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April2013 Vol.50 Issue:      2 Table of Contents
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Role of Serum and Cerebrospinal Fluid Cytokines in Differentiation of Vascular Cognitive Impairment and Mild Cognitive Impairment

Mohamed S. El-Tamawy1, Tarek Z. Tawfik1, Shereen Fathy1, Reem J. Farid2,

Sandra M. Ahmed1, Gihan A. Sleem3, Yasmine S. Kamal1

Departments of Neurology1, Clinical Patholology2, Internal Medicine3; Cairo University; Egypt



ABSTRACT

Background: Although Alzheimer’s (AD) dementia was considered to be the most common form of dementia, vascular cognitive impairment has been found to be more common than previously thought. Inflammatory cytokines has been proved to be related to both mild cognitive impairment (MCI) and vascular cognitive impairment (VCI). Objective: Find a difference in inflammatory cytokines between MCI and VCI and the possibility to use them as biomarkers to differentiate between them. Methods: Thirty-seven Egyptian patients with variable degree of cognitive impairment were included. Patients were primary selected using the mini-mental state examination. Patients were divided into two groups (MCI) and (VCI) by NINDS-AIREN criteria and MRI brain. Serum was analyzed for CRP, IL-1B, IL-6 and IL-16 and CSF analyzed for IL-1β, IL-6, IL-16. Results: No difference was found in proportion of patients with abnormally elevated serum level of IL-1β, IL-6, IL-16 and C-reactive protein (CRP) between both groups. IL-6 was found abnormally elevated in a higher proportion of patients with MCI compared to patients with VCI. Conclusion: IL-6 elevation in CSF of MCI may be used as a biomarker to differentiate it from VCI. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 195-198]

 Key Words: Mild cognitive impairment, vascular cognitive impairment, cytokines, inteleukin-6.

Correspondence to Shereen Fathi, Department of Neurology, Cairo University, Egypt. Tel.: +201113022610     e-mail: shereenfathi@gmail.com




INTRODUCTION

 

Dementia is a syndrome that involves a large number of distinctive brain disorders. Although memory dysfunction is the basis of most formal definitions of dementia, cognitive impairment other than memory still can cause serious impairment of patient functioning1.

Alzheimer’s (AD) dementia was considered to be the most common form of dementia but recent studies came to the conclusion that vascular-associated cognitive decline was found to be more common than previously thought either in isolation or associated with a neurodegenerative condition2,3. The differentiation between  vascular dementia (VaD) and  Alzheimer’s (AD) is not easy because VaD is a heterogeneous clinical entity including various subtypes of cerebrovascular disease  based on different vascular pathology4.

In the past decades a body of evidence has stressed the role of inflammation in the pathophysiology of acute brain ischemia5 and more recently these inflammatory cytokines had been related to the worse outcome of both ischemic and hemorrhagic stroke patients like elevation of C-reactive protein (CRP) and interleukin-6 (IL-6)6,7. These cytokines were proved to increase and being positively correlated to the presence of VaD8.

Aim of this study is to prove the role of inflammatory cytokines in the differentiation of vascular cognitive impairment (VCI) and mild cognitive impairment (MCI).

 

SUBJECTS AND METHODS

 

This study included 37 Egyptian patients recruited from the neurology outpatient clinic of Cairo University Hospital. We included any patients age >44 years presenting with history suggestive of cognitive impairment ranging from mild to severe (dementia). Preliminary selection and assessment was done using the mini-mental state examination (MMSE). Patients included were patients with score <28 for educated and score <26 for non-educated subjects. We excluded patients with any history of medical or psychiatric troubles. These patients were further subdivided into vascular cognitive impairment and mild cognitive impairment(MCI) using Petersen criteria for diagnosis of MCI9 NINDS-AIREN criteria for diagnosis of vascular dementia10. Magnetic resonance imaging was performed for all patients for further differentiation of VCI of MCI11. Montreal Cognitive Assessment was used to assess severity of cognitive impairment in both group12.

 

All patients underwent both serum and cerebro-spinal fluid (CSF) analysis for different cytokines. Samples were centrifuged and frozen at -20 °C.  In serum we measured C-reactive protein (CRP), Interleukin 1 beta (IL-1B), Interleukin 6 (IL-6) and Interleukin 16 (IL-16). In CSF we measured IL-1β, IL-6, IL 16 analyzed by ELISA enzyme linked immune-sorbant assay (Ani Bio tech, Orgenium, Finland).

