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Keywords:

  • Alzheimer's disease;
  • brain-derived neurotrophic factor (BDNF);
  • executive function;
  • Frontal Assessment Battery (FAB);
  • single nucleotide polymorphisms (SNPs)

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

Background:  To address the functional roles of genetic polymorphisms of brain-derived neurotrophic factor (BDNF) in Alzheimer's disease (AD) from a neuropsychological aspect, we used a cross-sectional study design to investigate the association between novel single nucleotide polymorphisms (SNPs) of the BDNF gene (Val66Met (G196A) and C270T) and the Frontal Assessment Battery (FAB) score, which reflects executive function as a non-memory cognitive impairment.

Methods:  One hundred and sixty-nine outpatients with AD or amnestic mild cognitive impairment (A-MCI) were recruited to the study and divided into three genotypic groups for each representative BDNF functional polymorphism as follows: (i) Val66Met (G196A): G/G (n= 45), G/A (n= 104), and A/A (n= 20); and (ii) C270T: C/C (n= 160), C/T (n= 9), and T/T (n= 0). Then, age, sex ratio, duration of illness (months), education years, Mini-Mental State Examination (MMSE) score, behavioral pathology in Alzheimer disease (Behave-AD) score, Clinical Dementia Rating (CDR) ratio, and total and subtest FAB scores were compared between the genotypic groups for each SNP.

Results:  Significant differences were found in the total (P < 0.01) and subtest (conflicting instructions and prehension behavior; P < 0.01) FAB scores between the C270T polymorphism groups (C/C and C/T), but not among the G196A polymorphism groups. However, no significant differences in age, sex ratio, duration of illness (months), education years, Behave-AD score, CDR ratio, or MMSE score (reflecting attention and memory function) were found between the individual polymorphism genotypes (G196A and C270T).

Conclusion:  Of the known BDNF polymorphisms, the C270T SNP may influence executive dysfunction as a non-memory cognitive impairment in Japanese patients with AD.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized mainly by memory disorder, visuospatial impairment, attentional impairment, and executive dysfunction as its core symptoms.1,2 From a neuropathological aspect, the association between tau pathology or β-amyloid (Aβ) depositions in the medial temporal lobe, including the hippocampus, and memory disorders (episodic and recent memory disorders) in patients with early AD and amnestic mild cognitive impairment (A-MCI) has been investigated in previous studies and significant results have been reported.3–7 However, few studies have examined executive dysfunction in early AD or A-MCI, and the clinicopathological mode of pathogenesis remains to be elucidated.1,2,8 In previous studies, executive dysfunction in early AD was reported as a risk factor for behavioral and psychological problems (e.g. delusional ideation and aberrant motor behavior), leading to increased caregiver's burden and facilitating the need for nursing home placement.9,10 Therefore, to predict the prognosis of AD patients, elucidating the epigenic or endogenic pathogenesis of executive dysfunction in patients with AD may be important.

Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), promote the developmental and survival or maintenance function of neural cells.11 Moreover, BDNF secretion within the synaptic cleft is modulated by an activity-dependent change, long-term potentiation (LTP), which, in turn, influences or links memory and learning function from a neurocognitive viewpoint.12,13 In a recent review and in other studies, BDNF has been described as a molecular regulator of neural plasticity that protects against neural cell death caused by the aggregation of Aβ and tau proteins during the neuropathological changes that occur in AD.14–16

Of the several BDNF gene polymorphisms, two novel single nucleotide polymorphisms (SNPs) have been widely reported. One of these common SNPs is G196A (rs6265), located in coding exon VIII. This SNP changes the amino acid (Val66Met) at codon 66 in the pro-BDNF protein.17,18 Although G196A has already been examined as a risk factor for AD, some previous studies have verified its role as a functional SNP, identifying it as a risk factor for cortical atrophy, brain hypometabolism, and affective problems in AD patients.18–24 Moreover, in elderly or healthy controls, an association between G196A and cognitive function, including memory and executive function, has been reported.25–29 Another functional SNP, namely C270T, located in a non-coding region of exon 5, was first reported by Kunugi et al., and a significant association with AD has been shown.30,31 In a large cohort study, the global cognition impairment in late-onset AD among the American Black population was influenced by the C270T polymorphism.32 Although G196A and C270T have both been reported to have significant effects in AD patients, their exact roles remain contentious.

