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Keywords:

  • Alzheimer's;
  • amyloid;
  • Aβ;
  • dementia;
  • depression;
  • serum

Abstract

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

Background:  Depression may increase the risk of developing Alzheimer's disease (AD). Recent large cohort studies have also shown that a low plasma amyloid β (Aβ)-42 level combined with a high Aβ40 level increases the risk of developing AD, suggesting plasma Aβ42/40 ratio as useful for identifying risk of developing mild cognitive impairment and AD. Although several studies have examined Aβ levels in the peripheral blood of elderly individuals with depression, results have been inconsistent. Furthermore, no results have been described for younger depression.

Methods:  Serum Aβ40, Aβ42 level and Aβ40/42 ratio were evaluated using enzyme-linked immunosorbent assay in 60 patients with major depressive disorder (MDD) and 60 healthy controls. The results were analyzed in two age groups (young, <60 years; elderly, ≥60 years).

Results:  Serum Aβ40 level was significantly higher in young MDD patients compared to young controls (< 0.001), but it was not significantly deferent in the elderly group. Serum Aβ42 level did not differ significantly in both young and elderly groups. Aβ40/42 ratio was significantly higher in both young (< 0.001) and elderly (< 0.001) patients with MDD compared to controls.

Conclusions:  Serum Aβ40/42 ratio was significantly higher in MDD patients than in controls, and this difference was seen for both elderly and young subjects. This may suggest that even young subjects with MDD undergo pathological changes in the very early stage of amyloid deposition.


INTRODUCTION

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

Depression may increase the risk for developing Alzheimer's disease (AD).1–3 The recent Rotterdam Scan Study also showed that a history of depression increases the risk of developing AD,4 particularly among subjects with early onset depression. AD is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain. The major protein component of senile plaques is amyloid β protein (Aβ). The protein is 40 or 42 amino acid peptide cleaved from the amyloid precursor protein (APP) by β-secretase and γ-secretase. Aβ deposition begins with Aβ42. Aβ42-positive and Aβ40-negative plaques may represent early stage diffuse-type senile plaques, with Aβ40-positive plaques appearing in the advanced stage, particularly in the core of the mature plaque.5 Deposition of Aβ has been visualized in positron emission tomography imaging by specific ligands, leading to diagnosis of AD.6 Aβ is normally present in the brain, cerebrospinal fluid (CSF) and peripheral blood, and change of levels of Aβ in biological fluid has been also applied for diagnosis of AD. The level of Aβ42 in CSF is significantly reduced both in patients with AD7,8 and in those with mild cognitive impairment (MCI), which precedes AD.8,9 It has suggested that Aβ42 levels are reduced in the CSF of patients with MCI and AD in association with selective deposition of Aβ42 in the brain.10 Increased plasma Aβ40 level and Aβ40/42 ratio, and decreased Aβ42 level in AD compared to control have been reported.11 Large cohort studies have also shown that a low plasma Aβ42 level combined with a high Aβ40 level increases the risk of developing AD, and Graff-Radford et al. concluded that plasma Aβ42/40 ratio may be useful for identifying risk for developing MCI and AD.10,12 History of depression is associated with increases in amyloid plaques and neurofibrillary tangles.13 Elevated plasma Aβ42 level and Aβ42/40 ratio has been reported with late-life depression.14 Conversely, lower plasma Aβ42 levels15,16 and higher Aβ40/42 ratio have been reported in elderly individuals with depression suggesting that ‘amyloid-associated depression’ may define a subtype of depression representing a prodromal manifestation of AD.17 Although several studies concerned with Aβ level in the peripheral blood of elderly subjects with depression have been reported, the results have been inconsistent. The elderly depression is heterogeneous, requiring various interventions,18–20 and different pathogenic processes are speculated with younger elderly and older elderly depression.21,22 No study, however, has been reported the Aβ levels in younger subjects with depression. The present study therefore examined serum Aβ40 and Aβ42 levels and the Aβ40/42 ratio in patients with major depressive disorder (MDD) and healthy controls, and compared young and elderly groups. This study is a part of the Juntendo University Mood Disorder Project (JUMP).

METHODS

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

Subjects

Sixty depressive inpatients (26 men, 34 women; mean age, 55.4 years; range, 33–71 years) were recruited from Juntendo Koshigaya Hospital. All patients fulfilled the Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) criteria for MDD. Patients were excluded if they had a history of other psychiatric disorders including delusions, severe or acute medical illnesses, neurological disorders, or use of drugs that may cause depression. All patients were on antidepressant medication at the time of the study.

Another 60 healthy control participants (25 men, 35 women; mean age, 56.3 years; range, 28–73 years) matched for age and years of education were also recruited.

Detailed demographic and clinical features of participants are shown in Table 1.

Table 1.  Demographic data for subjects
 Young (<60 years)Elderly (≥60 years)
Control (n = 30) Mean (SD)MDD (n = 30) Mean (SD)Control (n = 30) Mean (SD)MDD (n = 30) Mean (SD)
  1. HAM-D, Hamilton Rating Scale for Depression.

