0.20

4.2 ± 0.55

4.15 ± 0.33

7.13 ± 0.72

Urea (mg/dL)

33.8 ± 12.9

39.9 ± 12.7

40.5 ± 19.5

33.5 ± 7.42 1.33 ± 0.38

Creatinine (mg/dL)

0.99 ± 0.17

1.02 ± 0.30

1.46 ± 0.31

Vitamin B12 (pg/mL)

340.4 ± 254.6

333.8 ± 141.4

296.1 ± 159.5

284.2 ± 68.6

Folic acid (ng/mL)

12.1 ± 7.9

9.1 ± 3.56

8.9 ± 4.2

13.6 ± 7.5

Free T4 (ng/dL)

1.34 ± 0.21

1.83 ± 0.23

1.6 ± 1.2

2.12 ± 1.09

TSH (lIU/mL)

1.47 ± 0.60

1.70 ± 0.97

1.60 ± 0.52

1.22 ± 0.81

CEI treatment duration (years)





4.1 ± 2.5

4.7 ± 2.9

CEI cholinesterase inhibitor a

P \ 0.0001

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Table 2 Serum brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) levels in controls and dementia groups according to cognitive status (mean ± SD) Group

BDNF (pg/mL)

NGF (pg/mL)

NT-3 (pg/mL)

Controls (n: 20)

617.6 ± 205.9

779.4 ± 261.7

560.5 ± 332.5

a2

AD (n: 22)

879.7 ± 321.4

230.7 ± 93.5

620.7 ± 413.7

Early dementia (n: 12)

1094.1 ± 261.4a1,c2

231.7 ± 105.9a2

622.3 ± 324.9

Late dementia (n: 10)

662.7 ± 301.1

236.9 ± 97.9a2

670.6 ± 377.2

AD ? CEI (n: 32)

886.1 ± 342.1

387.4 ± 216.7a2,b

754.7 ± 471.3

Early dementia (n: 13)

610.1 ± 295.1d

359.9 ± 200.3a2,c

658.3 ± 353.6

a2,d

c1,e

Late dementia (n: 19) VaD ? CEI (n: 27)

972.8 ± 306.4 914.2 ± 322.1

395.7 ± 247.6 370.7 ± 138.6a2

798.4 ± 527.4 620.7 ± 413.7

Early dementia (n: 12)

985.1 ± 489.1

339.4 ± 144.2a2

855.1 ± 471.3

Late dementia (n: 15)

922.1 ± 305.8

237.6 ± 136.1a2

507.3 ± 389.1

AD Alzheimer dementia, VaD vascular dementia, CEI cholinesterase inhibitor a

Difference from controls 1P \ 0.005, 2P \ 0.0001

b

Difference from AD group, P \ 0.05

c

Difference from late dementia patients in AD group, 1P \ 0.05, 2P \ 0.005

d

Difference from patients with early dementia in AD group, P \ 0.005

e

Difference from patients with early dementia in AD ? CEI group, P \ 0.05, P \ 0.05; statistically significant

in AD group (P \ 0.005). No significant difference was found in serum BDNF levels between patients with early and late dementia in the VaD ? CEI group. Regarding the correlation analysis, there were a positive correlation between serum BDNF levels and MMSE scores in the AD group (r: 0.422, P \ 0.01) and a significant negative correlation between MMSE scores and serum BDNF levels in the AD ? CEI group (r: -0.357, P \ 0.005).

Discussion BDNF is a neurotrophic factor which plays an essential role in maintaining the functions of basal forebrain cholinergic neurons and is implicated in the development of the peripheral and central system and growth and survival of neurons, which hence is suggested to play a role in the pathogenesis of AD [11, 12]. BDNF is suggested to have a potential as a therapeutic agent because of its ability to cross the blood–brain barrier in either direction [13]. Contradictory results about BDNF levels in brain tissue and serum from Alzheimer’s patients were obtained from literatures [14–17]. In our study, although serum BDNF levels of AD patients were not different from those of control group, we found that serum BDNF levels were related with cognitive state in AD patients. Serum BDNF levels were reported by Yasutake et al. [18] to be lower in patients with late stage AD when compared with those in healthy controls. Laske

