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Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer's disease
Neuroscience Letters 436 (2008) 196–200
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease Tae-Suk Kim a , Hyun-Kook Lim a , Ji Youl Lee b , Dai-Jin Kim a , Sanghi Park c , Chul Lee a , Chang-Uk Lee a,∗ a
Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea Department of Urology, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea c Clinical Medicine Research Institute, Holy Family Hospital, Pucheon City, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 15 January 2008 Received in revised form 22 February 2008 Accepted 10 March 2008 Keywords: Alzheimer’s disease Chemokine Fractalkine Mild cognitive impairment Pathogenesis
a b s t r a c t Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer’s disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzymelinked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD. © 2008 Elsevier Ireland Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and it is the most common form of dementia affecting individuals aged 65 years and older [13]. The deposition of amyloid beta (A) in the brain is known to induce a chronic inflammatory response, which may lead to neuronal death [8]. Considerable evidence has suggested that the inflammatory process may be associated with the pathology of AD. The inflammatory components in AD include various brain cells, such as microglia and astrocytes; the complement system; and various inflammatory mediators, including cytokines and chemokines [29]. The chemokines are a superfamily of chemotactic cytokines that are essential for the activation and migration of leukocytes in both physiological and pathological contexts [21]. The results of several in vivo and in vitro studies support the involvement of various chemokines, including monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1, in the pathogenesis of AD [11,15,30]. In the first study to evaluate chemokine involvement in patients with clinical mild cognitive impairment (MCI) and AD patients, Galimberti et al. (2006) found an increase in the level of
∗ Corresponding author. Tel.: +82 2 590 2789; fax: +82 2 536 8744. E-mail address: [email protected] (C.-U. Lee). 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.03.019
peripheral serum MCP-1 in patients with MCI and mild AD in comparison to healthy controls, but this increase in peripheral serum MCP-1 was not found in patients with severe AD, suggesting that MCP-1 may be an early biomarker of AD pathogenesis [5]. The novel CX3C chemokine, fractalkine, is a 373-amino acid protein that has a chemokine domain located on top of a mucinlike stalk [2]. Neurons are the primary source of fractalkine in the brain [6]. Fractalkine can exist in both membrane-bound and soluble forms [7]. While membrane-bound fractalkine can serve as an adhesion molecule for leukocytes expressing the fractalkine receptor CX3CR1 [10], soluble fractalkine can function as a pro-inflammatory chemoattractant that activates receptive inflammatory cells [2,17]. However, more recent studies have demonstrated that soluble fractalkine might have antiinflammatory effects because it suppresses the cytotoxic activity of NK cells, which is enhanced by the increased expression of membrane-bound fractalkine on endothelial cells [31]. Soluble fractalkine also has neuroprotective effects in reducing neuronal apoptosis [27]. Previous studies have investigated the relationship between soluble fractalkine in the peripheral blood and inflammatory diseases of the central nervous system (CNS); however, the results of these studies have been contradictory. Increased levels of serum fractalkine have been reported in patients with multiple
T.-S. Kim et al. / Neuroscience Letters 436 (2008) 196–200