 

Statistical Analysis

Data were statistically described in terms of mean ± standard deviation (± SD), frequencies (number of cases) and percentages when appropriate. Comparison of age between the study groups was done using Student t test for independent samples. For comparing categorical data, Chi square (c2) test was performed. Exact test was used instead when the expected frequency is less than 5. A probability value (p value) less than 0.05 was considered statistically significant. All statistical calculations were done using computer programs Microsoft Excel 2007 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows.

 

RESULTS

 

Our 37 Egyptian patients were subdivided into two groups; Vascular cognitive impairment (VCI) (n=26) and mild cognitive impairment (MCI) (n=11). Both groups were age matched [SH2] VCI age 55.62±10.04 and MCI age 55.18±10.72, (P>0.05). They were also sex matched showing male predominance in both groups; VCI 84.6% and MCI 72.7%. [SH3] 

Descriptive data of both groups showed a higher proportion of patients with elevated triglycerides in VCI group compared to MCI group (P=0.011). Other risk factors didn’t show any statistical significant difference between both groups as shown in Table (1).

The proportion of patients with abnormal serum level of IL-1β, IL-6, IL-16 and C-reactive protein (CRP) showed no statistically significant difference between the 2 groups (p>0.05) as shown in Table (2).

Cerebrospinal fluid (CSF) analysis of IL-1B, IL-6 and IL-16 [SH4] showed only a statistically significant increase in proportion of patients with abnormally elevated IL-6 in MCI group compared to VCI group (P=0.016). IL-1B and IL-16 didn’t show any statistically significant difference between both groups as shown in Table (3).[SH5] 


 

Table 1. Comparison between proportion of patients with different risk factors in both (VCI) and (MCI) groups.

 

 

Group

P-value[SH6] 

VCI

MCI

HTN

Count

8

6

0.161

% within Group

30.8%

54.5%

Diabetes

Count

10

2

0.260

% within Group

38.5%

20.0%

LDL

Count

1

0

0.703

% within Group

3.8%

0.0%

HDL

Count

1

0

0.703

% within Group

3.8%

0.0%

Cholesterol

Count

6

1

0.310

% within Group

23.1%

9.1%

TGs

Count

17

2

0.011*

% within Group

65.4%

18.2%

Cardiac

Count

5

0

0.151

% within Group

19.2%

0.0%

Carotid artery disease

Count

7

4

0.420

% within Group

26.9%

36.4%

* Statistically significant at P>0.05

 

Table 2. Comparison between proportions of patients with abnormally elevated serum cytokines (IL-1β, IL-6, IL-16 and CRP) in both (VCI) and (MCI) groups.

 

 

% within Group

Group

P value

VCI

MCI

65.4%

18.2%

IL-1β

Count

1

1

0.281

% within Group

3.8%

9.1%

IL-6

Count

10

7

0.267

% within Group

38.5%

63.6%

IL-16

Count

8

3

0.985

% within Group

30.8%

27.3%

CRP

Count

11

4

0.479

% within Group

44.0%

36.4%

 

Table 3. Comparison between proportions of patients with abnormally elevated CSF cytokines (IL-1β, IL-6 and IL-16) in both (VCI) and (MCI) groups.

 

 

Group

P-value

VCI

MCI

IL-1B-CSF

Count

3

1

0.533

% within Group

12.5%

9.1%

IL6-CSF

Count

11

10

0.016*

% within Group

45.8%

90.9%

IL16-CSF

Count

19

9

0.806

% within Group

79.2%

81.8%

* Statistically significant at P>0.05

 

 


DISCUSSION

 

Our study showed that there was no difference in serum level of IL-1β, IL-6, IL-16 and CRP between both groups. CSF examination of IL-1β, IL-6 and IL-16 showed only a significant increase in IL-6 in patients with mild cognitive impairment (MCI) compared to patients with vascular cognitive impairment (VCI). 

Patient group with vascular cognitive impairment (VCI) showed a higher level of triglyceride compared to those with mild cognitive impairment (MCI). Triglyceride has previously been shown to be a risk factor for cognitive impairment either through direct affection of hippocampal N-methyl-d-aspartate component of  long-term potentiation (13) or as a part of metabolic syndrome which was proved to be a risk factor for vascular dementia14.