The Frontal Assessment Battery (FAB), consisting of six main components, is an easily administered test that can be completed at a patient's bedside within 10 min, enabling executive function to be measured without requiring the use of tools or other instruments.33,34 The total and subtest FAB scores are practical measures for evaluating the executive function of patients with frontal lobe dysfunction and are helpful for distinguishing AD from MCI and elderly patients with dementia, in which the presence of frontal lobe dysfunction supports the diagnosis.35–37 Some researchers have also suggested that because of its simplicity, the FAB may be useful for differentiating between degenerative disorders involving subcortical structures and for evaluating the progression of these disorders over time.33,35–37

Functional polymorphisms of the BDNF gene have been investigated in elderly and AD patients and the G196A and C270T SNPs were significantly associated with neurocognitive functions, including memory function.25,32 However, no reports have examined BDNF polymorphisms as a risk factor for executive dysfunction in terms of intelligence deterioration in AD or A-MCI patients only. Thus, in the present cross-sectional study, we investigated the association between novel BDNF gene SNPs (G196A and C270T) and executive function among non-memory function using the FAB and attempted to elucidate the role of BDNF gene SNPs in patients with AD or A-MCI.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

Participants

One hundred and sixty-nine consecutive Japanese patients with AD or A-MCI were recruited from among memory clinic outpatients visiting the Jikei University Hospital (Tokyo) or the Jikei University Kashiwa Hospital (Kashiwa City, Chiba Prefecture). All patients were diagnosed as having probable AD based on the National Institute of Neurology and Communicative Disorder and Stroke/Alzheimer Disease and Related Disorder Association (NINCDS/ADRDA) criteria or the diagnostic criteria for A-MCI.38,39 In the present study, A-MCI included both amnestic MCI-single domain and MCI-multiple domain types.39 All diagnoses were made after examination of the patients' past medical history, an evaluation of physical or neurological examinations, routine blood tests, and magnetic resonance imaging (MRI) findings by geriatric psychiatrists (one of four authors: TN, SS, YO, or SK). The exclusion criteria were other neurological diseases, a history of alcohol or other substance abuse, brain injury, major depressive or psychotic disorders, epilepsy, delirium, or metabolic disorders. Furthermore, brain MRI findings obtained at presentation were rechecked to support the diagnosis and to exclude patients with any one of the following: (i) more than four old lacuna infarctions within bilateral subcortical areas, including the basal ganglia; and (ii) periventricular hyperintensity (PVH) ≥10 mm or with continuous white matter lesions ≥25 mm. These patients were excluded to enable the study subjects to be discriminated from patients with subcortical vascular dementia or mixed-type dementia.40 Two neuropsychological tests, namely the FAB and the Mini-Mental State Examination (MMSE),41 were administrated by a clinical psychologist. To determine the severity of each patient's dementia, the geriatric psychiatrists used the Clinical Dementia Rating (CDR) scale (global CDR scores ranging from 0 to 3, where 0 = normal, 0.5 = questionable, 1 = mild,2 = moderate, and 3 = severe) while interviewing each patient's caregiver.42 The behavioral and psychological symptoms were assessed on the basis of information obtained from a structured interview with each patient's caregiver by the same geriatric psychiatrists using the behavioral pathology in Alzheimer disease (Behave-AD) scale.43 Finally, the four geriatric psychiatrists discussed the results of all the patients' diagnoses once a month to exclude other forms of dementia, such as frontotemporal lobar degeneration (FTLD), Lewy body disease, or idiopathic normal pressure hydrocephalus (iNPH). The four geriatric psychiatrists and clinical psychologist were experienced in performing neuropsychological and behavioral examinations, and the inter-rater validity of the scales was sustained by periodic discussions and the exchange of views.

The present study was approved by the Ethics Committee of Jikei University School of Medicine and written informed consent was obtained from both the patients and their caregivers.