sclerosis [12] and human immunodeficiency virus (HIV) with CNS complications [24], but these increased levels of serum fractalkine were not observed in patients with Guillain-Barre´ Syndrome and viral and bacterial meningitis [12]. Regarding the roles of fractalkine in AD pathogenesis, Streit et al (2001) [25] have hypothesized the loss of control of fractalkine over microglial activation, which has been considered a damaging process in AD pathogenesis. Also, Duan et al (2007) [4] have found the decreased fractalkine expression in cerebral cortex and hippocampus in aged brain of amyloid precursor protein (APP) transgenic mice. However, only a few studies have investigated the levels of soluble fractalkine in AD patients, especially in the peripheral blood. The various properties of soluble fractalkine and the lack of studies investigating the alternations of peripheral soluble fractalkine in AD prompted us to evaluate the levels of fractalkine in plasma samples from patients with MCI, which is regarded as a very early stage of AD [16], as well as in patients with AD and to compare the findings with those of healthy control subjects who did not have inflammatory diseases of the CNS. A total of 102 patients with cognitive impairment, including 51 patients with AD and 51 patients with MCI, who visited the Memory Disorders Clinic at Kangnam St. Mary’s Hospital between May 2006 and May 2007, were enrolled in the present study. Medical and psychiatric histories were obtained from each patient, and all patients underwent a series of standard clinical examinations, including physical, neurological and mental status examinations, laboratory screening tests, an electrocardiogram, neurocognitive tests, and brain magnetic resonance imaging. The Korean versions of the Mini-Mental Status Examination (MMSE) [18] were used to evaluate the severity of cognitive impairment in patients with MCI and AD. The diagnosis of AD was made in accordance with the criteria for dementia of the Alzheimer’s type outlined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [1], the guidelines of the National Institute of Neurological and Communicative Disorders and the Alzheimer’s Disease and Related Disorders Association criteria for probable AD [14]. Patients with vascular dementia or dementia due to medical conditions other than AD, or those with a score greater than 4 on the modified Hachinski Ischemic Rating Scale [22], were excluded from the study. Forty-eight patients were diagnosed with late-onset AD, and the other three patients were diagnosed with early-onset AD. The diagnosis of MCI was made according to the clinical criteria suggested by Petersen et al. [20]. Based on refined clinical criteria [19], 42 patients were classified as having the amnestic-MCI-single domain subtype of MCI and seven patients were classified as having the amnestic-MCI-multiple domain subtype of MCI. Two other patients were classified as having the non-amnestic-MCI-multiple domain subtype of MCI. The diagnoses of both AD and MCI were confirmed by the consensus of two board-certificated psychiatrists (H.K.L and C.U.L). The AD and MCI patients had no major medical illnesses, such as hypertension, diabetes, rheumatoid diseases, or cancer. There was no past or current history of major psychiatric illnesses, including major depression, schizophrenia, and bipolar disorder, in any of the patients. Fifty-seven healthy subjects were included in the control group. ‘Healthy’ was defined as a score of 26 or better on the MMSE, and the healthy subjects were determined to be nondemented by clinical assessment. Control subjects who had no individual or familial history of psychiatric disorders were recruited from the health promotion center in this hospital through an internal advertisement. The control subjects were aged 65 years or older. None of the subjects had a history of substance abuse, such as alcohol or nicotine abuse, within 6 months from the time of enrollment. None of the subjects were being treated with anti-inflammatory drugs at the time of the investigation. Informed consent was obtained from all
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Table 1 Demographic and clinical characteristics of 51 MCI patients, 51 AD patients, and 57 healthy control subjectsa Variables
MCI patients (n = 51)
AD patients (n = 51)
Healthy control subjects (n = 57)
Age (years)
74.6 ± 7.0
78.2 ± 6.1
70.5 ± 3.8
Gender, no. (%) Female
41 (80.4)
42 (82.4)
40 (70.2)
Body mass index (kg/m2 ) Education (years)
22.5 ± 3.1 6.2 ± 3.8
21.3 ± 2.9 5.4 ± 3.5
24.2 ± 3.4 6.9 ± 4.0
Marital status, no. (%) Married Separated Divorced Unmarried
24 (47.1) 25 (49.0) 2 (3.9) 0 (0.0)
22 (43.1) 27 (52.9) 2 (3.9) 0 (0.0)
29 (50.9) 22 (38.6) 3 (5.3) 3 (5.3)
Age at onset (years) Disease duration (years) MMSE score GDS score
73.5 ± 7.2 2.1 ± 1.1 22.1 ± 2.4 3.0 ± 0.0
76.0 ± 6.6 3.2 ± 1.7 15.3 ± 3.6 4.4 ± 0.7
– – 27.3 ± 1.0 1.8 ± 0.4
Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; MMSE, Mini-Mental Status Examination; GDS, Global Deterioration Scale; (–) not applicable. a Plus-minus values are mean ± standard deviation (S.D.).