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et al. [19] suggested that serum BDNF levels were increased in the early stage of Alzheimer’s disease and decreased during the course of the disease based on the severity of dementia. In another study, the same authors also reported no correlation between serum BDNF levels and MMSE scores [20]. It is considerably difficult to explain explicitly the cause of changes in serum BDNF levels. Based on results from other studies [21, 22], we thought that increased BDNF levels in AD patients maybe support the hypothesis of an up-regulation of BDNF in early stages of AD. It has also been suggested that parameters such as age, weight, gender or the menstrual cycle have a specific impact on stored (platelets) and circulating BDNF levels in healthy adults [23, 24]. We did not find any sex and age difference for neurotrophic factor levels. Therefore, increased serum BDNF levels may be sign of the systemic changes in the onset of Alzheimer’s disease. Our results showed that serum BDNF levels in AD patients receiving CEI treatment were also affected by the degree of dementia and a negative correlation was found between serum BDNF levels and MMSE scores. It has been reported that CEIs influence cholinergic anti-inflammatory mechanisms, suppress oxidative stress, regulate energy metabolism and gave evidence for neuroprotection [25]. Leyhe et al. [26] indicated that serum BDNF levels in AD patients (the mean MMSE score; 23.5 ± 1.6) were lower than in the controls before the treatment with donepezil and serum BDNF levels in AD patients were increased to that in the controls after a 15-month treatment.

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Thus, up-regulation of BDNF might be related to neuroprotective effects of CEIs in our AD patients. It has been demonstrated that CEI effects on peripheral cholinergic receptor and BDNF expresses in the peripheral tissues [27]. Additionally, it was also reported that exercise and physical activity may lead to an increase in BDNF levels [28] and decreased serum BDNF levels may increase suicidal tendency in patients with major depression [29]. The dementia patients enrolled in our study had no indication of depression and history of using antidepressant drug [29]. Hence, we consider that high levels of serum BDNF may play a role in preventing depression in late AD patients receiving CEI treatment. Our results also indicated that systemic BDNF response was related with the severity of dementia in only Alzheimer dementia groups. This may be resulting from the different pathogenesis of vascular dementia. NGF is implicated in growth, differentiation and survival of neurons and plays a role in nerve regeneration [13]. NGF is retrograde transported to basal forebrain, leading to an increase in cholinergic transmission [30]. Murase et al. [31] reported that serum NGF levels in brainCSF, hippocampus region and parietal cortex did not differ between AD patients and the controls. Schaub et al. [32] reported no difference in serum NGF levels between the controls and Alzheimer’s patients, whereas Ziegenhorn et al. [17] reported an increase in serum NGF levels of dementia patients. In this study, we found that serum NGF levels were decreased in all dementia groups and AD patients with CEI treatment have higher levels of NGF than AD patients without CEI treatment. Although the cause of this decrease remains unclear, we can conclude that NGF may play a role in the pathogenesis of dementia. We also investigated the serum NT-3 levels in dementia patients. It has been reported that NT-3 levels [33] showing differential distribution in various brain regions were decreased with advancing age [34] and were positively correlated with serum NT-3 levels [35]. It has also been suggested that NT-3 infusion causes an increase in BDNF levels, thus preventing depression [36]. In this study, no difference was found in serum NT-3 levels in dementia patients with or without CEI treatment and no change was induced in serum NT-3 levels by the severity of dementia. Limitations of the current findings suggest several areas in which further investigation is needed. For example, larger studies examining the longitudinal relationship between neurotrophic factor and neuropsychological function are important to determine the nature of their relationship (i.e., mediation, genotypes or exercise). Recent work indicates that genotypes are associated with structural brain differences in both younger and older adults [37]. Our current findings may help to account for the cognitive benefits of exercise, as physical activity appears to increase BDNF levels [38].

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In conclusion, we suggested that serum BDNF levels vary depending on the degree of dementia in Alzheimer disease and the decreased serum NGF levels may be associated with the presence of dementia. On the other hand, the cause of these changes are still unclear and the question ‘‘to what extent changes in serum neurotrophic factor levels influence the pathology of the brain?’’ is yet to be answered. Future studies should be planned to include larger number of patients and psychotic, exercise and depression-related changes in patients. Acknowledgments This work was supported by The Research Fund of Istanbul University (Project Number: 2578, UDP-24348).

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