Genotyping

Genomic DNA from mononuclear cells in the peripheral blood was obtained using the Qiagen (Valencia, CA, USA) DNA extraction kit. Each SNP locus was first amplified using the following primer sets: for G196A, 5′-ACTCTGGAGAGCGTGAAT-3′ (forward) and 5′-ATACTGTCACACACGCTC-3′ (reverse); and for C270T, 5′-CTGGGCGCTGGAGCCAGAATC-3′ (forward) and 5′-CTCCTGCACCAAGCCCCATTC-3′ (reverse). The 25-µL polymerase chain reaction (PCR) reaction mixtures contained 1.0 µL (100 ng) genomic DNA, 10 µL GoTaq Colorless Master Mix (Promega, Madison, WI, USA; 2× Taq DNA polymerase, 400 µL dNTP, 3 mM MgCl2, and reaction buffer, pH 8.5), and 6 pmol each primer. The PCR mixtures were subjected to 35 cycles of denaturing at 95°C for 5 min, annealing at 60°C for 30 s, and polymerization at 72°C for 40 s. The final polymerization was performed for 10 min at 72°C. Then, 5 µL of each PCR product was incubated with 2 µL Exo-sap IT (USB) containing Exonuclease and Shrimp Alkaline Phosphatase (SAP) at 37°C for 15 min and then at 80°C for a further 15 min to inactivate the enzymes. To determine the SNPs of each locus, we used the SNaPshot44 Multiplex kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. Briefly, 10 µL single base extension (SBE) reaction containing 5 µL SNaPshot Multiplex, 3 µL treated PCR product, and 0.2 µmol/L SBE primer was subjected to 25 cycles of denaturing at 96°C for 10 s, annealing at 50°C for 5s, and polymerization at 60°C for 30°s. The following primers were used for each locus: G196A, 5′-TTTTTTTGGCTGACACTTTCGAACAC-3′; and C270T, 5′-GTCCACACAAACCTCACG-3′. Then, 10 µL SBE product was incubated with 1 U/µL calf intestinal alkaline phosphatase (CIP; New England Biolabs, Ipswich, MA, USA) at 37°C for 60 min, followed by incubation at 80°C for 15 min to inactivate the enzymes. Finally, 10 µL sample mixtures containing 0.5 µL each SBE product, 9.25 µL Hi-Di formamide, and 0.25 µL GeneScan-120 LIZ size standard (Applied Biosystems) were denatured at 95°C for 5 min and subjected to analysis using an ABI 3100 Genetic Analyzer (Applied Biosystems). Samples were analyzed using GeneScan Analysis Software, version 3.5, and GeneMapper Software, version 4.0 (Applied Biosystems).

Assessment of FAB

The Japanese FAB version consists of six subtests: (i) similarities (conceptualization); (ii) lexical fluency (mental flexibility); (iii) motor series (programming); (iv) conflicting instructions (sensitivity to interference); (v) go/no go (inhibition control); and (vi) prehension behavior (environmental autonomy). Each subtest was rated from 3 to 0, with the total score ranging from 18 to 0.33,34

Statistical analysis

Statistical analyses were performed using SPSS 16.0J for Windows (SPSS Japan, Tokyo, Japan). To compare differences between each genotypic group and to control type I errors, one-way ANOVA with post hoc Tukey's was used to test for the effect of age, education (years), duration of illness (months), total and subtest MMSE scores, Behave-AD scores, CDR scale sum of boxes (CDR SB; ranging from 0 to 18), FAB total score, and the six FAB subtest scores. Sex (female : male) and CDR (0.5:1:2:3) ratios were assessed using a χ2 test. P < 0.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

Patient characteristics

A total of 169 patients, (n= 128 AD and n= 41 A-MCI patients) were selected and their BDNF genotypes for the G196A and C270T SNPs evaluated. The genotype and clinical characteristics for all patients are given in shown in Tables 1 and 2. The genotype distribution for C270T (C/C, n= 160; C/T, n= 9; T/T, n= 0) did not deviate significantly from Hardy–Weinberg equilibrium (χ2= 0.13; d.f. = 1; P > 0.05), although none of the patients was homozygous for the 270T allele. However, a significant difference was observed in the genotype distribution for G196A (G/G, n= 45; G/A, n= 104; A/A, n= 20; χ2= 13.57; d.f. = 1; P < 0.001). These genotype groups did not significantly influence the sex ratio, age, duration of illness (months), education (years), Behave-AD score, CDR SB score, MMSE total score (Tables 1,2), or representative subtest scores reflecting memory or attention function (memory registration, memory delayed recall, attention and calculation, and three-stage commands; data not shown). The frequency of the C270T genotype (C/C : C/T) for each CDR stage was 50:0 for the very mild stage (CDR = 0.5), 84:9 for the mild stage (CDR = 1), 24:0 for the moderate stage (CDR = 2), and 2:0 for the severe stage (CDR = 3). The T allele carriers were only observed for CDR 1 (Table 2). The ratios did not differ significantly (χ2= 7.769; d.f. = 3; P= 0.051; Table 2).