Serum level of different cytokines in serum did not show any difference between the two groups. This agree with Uslu et al.15, who found only a difference in serum level of  amyloid beta – 42 peptide (Aβ42) between Alzeheimer’s dementia and vascular dementia but did not find any difference between serum level of TNF-α or IL-6.

In this study we found that IL-6 in CSF was more elevated in patients with MCI relative to patients with VCI. It has been proved that interleukin-6 has a role in cognitive functions even in healthy adults in the absence of vascular risk factors16. Its role in vascular and mild cognitive impairment was demonstrated but with no significant difference in the level between both groups15. It was suggested that elderly AD and dementia patients have an altered immune profile with higher circulating levels of IL6 than their non-demented peers but whether this was a reflection of inflammatory processes in the brain or a consequence of peripheral immunological alterations due to disease was not established17.

Considering the IL-6 as a biomarker for either type of cognitive impairment has been debated and studied. CSF IL-6 has been proved to be a biomarker of vascular dementia in some studies18 and decreased in AD patients19. Although CSF IL-6 has not been proved to be a biomarker in diagnosis of mild cognitive impairment it has been shown to be a biomarker of progression of inflammatory process20. Further staging and categorization of cognitive functions of our patients was needed to get more accurate results.

In conclusion we found that CSF IL-6 was abnormally elevated in a higher proportion of patients with MCI compared to the group of patients with VCI. Yet we cannot assure its usefulness as a biomarker for MCI diagnosis and differentiation from VCI. More categorization of cognitive dysfunction is needed as IL-6 level varies in different stage of the disease.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

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7.      Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, et al. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med. 2009; 6(9): e1000145.

8.      Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, et al. Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res. 2007; 41(8): 686-93.

9.      Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999; 56(3): 303-8.

10.    Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993; 43(2): 250-60.

11.    Jack CR, Petersen RC, Xu YC, O'Brien PC, Smith GE, Ivnik RJ, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999; 52(7): 1397-403.

 

12.    Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005; 53(4): 695-9.

13.    Farr SA, Yamada KA, Butterfield DA, Abdul HM, Xu L, Miller NE, et al. Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology. 2008; 149(5): 2628-36.

14.    Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C, et al. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-City Study. Diabetes Care. 2009; 32(1): 169-74.

15.    Uslu S, Akarkarasu ZE, Ozbabalik D, Ozkan S, Colak O, Demirkan ES, et al. Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer's disease and vascular dementia. Neurochem Res. 2012; 37(7): 1554-9.

16.    Sasayama D, Hori H, Teraishi T, Hattori K, Ota M, Matsuo J, et al. Association of cognitive performance with interleukin-6 receptor Asp358Ala polymorphism in healthy adults. J Neural Transm. 2012; 119(3): 313-8.

17.    Eriksson UK, Pedersen NL, Reynolds CA, Hong MG, Prince JA, Gatz M, et al. Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer's disease and dementia. J Alzheimers Dis. 2011; 23(2): 361-9.

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الملخص العربى

 

يعتبر مرض ألزهايمر هو المرض الأكثر شيوعا الذى يؤثر على الوظائف الذهنية. تبين حديثا أن أمراض الشرايين والجلطات المخية قد تكون أكثر شيوعا مما نتوقع. ـتهدف هذه الدراسة إلى محاولة التفرقة ما بين تدهور الوظائف الذهنية الناتجة عن تنكس الخلاية العصبية وأمراض الشرايين بالمخ باستخدام السيتوكينات كمؤشرات حيوية. تتضمن هذه الدراسة 37 مريض تتفاوت درجة تدهور قدراتهم الذهنية. تم تقسيمهم إلى مجموعتين إحداهما تعانى التنكس الخلوى للخلاية العصبية والأخرى تعانى من أمراض الشرايين المزمنة  بالمخ. تم قياس السيتوكينات بالدم والسائل النخاعى فى كلا المجموعتين. لم تتمكن الدراسة من اثبات وجود فرق ما بين السيتوكينات فى الدم بين المجموعتين. اظهر السائل النخاعى وجود فرق ذو دلالة إحصائية فى الإنترلوكين-6 فقط حيث إنه تبين وجوده بصورة أعلى فى مرضى التنكس الخلوى للخلاية العصبية.



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