Abstract
Objective
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is widely expressed in the mammalian brain and acts to regulate neuronal survival and influence cognitive processes. The present study measured serum BDNF levels to investigate the associations of the BDNF Val66Met and 5-hydroxytryptamine transporter linked promoter region (5-HTTLPR) polymorphisms with cognitive function in elderly Korean individuals.
Methods
Over 60 years, a total of 834 subjects were recruited for the present study. The subjects were classified into groups based on the degree of cognitive impairment (age-associated cognitive decline, mild cognitive impairment, and Alzheimer’s disease) and compared with normal controls in terms of a neuropsychological assessment and a clinical evaluation.
Results
Of the initial 834 study participants, 165 (59 controls and 106 subjects with cognitive impairments) completed the study. There was a significant increase in serum BDNF levels in subjects with cognitive impairments relative to the control group and the BDNF Val66Met polymorphism was significantly associated with cognitive function but not serum BDNF levels. The 5-HTTLPR polymorphism did not have any associations with cognitive impairment or serum BDNF levels.
Conclusion
The present findings suggest that BDNF may play a role in the pathophysiology of cognitive impairment and the BDNF Val66Met polymorphism may be an important factor in the susceptibility to these age-related deficits.
Keywords: Brain-derived neurotrophic factor, Dementia, Cognition, Genetic polymorphism
INTRODUCTION
The lifetime risk of Alzheimer’s disease (AD) is 1 in 51) and the number of affected people is rising rapidly as life expectancy increases.2) However, despite intensive study in recent years, there is still an incomplete understanding of the etiology and pathophysiology of this disease.
Brain-derived neurotrophic factor (BDNF) is one of a family of neurotrophins that plays an important role in the development, maintenance, and function of neurons.3) BDNF is critical for neuronal plasticity and facilitates hippocampal and cortical long-term potentiation,4) which are processes that are particularly important for learning and memory. These processes are substantially affected in patients with AD, largely due to impaired neuronal plasticity.5) In AD patients, BDNF expression is prominently reduced in the hippocampus and the entorhinal cortex6) but there is conflicting evidence regarding the association between serum BDNF levels and the expression of AD.7–12)
A number of studies have identified genes that could be potential risk factors for AD but few of these findings have been replicated. Several studies have indicated that a single-nucleotide polymorphism (SNP) in the BDNF gene (dbSNP number rs6265) that results in a valine to methionine substitution at codon 66 (Val66Met) in the pro- BDNF sequence is associated with cognitive dysfunction and AD.13,14) Similarly, a relationship between a functional polymorphism within the promoter region of the 5-HT transporter gene (5-HTTLPR) and the psychiatric symptoms of AD has also been demonstrated.15)
Thus, the present study investigated differences in serum BDNF levels and the distributions of the BDNF and 5-HTTLPR genotypes in subjects with cognitive impairment and a normal control group of elderly Korean people.
METHODS
Subjects
The present study assessed 834 elderly individuals over 60 years of age. All subjects voluntarily participated in this study and written consent for all biological and genetic procedures was obtained. The study protocol was approved by the institutional review board of Busan Paik Hospital in Busan, South Korea. Subjects with psychotic features or depressive episodes based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and subjects with a history of organic brain abnormalities (e.g., vascular dementia, Parkinson’s disease, etc) were excluded from the study.
Assessment
A screening test for dementia was performed on all subjects using the Korean version of the Mini-Mental Status Examination (MMSE-KC). Of the 626 subjects who had a score >1.5 standard deviations (SD) above the mean MMSE-KC score, 59 were randomly selected as the control group. Of the 208 subjects who had a score >1.5 SD below the mean MMSE-KC score, 106 agreed to undergo blood sampling and further examination. These additional assessments included the Consortium to Establish a Registry for AD, Korean version (CERAD-K), the Korean version of the Geriatric Depression Scale (K-GDS), the Hachinski Ischemic Scale, the Clinical Dementia Rating Scale (CDRS), and the DSM-IV diagnostic criteria.
The subjects were classified into cognitive impairment groups based on the results of their psychological tests and clinical evaluation: 26 subjects were classified with age- associated cognitive decline (AACD), 55 subjects with mild cognitive impairment (MCI), and 25 subjects with AD.
Biological Measurements
Venous blood samples (5 ml) from each subject were collected between 08:00 h and 10:00 h. Serum BDNF levels were measured using enzyme-linked immunosorbent assay (ELISA) kits (Promega, Maidison, WI, USA) and BDNF and 5-HTTLPR genotyping was performed.
Statistical Analysis
All analyses were conducted with PASW Statistics ver. 18.0 software for Windows (IBM Co., Armonk, NY, USA). An analysis of variance (ANOVA) was performed to assess the differences in clinical data among the groups and Student’s t-tests were used to compare the serum BDNF concentrations of the subjects with cognitive impairments (AACD, MCI, and AD) with those of the control subjects. ANOVAs were used to assess differences in mean scores on the MMSE-KC and K-GDS and serum BDNF concentrations according to BDNF and 5-HTTLPR genotyping. Chi-square tests were performed to assess differences in the genotype and allelic frequencies between subjects with cognitive impairment and the control subjects. A p value <0.05 was considered to indicate statistical significance.