subjects after they were given a complete description of the study. The Institutional Review Board of Kangnam St. Mary’s Hospital approved the study. Blood was obtained from the antecubital vein in all subjects between 8:00 and 9:00 a.m. after a fast of at least 8 h. The plasma samples were centrifuged and stored in a refrigerator at −70 ◦ C prior to the biochemical analyses. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay (ELISA). All reagents were obtained from Antigenix America (New York, NY). Briefly, 96-well polystyrene plates were coated overnight at 25 ◦ C with 1 g/ml purified goat IgG anti-human fractalkine antibody. After washing, the plates were blocked for 1 h at 20 ◦ C with an ELISA coating stabilizer and then removed for drying. Recombinant human fractalkine and plasma samples were added in duplicate, and the plates were incubated for 2 h at 20 ◦ C. After washing, the plates were incubated with biotinylated goat anti-human fractalkine antibody (250 ng/ml) for 2 h at 20 ◦ C and then with streptotavidin-peroxidase for 30 min at 20 ◦ C. Plasma samples were developed with 0.1 ml per well of tetramethylbenzidine substrate diluted in a citrate-phosphate buffer. The reactions were terminated by the addition of 1 mol/l H2 SO4 , and the plates were read at 450 nm. The limit of detection was 78 pg/ml. Values that fell short of this threshold were considered to be 78 pg/ml in the statistical analysis. The intraclass correlation coefficient (ICC) of plasma soluble fractalkine levels in duplicate measurements is 0.97. Group comparisons were performed using an unpaired t-test, and an analysis of variance (ANOVA), or an analysis of covariance (ANCOVA) when covariance was found. 2 -Analyses were conducted to compare categorical variables. Pearson correlation coefficients were calculated in order to assess the associations between the clinical data and plasma soluble fractalkine. The probability value (p) was set at <0.05. All statistical analyses were conducted using SAS (Statistical Analysis System), Version 9.1 (SAS Institute Inc., Cary, NC). There were no significant differences in gender, years of education, and marital status between the three groups (p = 0.263; p = 0.126; p = 0.307, respectively), but there were significant differences in age and body mass index (BMI, kg/m2 ) between the three groups (F = 24.4, p < 0.0001; F = 12.3, p < 0.0001, respectively) (Table 1).
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T.-S. Kim et al. / Neuroscience Letters 436 (2008) 196–200
There was a significant difference in disease duration (t = −3.714, p < 0.0001) between the MCI and AD group, but there was no significant difference between the groups in age at onset (t = −1.866, p = 0.065, respectively) (Table 1). ANCOVA with adjustment for age and BMI revealed a significant group difference in the levels of plasma soluble fractalkine between the MCI group (n = 51, 384.2 ± 308.7 pg/ml), AD group (n = 51, 294.2 ± 207.7 pg/ml), and control group (n = 57, 172.5 ± 100.8 pg/ml) (F = 11.9, p = 0.0002, Fig. 1). Post hoc analyses using the Newman-Keuls test revealed significant differences between the MCI and control groups (p = 0.00002), the AD and control groups (p = 0.0043), and the MCI and AD groups (p = 0.034). ANCOVA revealed that the level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD (MMSE score >14, n = 30, 360.6 ± 237.0 pg/ml) than in the patients with severe AD (MMSE score ≤14, n = 21, 191.2 ± 80.9 pg/ml) after controlling for age and BMI (F = 3.48, p = 0.023, Fig. 1). Moreover, these findings were corroborated by a significant positive correlation between the MMSE scores and plasma soluble fractalkine levels in the patients with AD (r = 0.347, p = 0.013, Fig. 2). In the present study, the levels of plasma soluble fractalkine in patients with MCI and AD were found to be significantly increased in comparison to healthy control subjects. In addition, the patients with MCI had higher levels of plasma soluble fractalkine than the patients with AD. Fractalkine is a chemokine that plays the role of an inflammatory mediator. Considering that MCI may be a very early stage of AD, these findings support the early involvement of inflammation in the pathogenesis of AD and are in agreement with the findings of previous studies [13,29]. The increased levels of plasma soluble fractalkine in patients with MCI and AD may be attributable to the functional role of soluble fractalkine as an inflammatory mediator. Unlike most chemokines, which are highly expressed in leukocytes, the mRNA expression levels of fractalkine were determined to be highest in the heart and brain, and no fractalkine mRNA was observed in the peripheral blood [2]. The expression of fractalkine in the brain has been primarily observed in neurons and endothelial cells [23]. Fractalkine expression is reportedly restricted to the luminal endothelium in cerebral blood vessels [17], and it can be proteolytically cleaved by various proteases [28]. Thus, the release of soluble fractalkine from endothelial cells may be a primary source of fractalkine in the peripheral circulation. Soluble fractalkine has been suggested to act as a pro-inflammatory chemoattractant for T cells, NK cells, and monocytes during the early stage of AD [2].