Age (years)42.9 (12.2)42.5 (8.9)69.7 (4.7)68.2 (5.6)
Sex (M/F)10/2015/1515/1511/19
Education (years)13.1 (3.3)13.9 (2.4)11.7 (2.8)12.7 (2.8)
Duration of current episode (months) 2.5 (1.4) 4.1 (4.6)
HAM-D score 17.4 (8.4) 22.8 (10.4)
MMSE score28.2 (1.9)27.9 (1.7)26.6 (1.4)25.9 (0.8)

Based on recent studies having reported individuals ≥60 years old as geriatric subjects,23,24 we divided both MDD patients and controls into two age groups (young, <60 years; and elderly, ≥60 years). Results were then compared between the four groups. Subjects showing clinical evidence of dementia or with mini-mental state examination (MMSE) scores <24 were excluded.

The study protocols were approved by the Medical Ethics Committee of Juntendo University, and were performed in accordance with the regulations outlined by the university. All participants provided written informed consent prior to participation.

Serum Aβ40 and Aβ42 measurements

Blood samples were centrifuged immediately after blood was drawn. Serum samples were stored at −80°C until use. A sandwich Aβ enzyme-linked immunosorbent assay kit was used (Wako, Osaka, Japan). The Aβ(1–40) kit uses the BAN50 monoclonal antibody, which specifically detects the N-terminal portion of human Aβ(1–16), and the BA27 monoclonal antibody, which detects the C-terminal portion of Aβ(1–40). The Aβ(1–42) kit uses BAN50 and the BC05 monoclonal antibody, which detects the C-terminal portion of Aβ(1–42). The sensitivity was 0.019 pmol/L (dynamic range, 1.0–100 pmol/L) for Aβ40, and 0.06 pmol/L (dynamic range, 0.1–20 pmol/L) for Aβ42.

Data analysis

For statistical analysis, age, education, MMSE score, serum Aβ concentration and Aβ40/42 ratio were compared between MDD and controls using the two-tailed unpaired Student's t-test within each age group. Bonferroni correction was applied, and a 2.5% level of significance was adopted. Correlations between age and each serum Aβ concentration and Aβ40/42 ratio were analyzed using Pearson's correlation. The χ2-test was used to compare variables of sex. Statistical procedures were performed using the Japanese version of SPSS (version 15.1; SPSS Japan, Tokyo, Japan).

RESULTS

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

No significant differences in age, sex, education, duration of current episode, Hamilton Rating Scale for Depression (HAM-D) score or MMSE score were identified between MDD and controls in both the young and elderly groups (Table 1). Distributions of serum levels of Aβ40 and Aβ42 are shown in Fig. 1a,b, and Aβ40/42 ratio is shown in Fig. 1c. The concentration of Aβ40 correlated with age in controls (= 0.43, P < 0.005), but not in the MDD group. Aβ42 level and Aβ40/42 ratio did not correlate with age in either the control or MDD groups.

image

Figure 1. The distribution of serum levels of amyloid β (Aβ)−40 (a), Aβ42 (b) and Aβ40/42 ratio (c). MDD, major depressive disorder.

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The HAM-D score did not correlate with Aβ40, 42 levels and Aβ40/42 ratio.

Means and standard deviations (SD) of serum levels of Aβ40 and Aβ42, and Aβ40/42 ratio are presented in Table 2.

Table 2.  Serum amyloid β (Aβ) levels and Aβ40/42 ratios in the four groups
 Young (<60 years)P-valuesElderly (≥60 years)P-values
Control (n = 30) Mean (SD)MDD (n = 30) Mean (SD)Control (n = 30) Mean (SD)MDD (n = 30) Mean (SD)
  1. Two-tailed paired Student's t-test within each age group.

Aβ40 (pmol/L)16.2 (5.6)24.3 (10.2)<0.00128.6 (15.5)28.0 (11.9)0.870
Aβ42 (pmol/L)2.5 (2.1)2.6 (3.6)0.983.9 (2.8)2.6 (2.6)0.074
Aβ40/42 ratio8.1 (4.3)19.6 (13.8)<0.0019.4 (5.5)16.9 (8.9)<0.001

Serum Aβ40 level was significantly higher in young MDD patients than in young controls (< 0.001), but did not differ significantly between elderly MDD patients and controls. Serum Aβ42 level did not differ significantly between MDD and controls in both young and elderly groups. Aβ40/42 ratio was significantly higher in both young MDD (< 0.001) and elderly MDD (< 0.001) patients compared to controls (Fig. 2).

image

Figure 2. The concentrations of serum levels of amyloid β (Aβ)−40 (a), Aβ42 (b) and Aβ40/42 ratio (c) Error bars: standard deviation, *P < 0.001.