Table 1.  Subject characteristics (mean ± SD) according to G196A polymorphism
GroupG/G (n= 45)G/A (n= 104)A/A (n= 20)χ2 or F scoreP value
  • Unless indicated otherwise, data are the mean ± SD.

  • The sex ratio and global Clinical Dementia Rating (CDR) score were analyzed using χ2 test.

  • χ2 score.

  • MMSE, Mini-Mental State Examination; Behave-AD, behavioral pathology in Alzheimer's disease; FAB, Frontal Assessment Battery; CDR SB, CDR Scale sum of boxes (ranging from 0 to 18).

Sex (male/female)17/2832/726/140.7700.681
Age (years)76.4 ± 7.777.9 ± 5.977.8 ± 6.10.0830.921
Education (years)12.4 ± 3.011.8 ± 2.611.2 ± 3.41.3000.275
Duration of illness (months)32.5 ± 21.030.9 ± 23.331.8 ± 21.70.0830.921
MMSE score22.1 ± 4.921.0 ± 5.120.3 ± 5.41.0150.365
FAB score11.3 ± 4.312.1 ± 3.311.3 ± 3.40.8780.418
Behave-AD score6.4 ± 5.46.5 ± 4.96.5 ± 7.50.0080.992
CDR SB5.4 ± 3.25.8 ± 3.36.0 ± 3.70.3000.741
Global CDR ratio (0.5:1:2:3)15:24:6:029:60:13:26:9:5:03.9680.681
Table 2.  Subject characteristics according to C270T polymorphism
GroupC/C (n= 160)C/T (n= 9)T/T (n= 0)χ2 or F scoreP value
  • Unless indicated otherwise, data are the mean ± SD.

  • **

    P < 0.01 (one-way ANOVA with post hoc test).

  • The sex ratio and global Clinical Dementia Rating (CDR) score were analyzed using a χ2 test.

  • χ2 score.

  • MMSE, Mini-Mental State Examination; Behave-AD, behavioral pathology in Alzheimer's disease; FAB, Frontal Assessment Battery; CDR SB, CDR Scale sum of boxes (ranging from 0 to 18).

Sex (male/female)52/1083/60.0030.959
Age (years)77.5 ± 6.578.1 ± 6.80.0850.770
Education (years)11.9 ± 2.811.2 ± 3.40.5210.471
Duration of illness (months)30.9 ± 22.440.2 ± 22.11.4610.228
MMSE score21.3 ± 5.118.8 ± 3.92.1550.144
FAB score12.0 ± 3.48.4 ± 5.08.8920.003**
Behave-AD score6.4 ± 5.47.6 ± 4.20.4040.526
CDR SB5.7 ± 3.45.7 ± 1.20.0000.992
Global CDR ratio (0.5:1:2:3)50:84:24:20:9:0:07.7690.051

Total and subtest FAB scores

The FAB score was significantly different only between the C270T genotypes (F= 8.892; d.f. = 1; P= 0.003) and not among the G196A genotypes (F= 0.878; d.f. = 2; P= 0.418). Two FAB subtest scores (conflicting instructions (P= 0.001) and prehension behavior (P= 0.008)) differed significantly between the C270T genotypes (Tables 1–3).

Table 3.  Frontal Assessment Battery subtest scores according to C270T polymorphism
SubtestC/C (n= 160)C/T (n= 9)T/T (n= 0)F scoreP value
  1. Unless indicated otherwise, data are the mean ± SD. **P < 0.01 (one-way ANOVA with post hoc test).