RESULTS
Compared with the control group, subjects with cognitive impairment had higher K-GDS scores (Table 1) and increased serum BDNF concentrations (26.8±5.3 ng/ml vs. 28.9±6.9 ng/ml, p<0.05; Table 2). However, there were no significant differences in the mean scores on the MMSE-KC and K-GDS between the BDNF Val66Met and 5-HTTLPR genotypes or any significant associations of the BDNF Val66Met and 5-HTTLPR polymorphisms with serum BDNF levels (Table 3).
Table 1.
Clinical data of subjects
| MMSE-KC <1.5 SD (normal cognition) | MMSE-KC ≥1.5 SD (impaired cognition) | p value | |||
|---|---|---|---|---|---|
|
|
|
||||
| Control | AACD | MCI | AD | ||
| CDR | 0 | 0 | 0.5 | ≥0.5 | |
| Subject (n) | 59 | 26 | 55 | 25 | |
| Age (yr) | 72.0±5.8 | 70.8±4.4 | 71.5±4.7 | 73.3±6.8 | 0.202 |
| Education (yr)* | 6.3±4.3 | 8.7±2.7 | 6.6±4.3 | 4.8±4.0 | 0.001 |
| MMSE-KC* | 24.7±3.7 | 21.3±2.3 | 19.5±3.4 | 16.2±4.1 | 0.001 |
| K-GDS* | 12.0±6.7 | 13.6±7.5 | 16.4±7.2 | 20.0±6.5 | 0.000 |
| Hachinski score* | - | 1.3±1.3 | 1.4±1.5 | 2.2±2.0 | 0.016 |
Values are presented as mean±standard deviation (SD).
MMSE-KC, Mini-Mental State Examination of Korean version; AACD, age associated cognitive decline; MCI, mild cognitive impairment; AD, Alzheimer’s disease; CDR, Clinical Dementia Rating Scale; K-GDS, Korean version of Geriatric Depression Scale.
p<0.05.
Table 2.
The serum BDNF levels in the subjects with cognitive impairments and controls
| MMSE-KC<1.5 SD | MMSE-KC≥1.5 SD | p value | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Control | AACD | MCI | AD | Total | ||
| BDNF concentration* | 26.8±5.3 | 28.9±6.1 | 28.7±7.0 | 29.1±7.7 | 28.9±6.9 | 0.030 |
Values are presented as mean±standard deviation (SD).
BDNF, brain-derived neurotropic factor; MMSE-KC, Mini-Mental State Examination of Korean version; AACD, age associated cognitive decline; MCI, mild cognitive impairment; AD, Alzheimer’s disease; CDR, Clinical Dementia Rating Scale.
p<0.05 control versus total subjects with cognitive impairment.
Table 3.
Genotypic differences in the mean scores of MMSE-KC and K-GDS, and the serum BDNF levels
| BDNF Val66Met polymorphism | p value | 5-HTTLPR polymorphism | p value | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| V/V | V/M | M/M | s/s | s/l | l/l | |||
| MMSE-KC | 22.0±4.7 | 21.0±4.6 | 20.7±4.5 | 0.47 | 20.8±4.6 | 21.3±4.8 | 23.8±3.1 | 0.11 |
| K-GDS | 14.2±7.4 | 14.5±7.5 | 16.4±7.5 | 0.37 | 15.0±7.0 | 15.5±8.3 | 10.6±5.8 | 0.11 |
| BDNF concentration | 27.4±7.8 | 28.5±5.8 | 27.9±6.6 | 0.69 | 28.4±6.4 | 28.1±6.9 | 26.0±4,0 | 0.50 |
Values are presented as mean±standard deviation.
MMSE-KC, Mini-Mental State Examination of Korean version; K-GDS, Korean version of Geriatric Depression Scale; BDNF, brain-derived neurotropic factor; 5-HTTLPR, 5-hydroxytryptamine transporter-linked promotor region.
The frequency of the BDNF Met/Met genotype was higher in subjects with cognitive impairment than in the controls (27.4% vs. 15.3%, p<0.05; Table 4) but no significant differences in BDNF allele distribution were found. The distributions of the 5-HTTLPR genotype and allele did not differ significantly between the two groups (Table 4).
Table 4.