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DISCUSSION

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

In the present study, serum Aβ40 level was higher in young MDD patients than in young controls, but no difference was found between elderly MDD patients and controls. While elderly MDD patients tended to show lower serum Aβ42 levels than elderly controls (= 0.074), no difference was seen between young MDD patients and controls. Our most important finding was that Aβ40/42 ratio was significantly higher in MDD patients than in controls for both elderly and young subjects (Table 2, Fig. 2). To the best of our knowledge, this is the first report of Aβ concentrations in the peripheral blood of younger patients with depression.

The first study of Aβ concentrations in the peripheral blood of patients with depression was reported by Pomara et al.,14 and reported higher plasma Aβ42 levels and Aβ42/40 ratio in 35 elderly patients compared to 47 controls. Their findings differ from our results for the elderly group. Their subjects with depression (mean age, 80.0 years) were significantly older than the controls (mean age, 69.1 years), and MMSE score was also significantly lower in depression patients compared to controls. Moreover, the cut-off MMSE score was 18. They then picked subjects with MMSE scores ≥25 and were matched for age and gender, and repeated the analyses. Nevertheless, they asserted that the results were similar to the overall group analyses, but the matched sample size was considered too small (14 depression patients, 14 controls).

Qiu15 and Sun et al.16,17 reported large sample studies of plasma Aβ in elderly subjects with depression. Sun et al. measured plasma Aβ40 and Aβ42 in elderly subjects with depression (n = 101) and without depression (n = 223) in the absence of cardiovascular disease (CVD).16 Their study showed that elderly subjects with depression had a lower concentration of plasma Aβ42 than those without depression. However, no difference was seen in concentrations of plasma Aβ40 between the two subgroups. Their results for Aβ40 were consistent with our results and their results for Aβ42 resembled our own results in elderly subjects. Another study using 515 elderly subjects (161 depressed, 354 non-depressed) demonstrated similar results, and showed that depressive symptoms were associated with low plasma Aβ42 independent of CVD in elderly subjects.15 In that investigation, CVD was used to indicate vascular depression,25 and the subtype of elderly subjects with depression associated with Aβ was considered to show ‘amyloid-associated depression’ as opposed to vascular depression. More recently, the same group investigated 995 elderly subjects and characterized ‘amyloid-associated depression’ by a high Aβ40/42 ratio.17 That study also showed lower plasma Aβ42 levels and a higher Aβ40/42 ratio in elderly subjects with depression, similar to our results, and demonstrated an association between ‘amyloid-associated depression’ and greater cognitive impairment compared to nonamyloid depression. In those studies, other neuropsychiatric diseases including dementia might not have been eliminated, and international diagnostic criteria (DSM-IV) were not used for the diagnosis of depression. The present study therefore excluded dementia based on clinical evidence and MMSE scores, and diagnosed MDD using DSM-IV. Our similar results support their findings for elderly subjects.

Moreover, the present study demonstrated a higher serum Aβ40 level and Aβ40/42 ratio in young MDD patients compared to young controls. Serum Aβ42 level was not significantly different, but tended to be higher in young MDD patients than in young controls, in contrast to elderly subjects. The Rotterdam Scan Study was a large population-based prospective study in which 503 elderly individuals were followed for an average of 6 years for the development of AD.4 The result showed that a history of late-onset depression increased risk for AD (hazard ratio, 2.34), while subjects with a history of early onset depression showed even higher risk (hazard ratio, 3.76). This result may suggest that depression, even early onset, has some relationship with AD. One report showed that plasma Aβ40 and Aβ42 levels were elevated in asymptomatic first-degree relatives of patients with AD.26 Graff-Radford et al. suggested that plasma Aβ42 level and Aβ42/40 ratio may decline in parallel, but in many at-risk individuals plasma Aβ40 and Aβ42 levels appear to be elevated initially. Plasma Aβ42 level may thus decline to within the normal range as Aβ42 deposition commences.10 Combining these findings, one may speculate that even young subjects with MDD show pathological changes in the very early stage of amyloid deposition.

A key limitation of the present study was that all MDD subjects were on antidepressant medication and serum Aβ levels might have been influenced by this medication. Sun et al. found no difference in plasma Aβ42 levels between depressed subjects with and without use of antidepressants. In contrast, for Aβ40, patients on antidepressants showed lower plasma Aβ40 than those without treatment.16 Imipramine and citalopram reportedly increase APP secretion in primary rat neuronal cultures.27 Another study using a transgenic mouse model of AD28 showed that levels of Aβ and numbers of Aβ-immunoreactive neurons were significantly reduced in the hippocampus of paroxetine-treated mice. Accordingly, drug-free patients should be investigated in future research.

CONCLUSION

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

Aβ40/42 ratio in serum was significantly higher for MDD patients than for controls, with these differences seen in both elderly and young subjects. This suggests that even young subjects with MDD may undergo pathological changes in the very early stages of amyloid deposition.

REFERENCES

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