Similarities1.74 ± 1.051.67 ± 1.120.0510.822
Lexical fluency1.61 ± 0.901.22 ± 0.971.5450.216
Motor series2.07 ± 1.041.56 ± 1.242.0520.154
Conflicting instructions2.46 ± 0.941.33 ± 1.4111.4840.001**
Go/no go1.47 ± 1.130.78 ± 1.093.2010.076
Prehension behavior2.66 ± 0.791.89 ± 1.367.2820.008**

Comparison of total and subtest FAB scores between C270T genotypes in patients with CDR 1

Although the 160 patients who were homozygous for C (C/C) had a CDR global score ranging from 0.5 to 3.0, the scores of all nine heterozygous patients (C/T) were 1.0 (i.e. a mild stage of dementia; Table 2). Therefore, to correct for the deviation in the CDR ratio among the C270T genotypes, we selected 93 subjects with a CDR of 1 from among all 169 AD patients and compared the FAB total and subtest scores between the C/C group (n= 84) and the C/T group (n= 9). We confirmed a significant difference in the total FAB score (F= 7.644; d.f. = 1; P= 0.007) and two subtest scores, specifically conflicting instructions (P= 0.002) and prehension behavior (P= 0.010), between the C/T and C/C patients with the same dementia stage (CDR 1), despite the absence of a significant difference in the sex ratio, age, duration of illness (months), education (years), Behave-AD score, CDR SB score, total MMSE score (Tables 4,5), and representative subtest scores (memory registration, memory delayed recall, attention and calculation, and three-stage commands; data not shown).

Table 4.  Subject characteristics according to C270T polymorphism among patients with a Clinical Dementia Rating (CDR) score of 1.0
GroupC/C (n= 84)C/T (n= 9)χ2 or F scoreP value
  • Unless indicated otherwise, data are the mean ± SD. **P < 0.01 (one-way ANOVA with post hoc test).

  • The sex ratio was analyzed using a χ2 test.

  • χ2 score.

  • MMSE, Mini-Mental State Examination; Behave-AD, behavioral pathology in Alzheimer's disease; FAB, Frontal Assessment Battery.

Sex (male/female)23/613/60.1430.705
Age (years)78.3 ± 7.078.1 ± 6.80.0040.951
Education (years)11.8 ± 2.511.2 ± 3.40.3940.532
Duration of illness (months)31.8 ± 21.140.2 ± 22.11.2940.258
MMSE score20.7 ± 3.718.8 ± 3.92.0800.153
FAB score11.7 ± 3.18.4 ± 5.07.6440.007**
Behave-AD score7.3 ± 5.17.6 ± 4.20.0280.869
Table 5.  Frontal Assessment Battery subtest scores according to C270T polymorphism among patients with a Clinical Dementia Rating (CDR) score of 1.0
SubtestC/C (n= 84)C/T (n= 9)F scoreP value
  1. Unless indicated otherwise, data are the mean ± SD. *P < 0.05, **P < 0.01 (one-way ANOVA with post hoc test).

Similarities1.74 ± 1.051.67 ± 1.120.0350.853
Lexical fluency1.58 ± 0.851.22 ± 0.971.3960.241
Motor series1.99 ± 1.031.56 ± 1.241.3430.250
Conflicting instructions2.44 ± 0.921.33 ± 1.4110.2970.002**
Go/no go1.31 ± 1.100.78 ± 1.091.8560.177
Prehension behavior2.64 ± 0.721.89 ± 1.366.9030.010*

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

In the present study, we found that the total and subtest FAB scores representing executive function as a non-memory function were significantly different between BDNF polymorphism C270T genotypes, regardless of the absence of associations with MMSE scores reflecting attention and memory function. Kunugi et al. reported that the C270T SNP is located in a non-coding region of the 5′-untranslated region (UTR) of the BDNF gene and that this SNP acts as a functional promoter polymorphism representing an AD risk factor.30 However, in a subsequent meta-analysis that included individuals from various countries, it was suggested that C270T polymorphisms may not be significantly associated with AD.24 In a previous large study, C270T polymorphisms influenced the MMSE score in patients with late-onset AD and T allele carriers were associated with a reduction in neurocognitive function.32 In the present study, no differences in the total MMSE score or in MMSE subtest scores were observed between the C270T polymorphism genotypes independent of dementia stage (global CDR). Whether the C270T polymorphism affects memory or non-memory function (such as executive function) among neurocognitive functions may differ among races or peoples, despite the presence of similar allele frequencies.18,20,30,32,45 In addition, because the C270T position is located in a non-coding region with a promoter function (5′-UTR), it may alter or control the efficacy of BDNF translation in the neural soma, dendritic, or axonal regions, leading to region-specific quantitative BDNF imbalances in AD cortical areas.46,47 However, the role of C270T continues to be discussed in some studies and remains unclear at present.17,48