Fig. 2. The MMSE scores showed a significant positive correlation with the levels of plasma soluble fractalkine in 51 patients with AD.
Thus, it may simply be postulated that increased plasma soluble fractalkine is related to the induction of the inflammatory process in the AD brain and may result from inflammatory processes in the AD brain. However, emerging evidence for the anti-inflammatory and even neuroprotective activities of soluble fractalkine [27,32] suggest the possibility of a better explanation for the increased levels of plasma soluble fractalkine in patients with cognitive impairment. If the inflammatory process leading to neuronal death or microvascular disruption occurs in the AD brain, the proteolytic release of soluble fractalkine from neurons and endothelial cells may increase in order to protect the brain from the insult, which may lead to increases in the levels of peripheral soluble fractalkine. However, the increased level of soluble fractalkine in the cerebrospinal fluid (CSF) of patients with AD should be confirmed in future studies in order to support this reasoning. In the present study, we also found that the level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD, and this finding was strengthened by a significant positive correlation between MMSE scores and plasma soluble fractalkine levels in patients with AD. These results suggest that the amount of plasma soluble fractalkine may decrease between the early and late stages of AD. In addition, these results are in agreement with previous findings that the level of serum MCP-1, which may have a neuroprotective effect, increases during the progression from MCI to early AD, but not during the progression from mild to severe AD [5]. These findings may partially support the hypothetical role of fractalkine in the pathogenesis of AD, especially in the interactions between neurons and microglia, as proposed by Streit et al (2001) [25]. In this study, the highest peaks of plasma soluble fractalkine were observed in patients with MCI, which is regarded as a turning point from normal aging to overt AD. Considering that CNS inflammation precedes the development of AD, it is reasonable to believe that the increased levels of soluble fractalkine may be specific to the early stages of AD [26]. Given the possible anti-inflammatory or neuroprotective activities of soluble fractalkine, the increased levels of soluble fractalkine during the early stages of AD may be related to an attempt of neurons and vascular endothelial cells to prompt microglia to phagocytose the -amyloid plaques [3]. However, after the disruptive inflammatory processes in the brain exceed the efforts to protect the normal brain environment, neurons and endothelial cells die away, resulting in decreased production of soluble fractalkine, as observed in the patients with severe AD. To solidify this description, further studies will be needed in order to investigate the levels of soluble fractalkine in the CSF of patients with MCI and AD. Prospective studies of the changes in the levels of soluble fractalkine during the progression from MCI to AD over time are also needed. To the best of our knowledge, this is the first study to investigate the levels of peripheral soluble fractalkine in clinical samples of patients with cognitive impairment. Several limitations should be noted when interpreting our results. First, since diet may be a confounding factor in the interpretation of chemokine alteration [9], the patient and control groups were matched according nutrition status, as indirectly evidenced by BMI. Although the mean BMI score of the patients was lower than that of the healthy controls, most of the AD patients were well nourished, as their BMI scores were in the normal or overweight range. However, the findings from this study do not exclude the possibility that plasma fractalkine may be modified by dietary factors that are not reflected by BMI. Second, anti-dementia medication, which might affect the levels of plasma soluble fractalkine, was not completely excluded as a possible confounding factor. Fourteen of the AD patients (27.5%) had taken one or more anti-dementia medications (donepezil, n = 8; galantamine, n = 3; memantine, n = 2; donepezil + memantine, n = 1),
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Fig. 1. The levels of plasma soluble fractalkine in patients with MCI, patients with AD and healthy control subjects. The patients with AD were divided into two groups: those with mild to moderate AD and those with severe AD. The horizontal bars represent mean values, with statistically significant differences between the groups indicated.
whereas none of the MCI patients had taken any anti-dementia medication. In conclusion, our findings showed that patients with MCI and AD had higher levels of plasma soluble fractakline than healthy control subjects. In addition, the patients with mild to moderate AD had higher levels of plasma soluble fractalkine than the patients with severe AD. This study provides preliminary evidence that soluble fractalkine is likely to play some important roles in the pathogenesis of AD.