Comparison of the genotype and allelic frequencies of BDNF Val66Met and 5-HTTLPR between groups
| MMSE-KC <1.5 SD | MMSE-KC ≥1.5 SD | p value | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Control | AACD | MCI | AD | Total | ||
| BDNF Val66Met genotype (%) | 0.032 | |||||
| V/V | 30.5 | 11.5 | 18.2 | 12.0 | 15.1 | |
| V/M | 54.2 | 57.7 | 56.4 | 60.0 | 57.5 | |
| M/M* | 15.3 | 30.8 | 25.5 | 28.0 | 27.4 | |
| Allele frequency (%) | 0.096 | |||||
| V Allele | 57.6 | 40.4 | 46.4 | 42.0 | 48.8 | |
| M Allele | 42.4 | 59.6 | 53.6 | 58.0 | 51.2 | |
| 5-HTTLPR genotype (%) | 0.648 | |||||
| s/s | 50.8 | 53.8 | 61.8 | 64.0 | 57.0 | |
| s/l | 37.3 | 42.3 | 32.7 | 32.0 | 35.8 | |
| l/l | 11.9 | 3.8 | 5.5 | 4.0 | 7.3 | |
| Allele frequency (%) | 0.369 | |||||
| s allele | 69.5 | 75.0 | 78.2 | 80.0 | 74.8 | |
| l allele | 30.5 | 25.0 | 21.8 | 20.0 | 25.2 | |
BDNF, brain-derived neurotropic factor; 5-HTTLPR, 5-hydroxytryptamine transporter-linked promotor region; SD, standard deviation; MMSE-KC, Mini-Mental State Examination of Korean version; AACD, age associated cognitive decline; MCI, mild cognitive impairment; AD, Alzheimer’s disease; CDR: Clinical Dementia Rating Scale.
p value, control versus total subjects with cognitive impairment;
p<0.05.
DISCUSSION
Serum BDNF Concentrations in the Subjects with Cognitive Impairment
Recent findings have demonstrated that neurotrophic factors such as BDNF are associated with the pathophysiology of AD. BDNF is critical for the function and survival of neurons that degenerate in AD16) and, thus, represents a potential neuroprotective agent that may be useful for the prevention of neurodegeneration; this has been clearly demonstrated in animal models.17,18) Several studies have identified alterations in the serum BDNF levels of AD patients but often with contrasting results. A majority of studies observed a decrease in serum BDNF levels7–11) while fewer studies reported increased BDNF concentrations.12)
These discrepancies might be explained by differences in the severity of the cognitive impairments associated with the AD samples in different studies. Increased serum BDNF levels have been observed in patients with MCI and early AD,12,19) which supports the notion that there is possibly a compensatory augmentation of neurotrophin synthesis in the earliest stages of AD progression. In line with these findings, the present study found increased serum BDNF levels in subjects with cognitive impairment. This may be due to the high proportion of subjects in the relatively early stages of cognitive impairment in the present sample.
Associations of the BDNF Val66Met and 5-HTTLPR Polymorphisms with Cognitive Impairment
Several recent studies investigated the association between the Val66Met allele of the BDNF gene and AD but the findings are ambiguous. While some studies found that this SNP was associated with AD,13,14) others failed to find a significant association between the two.20–23) Case-control studies addressing the association of 5-HTTLPR with AD have also produced conflicting results, but the majority were negative findings.24–27)
In the present study, there were significant differences in the genotype distribution of the BDNF Val66Met polymorphism, but not the 5-HTTLPR polymorphism, between the cognitive impairment and normal control groups. The distribution of the BDNF Met/Met genotype was higher in subjects with cognitive impairment (AACD, MCI, and AD) compared to the controls (p<0.05).
The BDNF Val66Met polymorphism affects the secretion of mature BDNF and has been implicated in the learning and memory processes of healthy humans. For example, carriage of the Met allele is associated with poor memory, reduced hippocampal volume, and lower hippocampal activation during functional imaging.28–30) Cross- sectional genetic association studies of subjects with AD have demonstrated that Met carriers exhibit greater impairments in memory and executive function,13) a tendency for the earlier onset of AD,31) reduced regional cerebral blood flow in the hippocampal and medial temporal lobe regions,32) and reduced hippocampal and prefrontal cortical volumes.33) However, other studies have observed greater levels of cognitive impairment, reduced brain structure volumes, and an increased risk of AD in subjects with the Val/Val genotype.34–36) The absence of a clear relationship between the BDNF Val66Met allele and AD in previous studies could have been due to small sample sizes, different cross-sectional study designs, or the moderating influence of factors such as age and gender.
The present study has several limitations. Due to the cross-sectional design of the study, it is not clear whether the changes in BDNF levels preceded or followed the cognitive decline of the subjects. Additionally, it was not possible to adjust for potential confounding factors (e.g., age, sex, or smoking status) that could have influenced serum BDNF levels and the small sample size limits the generalizability of the present findings.
In summary, subjects with cognitive impairment (AACD, MCI, and AD) had significantly higher serum BDNF levels than the normal control group in the present study. Furthermore, the BDNF Met/Met genotype was more frequently identified in subjects with cognitive impairment, which indicates that this allele might be associated with a susceptibility to cognitive impairment. These findings suggest that BDNF may be an important biological component underlying the pathophysiology of cognitive impairment and that the BDNF Val66Met polymorphism may be an important factor in the susceptibility to cognitive impairment.
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