Of the six FAB subtests, the ‘conflicting instruments’ subtest resembles the Stroop test task and requires the capacity to perform a contrary reaction to each of two pattern directions, whereas the ‘prehension behavior’ subtest is dependent on environmental cues.33 Both subtests reflect executive function weighing on the performance of actions, rather than verbal ability, as conceptualization or lexical fluency in six FAB subtests. Conflicting instruments and prehension behavior subtests require the ability to respond to contrary tasks correctly, and these two subtests are somewhat similar. Therefore, we need to elucidate this association between BDNF genotypes and neurocognitive function in patients with AD using neuroimaging or neurophysiological methods in the future.

In previous studies, the association between G196A polymorphisms and cognitive function was investigated in AD patients, but no conclusion was reached.25,32,49 From a neurobiological viewpoint, the A allele (minor allele) influences the reduction in intracellular trafficking and activity-dependent secretion of BDNF in the hippocampus, possibly resulting in episodic and memory decrements.50–52 The present study did not show a functional significance of G196A SNPs among a Japanese population. Differences in ethnicity may have contributed to the discrepancy between our study and other studies. The frequency of heterozygosity (G/A) among Japanese AD patients was comparatively high and a significant difference from Hardy-Weinberg equilibrium was demonstrated statistically.20,53 Although interethnic differences in the allele frequencies of G196A polymorphisms seem to exist, Japanese studies have reported almost the same frequencies, with a comparatively high number of heterozygous individuals.20,22,24,53–55 As one possible reason for this finding, some population stratification may have existed among the subjects in the present study, although the subjects were enrolled in Tokyo and Kashiwa city, both of which have populations of over 100 000 people and may exhibit more population fluidity than other areas of Japan. Furthermore, if the genotype of the SNPs was unclear or ambiguous using the SNaPshot method, we rechecked and confirmed the genotype using PCR products and direct nucleotide sequencing with an ABI 3730 DNA Analyzer (sequencing reactions were performed using the BigDye Terminator v3.1 Cycle Sequencing Kits; Applied Biosystems). All the sequence analyses were performed using DNA Sequencing Analysis software version 5.3.1 (Applied Biosystems). In a recent population genetics study, Asians, including Japanese, were shown to have a higher frequency of the A (Met amino acid) allele than Caucasians or Africans.56 Thus, this genetic phenomenon involving a deviated genotype frequency in Japan should be investigated and explained in future studies.

The present study had some limitations. First, the sample size in the present study was comparatively small; therefore, some type II errors may have existed. In particular, only nine T allele carriers were included in the study, compared with 160 subjects with a C/C genotype. Because previous studies have reported that the proportion of T allele carriers in patients with AD is <10% (range 5%–10%), the proportion in the present study was similar.30,32,55 Moreover, the C270T SNP has been reported to play a significant role in patients with schizophrenia, AD, or autism as a candidate or functional polymorphism.30,32,55,57,58 To verify the association between C270T and executive function, we re-evaluated the total and subtest FAB scores in patients with only mild-stage AD (CDR = 1.0). However, additional studies with a much larger sample size are needed to confirm the association between C270T and executive function. Second, different genes may interact and the possible effects of linkage disequilibria with nearby BDNF genes and haplotypes on executive dysfunction as a non-memory disorder should be evaluated. Third, the present study was of a cross-sectional design and significant associations were observed between BDNF polymorphisms and executive function in patients with AD. If the clinical course of the subjects, including healthy controls, were to be pursued longitudinally, we would be able to confirm these results and the functional significance of the BDNF gene.

In conclusion, to investigate the cognitive significance of BDNF polymorphisms in patients with AD or A-MCI, we focused on executive dysfunction as a non-memory function, which is a core symptom, and found a significant association between the total and subtest (conflicting instruments and prehension behavior) FAB scores and the C270T polymorphism. An association between the C270T polymorphism and executive function has not been reported previously and our results may contribute to a better understanding of the actual disease pathogenesis. Furthermore, elucidating the detailed associations between BDNF gene diversity and behaviors in patients with AD will be an important future task.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES

The authors are grateful to Dr Nobuto Shibata (Department of Psychiatry, Juntendo University School of Medicine) for his constructive advice regarding the design of the present study.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENT
  8. REFERENCES