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Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079).
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Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease Tae-Suk Kim a , Hyun-Kook Lim a , Ji Youl Lee b , Dai-Jin Kim a , Sanghi Park c , Chul Lee a , Chang-Uk Lee a,∗ a
Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea Department of Urology, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea c Clinical Medicine Research Institute, Holy Family Hospital, Pucheon City, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 15 January 2008 Received in revised form 22 February 2008 Accepted 10 March 2008 Keywords: Alzheimer’s disease Chemokine Fractalkine Mild cognitive impairment Pathogenesis
a b s t r a c t Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer’s disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzymelinked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD. © 2008 Elsevier Ireland Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and it is the most common form of dementia affecting individuals aged 65 years and older [13]. The deposition of amyloid beta (A) in the brain is known to induce a chronic inflammatory response, which may lead to neuronal death [8]. Considerable evidence has suggested that the inflammatory process may be associated with the pathology of AD. The inflammatory components in AD include various brain cells, such as microglia and astrocytes; the complement system; and various inflammatory mediators, including cytokines and chemokines [29]. The chemokines are a superfamily of chemotactic cytokines that are essential for the activation and migration of leukocytes in both physiological and pathological contexts [21]. The results of several in vivo and in vitro studies support the involvement of various chemokines, including monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1, in the pathogenesis of AD [11,15,30]. In the first study to evaluate chemokine involvement in patients with clinical mild cognitive impairment (MCI) and AD patients, Galimberti et al. (2006) found an increase in the level of
∗ Corresponding author. Tel.: +82 2 590 2789; fax: +82 2 536 8744. E-mail address: [email protected] (C.-U. Lee). 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.03.019
peripheral serum MCP-1 in patients with MCI and mild AD in comparison to healthy controls, but this increase in peripheral serum MCP-1 was not found in patients with severe AD, suggesting that MCP-1 may be an early biomarker of AD pathogenesis [5]. The novel CX3C chemokine, fractalkine, is a 373-amino acid protein that has a chemokine domain located on top of a mucinlike stalk [2]. Neurons are the primary source of fractalkine in the brain [6]. Fractalkine can exist in both membrane-bound and soluble forms [7]. While membrane-bound fractalkine can serve as an adhesion molecule for leukocytes expressing the fractalkine receptor CX3CR1 [10], soluble fractalkine can function as a pro-inflammatory chemoattractant that activates receptive inflammatory cells [2,17]. However, more recent studies have demonstrated that soluble fractalkine might have antiinflammatory effects because it suppresses the cytotoxic activity of NK cells, which is enhanced by the increased expression of membrane-bound fractalkine on endothelial cells [31]. Soluble fractalkine also has neuroprotective effects in reducing neuronal apoptosis [27]. Previous studies have investigated the relationship between soluble fractalkine in the peripheral blood and inflammatory diseases of the central nervous system (CNS); however, the results of these studies have been contradictory. Increased levels of serum fractalkine have been reported in patients with multiple
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sclerosis [12] and human immunodeficiency virus (HIV) with CNS complications [24], but these increased levels of serum fractalkine were not observed in patients with Guillain-Barre´ Syndrome and viral and bacterial meningitis [12]. Regarding the roles of fractalkine in AD pathogenesis, Streit et al (2001) [25] have hypothesized the loss of control of fractalkine over microglial activation, which has been considered a damaging process in AD pathogenesis. Also, Duan et al (2007) [4] have found the decreased fractalkine expression in cerebral cortex and hippocampus in aged brain of amyloid precursor protein (APP) transgenic mice. However, only a few studies have investigated the levels of soluble fractalkine in AD patients, especially in the peripheral blood. The various properties of soluble fractalkine and the lack of studies investigating the alternations of peripheral soluble fractalkine in AD prompted us to evaluate the levels of fractalkine in plasma samples from patients with MCI, which is regarded as a very early stage of AD [16], as well as in patients with AD and to compare the findings with those of healthy control subjects who did not have inflammatory diseases of the CNS. A total of 102 patients with cognitive impairment, including 51 patients with AD and 51 patients with MCI, who visited the Memory Disorders Clinic at Kangnam St. Mary’s Hospital between May 2006 and May 2007, were enrolled in the present study. Medical and psychiatric histories were obtained from each patient, and all patients underwent a series of standard clinical examinations, including physical, neurological and mental status examinations, laboratory screening tests, an electrocardiogram, neurocognitive tests, and brain magnetic resonance imaging. The Korean versions of the Mini-Mental Status Examination (MMSE) [18] were used to evaluate the severity of cognitive impairment in patients with MCI and AD. The diagnosis of AD was made in accordance with the criteria for dementia of the Alzheimer’s type outlined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [1], the guidelines of the National Institute of Neurological and Communicative Disorders and the Alzheimer’s Disease and Related Disorders Association criteria for probable AD [14]. Patients with vascular dementia or dementia due to medical conditions other than AD, or those with a score greater than 4 on the modified Hachinski Ischemic Rating Scale [22], were excluded from the study. Forty-eight patients were diagnosed with late-onset AD, and the other three patients were diagnosed with early-onset AD. The diagnosis of MCI was made according to the clinical criteria suggested by Petersen et al. [20]. Based on refined clinical criteria [19], 42 patients were classified as having the amnestic-MCI-single domain subtype of MCI and seven patients were classified as having the amnestic-MCI-multiple domain subtype of MCI. Two other patients were classified as having the non-amnestic-MCI-multiple domain subtype of MCI. The diagnoses of both AD and MCI were confirmed by the consensus of two board-certificated psychiatrists (H.K.L and C.U.L). The AD and MCI patients had no major medical illnesses, such as hypertension, diabetes, rheumatoid diseases, or cancer. There was no past or current history of major psychiatric illnesses, including major depression, schizophrenia, and bipolar disorder, in any of the patients. Fifty-seven healthy subjects were included in the control group. ‘Healthy’ was defined as a score of 26 or better on the MMSE, and the healthy subjects were determined to be nondemented by clinical assessment. Control subjects who had no individual or familial history of psychiatric disorders were recruited from the health promotion center in this hospital through an internal advertisement. The control subjects were aged 65 years or older. None of the subjects had a history of substance abuse, such as alcohol or nicotine abuse, within 6 months from the time of enrollment. None of the subjects were being treated with anti-inflammatory drugs at the time of the investigation. Informed consent was obtained from all
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Table 1 Demographic and clinical characteristics of 51 MCI patients, 51 AD patients, and 57 healthy control subjectsa Variables
MCI patients (n = 51)
AD patients (n = 51)
Healthy control subjects (n = 57)
Age (years)
74.6 ± 7.0
78.2 ± 6.1
70.5 ± 3.8
Gender, no. (%) Female
41 (80.4)
42 (82.4)
40 (70.2)
Body mass index (kg/m2 ) Education (years)
22.5 ± 3.1 6.2 ± 3.8
21.3 ± 2.9 5.4 ± 3.5
24.2 ± 3.4 6.9 ± 4.0
Marital status, no. (%) Married Separated Divorced Unmarried
24 (47.1) 25 (49.0) 2 (3.9) 0 (0.0)
22 (43.1) 27 (52.9) 2 (3.9) 0 (0.0)
29 (50.9) 22 (38.6) 3 (5.3) 3 (5.3)
Age at onset (years) Disease duration (years) MMSE score GDS score
73.5 ± 7.2 2.1 ± 1.1 22.1 ± 2.4 3.0 ± 0.0
76.0 ± 6.6 3.2 ± 1.7 15.3 ± 3.6 4.4 ± 0.7
– – 27.3 ± 1.0 1.8 ± 0.4
Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; MMSE, Mini-Mental Status Examination; GDS, Global Deterioration Scale; (–) not applicable. a Plus-minus values are mean ± standard deviation (S.D.).
subjects after they were given a complete description of the study. The Institutional Review Board of Kangnam St. Mary’s Hospital approved the study. Blood was obtained from the antecubital vein in all subjects between 8:00 and 9:00 a.m. after a fast of at least 8 h. The plasma samples were centrifuged and stored in a refrigerator at −70 ◦ C prior to the biochemical analyses. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay (ELISA). All reagents were obtained from Antigenix America (New York, NY). Briefly, 96-well polystyrene plates were coated overnight at 25 ◦ C with 1 g/ml purified goat IgG anti-human fractalkine antibody. After washing, the plates were blocked for 1 h at 20 ◦ C with an ELISA coating stabilizer and then removed for drying. Recombinant human fractalkine and plasma samples were added in duplicate, and the plates were incubated for 2 h at 20 ◦ C. After washing, the plates were incubated with biotinylated goat anti-human fractalkine antibody (250 ng/ml) for 2 h at 20 ◦ C and then with streptotavidin-peroxidase for 30 min at 20 ◦ C. Plasma samples were developed with 0.1 ml per well of tetramethylbenzidine substrate diluted in a citrate-phosphate buffer. The reactions were terminated by the addition of 1 mol/l H2 SO4 , and the plates were read at 450 nm. The limit of detection was 78 pg/ml. Values that fell short of this threshold were considered to be 78 pg/ml in the statistical analysis. The intraclass correlation coefficient (ICC) of plasma soluble fractalkine levels in duplicate measurements is 0.97. Group comparisons were performed using an unpaired t-test, and an analysis of variance (ANOVA), or an analysis of covariance (ANCOVA) when covariance was found. 2 -Analyses were conducted to compare categorical variables. Pearson correlation coefficients were calculated in order to assess the associations between the clinical data and plasma soluble fractalkine. The probability value (p) was set at <0.05. All statistical analyses were conducted using SAS (Statistical Analysis System), Version 9.1 (SAS Institute Inc., Cary, NC). There were no significant differences in gender, years of education, and marital status between the three groups (p = 0.263; p = 0.126; p = 0.307, respectively), but there were significant differences in age and body mass index (BMI, kg/m2 ) between the three groups (F = 24.4, p < 0.0001; F = 12.3, p < 0.0001, respectively) (Table 1).
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There was a significant difference in disease duration (t = −3.714, p < 0.0001) between the MCI and AD group, but there was no significant difference between the groups in age at onset (t = −1.866, p = 0.065, respectively) (Table 1). ANCOVA with adjustment for age and BMI revealed a significant group difference in the levels of plasma soluble fractalkine between the MCI group (n = 51, 384.2 ± 308.7 pg/ml), AD group (n = 51, 294.2 ± 207.7 pg/ml), and control group (n = 57, 172.5 ± 100.8 pg/ml) (F = 11.9, p = 0.0002, Fig. 1). Post hoc analyses using the Newman-Keuls test revealed significant differences between the MCI and control groups (p = 0.00002), the AD and control groups (p = 0.0043), and the MCI and AD groups (p = 0.034). ANCOVA revealed that the level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD (MMSE score >14, n = 30, 360.6 ± 237.0 pg/ml) than in the patients with severe AD (MMSE score ≤14, n = 21, 191.2 ± 80.9 pg/ml) after controlling for age and BMI (F = 3.48, p = 0.023, Fig. 1). Moreover, these findings were corroborated by a significant positive correlation between the MMSE scores and plasma soluble fractalkine levels in the patients with AD (r = 0.347, p = 0.013, Fig. 2). In the present study, the levels of plasma soluble fractalkine in patients with MCI and AD were found to be significantly increased in comparison to healthy control subjects. In addition, the patients with MCI had higher levels of plasma soluble fractalkine than the patients with AD. Fractalkine is a chemokine that plays the role of an inflammatory mediator. Considering that MCI may be a very early stage of AD, these findings support the early involvement of inflammation in the pathogenesis of AD and are in agreement with the findings of previous studies [13,29]. The increased levels of plasma soluble fractalkine in patients with MCI and AD may be attributable to the functional role of soluble fractalkine as an inflammatory mediator. Unlike most chemokines, which are highly expressed in leukocytes, the mRNA expression levels of fractalkine were determined to be highest in the heart and brain, and no fractalkine mRNA was observed in the peripheral blood [2]. The expression of fractalkine in the brain has been primarily observed in neurons and endothelial cells [23]. Fractalkine expression is reportedly restricted to the luminal endothelium in cerebral blood vessels [17], and it can be proteolytically cleaved by various proteases [28]. Thus, the release of soluble fractalkine from endothelial cells may be a primary source of fractalkine in the peripheral circulation. Soluble fractalkine has been suggested to act as a pro-inflammatory chemoattractant for T cells, NK cells, and monocytes during the early stage of AD [2].
Fig. 2. The MMSE scores showed a significant positive correlation with the levels of plasma soluble fractalkine in 51 patients with AD.
Thus, it may simply be postulated that increased plasma soluble fractalkine is related to the induction of the inflammatory process in the AD brain and may result from inflammatory processes in the AD brain. However, emerging evidence for the anti-inflammatory and even neuroprotective activities of soluble fractalkine [27,32] suggest the possibility of a better explanation for the increased levels of plasma soluble fractalkine in patients with cognitive impairment. If the inflammatory process leading to neuronal death or microvascular disruption occurs in the AD brain, the proteolytic release of soluble fractalkine from neurons and endothelial cells may increase in order to protect the brain from the insult, which may lead to increases in the levels of peripheral soluble fractalkine. However, the increased level of soluble fractalkine in the cerebrospinal fluid (CSF) of patients with AD should be confirmed in future studies in order to support this reasoning. In the present study, we also found that the level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD, and this finding was strengthened by a significant positive correlation between MMSE scores and plasma soluble fractalkine levels in patients with AD. These results suggest that the amount of plasma soluble fractalkine may decrease between the early and late stages of AD. In addition, these results are in agreement with previous findings that the level of serum MCP-1, which may have a neuroprotective effect, increases during the progression from MCI to early AD, but not during the progression from mild to severe AD [5]. These findings may partially support the hypothetical role of fractalkine in the pathogenesis of AD, especially in the interactions between neurons and microglia, as proposed by Streit et al (2001) [25]. In this study, the highest peaks of plasma soluble fractalkine were observed in patients with MCI, which is regarded as a turning point from normal aging to overt AD. Considering that CNS inflammation precedes the development of AD, it is reasonable to believe that the increased levels of soluble fractalkine may be specific to the early stages of AD [26]. Given the possible anti-inflammatory or neuroprotective activities of soluble fractalkine, the increased levels of soluble fractalkine during the early stages of AD may be related to an attempt of neurons and vascular endothelial cells to prompt microglia to phagocytose the -amyloid plaques [3]. However, after the disruptive inflammatory processes in the brain exceed the efforts to protect the normal brain environment, neurons and endothelial cells die away, resulting in decreased production of soluble fractalkine, as observed in the patients with severe AD. To solidify this description, further studies will be needed in order to investigate the levels of soluble fractalkine in the CSF of patients with MCI and AD. Prospective studies of the changes in the levels of soluble fractalkine during the progression from MCI to AD over time are also needed. To the best of our knowledge, this is the first study to investigate the levels of peripheral soluble fractalkine in clinical samples of patients with cognitive impairment. Several limitations should be noted when interpreting our results. First, since diet may be a confounding factor in the interpretation of chemokine alteration [9], the patient and control groups were matched according nutrition status, as indirectly evidenced by BMI. Although the mean BMI score of the patients was lower than that of the healthy controls, most of the AD patients were well nourished, as their BMI scores were in the normal or overweight range. However, the findings from this study do not exclude the possibility that plasma fractalkine may be modified by dietary factors that are not reflected by BMI. Second, anti-dementia medication, which might affect the levels of plasma soluble fractalkine, was not completely excluded as a possible confounding factor. Fourteen of the AD patients (27.5%) had taken one or more anti-dementia medications (donepezil, n = 8; galantamine, n = 3; memantine, n = 2; donepezil + memantine, n = 1),
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Fig. 1. The levels of plasma soluble fractalkine in patients with MCI, patients with AD and healthy control subjects. The patients with AD were divided into two groups: those with mild to moderate AD and those with severe AD. The horizontal bars represent mean values, with statistically significant differences between the groups indicated.
whereas none of the MCI patients had taken any anti-dementia medication. In conclusion, our findings showed that patients with MCI and AD had higher levels of plasma soluble fractakline than healthy control subjects. In addition, the patients with mild to moderate AD had higher levels of plasma soluble fractalkine than the patients with severe AD. This study provides preliminary evidence that soluble fractalkine is likely to play some important roles in the pathogenesis of AD.
[11]
[12]
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Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079).
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