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Etemadifar M, Ghadimi M, Ghadimi K, Alsahebfosoul F. The Serum Amyloid β Level in Multiple Sclerosis: A Case- Control Study . Caspian.J.Neurol.Sci. 2017; 3 (11) :214-221
URL: http://cjns.gums.ac.ir/article-1-204-en.html
1- Iranian Multiple Sclerosis and Neuroimmunology Research Center, Isfahan, Iran
2- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3- Iranian Multiple Sclerosis and Neuroimmunology Research Center, Isfahan, Iran; keyvanghadimi@yahoo.com
4- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Introduction
Multiple sclerosis (MS) is one of the most common chronic inflammatory diseases in the central nervous system (CNS), which demyelination, destruction or loss of axons, and gliosis are its major characteristics. About 2.5 million people deal with MS worldwide (1) and in spite of a multitude of studies on the disease, its etiology as well as pathophysiology remained unknown.MS is usually considered as a demyelinating while-matter disease and there is substantial evidence on the loss of axons and neurons in clinical stages of the disease based the pathophysiological findings; in other words, there is a direct correlation between the damage to axons and severity of MS (2). Also, neuron destruction plays a major role in the incidence of physical and cognitive disabilities (3). However, MS is diagnosed by the cerebrospinal fluid (CSF) findings as well as magnetic resonance imaging (MRI) analyses, and rejection of other suspicious diseases. The most common type of the disease is called relapsing-remitting MS (RRMS); in addition, other forms of the disease include secondary-progressive MS (SPMS), primary-progressive MS (PPMS), and progressive-relapsing MS (PRMS). Patients with RRMS experience attack and remission episodes, which indicate defective demyelination. The capacity of demyelination is reduced over time, particularly in SPMS cases (4,5). Recently several studies were conducted on the impact of amyloid protein precursor (APP) and its destructive product, amyloid β (Aβ), on Alzheimer’s disease (AD) and reported that the reduction of Aβ level in CSF has a diagnostic value in AD. In spite of AD,  the  level  of  APP  metabolites  in  CSF,
including Aβ peptides, soluble APP (sAPP), α-sAPP, and β-s, are also reduced in CNS inflammatory diseases such as Lime disease, opportunistic infections in patients with HIV, acute bacterial meningitis, systemic lupus erythematosus, and MS (7-11). Some studies indicated that in the active form of MS, active demyelination, the activity of APP is high; however, it is not in chronic MS, the inactive form of the disease. Hence, APP metabolism varies in different stages of the disease (12). In addition, Aβ has positive regulatory effect in chronic and active lesions and is considered as a sensitive immunohistochemical marker in axon damage (13,14). On the other hand, former studies suggested a protective role for the increased serum Aβ in the rat models of MS (15). Hence, due to the role of Aβ in both acute and chronic phases of MS disease and lack of data on the serum level of Aβ in patients with MS, particularly RRMS, the current study aimed at evaluating and comparing the serum level of Aβ between the patients with RRMS and the healthy controls.
Materials and Methods
Subjects:
The current case-control study was authorized by the Vice President of Research of Isfahan University of Medical Sciences (code number: 395371) and a total of 48 eligible patients with RRMS (30 females and 18 males, mean ages 34.45±9.52 years) who met the inclusion criteria were selected out of the patients who referred to MS Center of Isfahan, Iran, from 2014 to 2016. The inclusion criteria were patients with RRMS within the age range of 16 to 60 years who were   diagnosed   based  on  the  McDonald’s
criteria (2010) (16) as well as clinical signs and symptoms, brain magnetic resonance image (MRI) and CSF findings, expanded disability status scale (EDSS) <5 with a stable conditions a month prior to the study, being under the treatment with the first line immunomodulatory drugs, and being in recovery period. All subjects should sign the written informed consent form. The subjects who were in the relapsing period during the last 3 months or had the history of inflammatory diseases, except MS, were excluded. In addition, 33 healthy controls (22 females and 11 males, 35.78±10.85 years) were recruited out of 220 healthy people with normal neurologic status and lack of the history of inflammatory, autoimmune or neurologic diseases who referred to the Iranian Blood Transfusion Organization (IBTO) in 2014. All neurologic experiments were performed by a neurologist in the both patients and healthy controls. Case and control groups were matched by age and gender.
MS severity was assessed by EDSS; it has direct correlation with MS severity and lower scores indicate mild MS and all patients with lower EDSS scores show normal symptoms. But, by increasing EDSS scores the severity of symptoms also increases in such extents that score 10 causes death (17). In addition, demographic data of the patients including age and gender were also recorded.
Four-mL blood specimens were taken from the case and control subjects by a routineblood collection method without adding anti-coagulant agent. The serum samples of the subjects were separated and stored at -20°C until it was tested. The serum levels of Aβ (pg/mL) were measured by the enzyme-linked immunosorbent assay (ELISA) technique according to the instructions of the manufacturer (Convance, Princeton, NJ, USA).
 
Statistical analysis:
Data of the current study was entered into SPSS version 24. The Kolmogorov-Smirnov test was used to assess the normality of data. To compare the case and control groups, chi-square and independent t test were used. In addition, the Pearson correlation was used to evaluate the correlation between the data. The qualitative data were expressed as numbers or percentages and the quantitative data as mean±standard deviation (SD); p<0.05 was considered as the level of significance.
 
Results
In the current study, there were no significant differences between RRMS patients and healthy control regarding to gender (p=0.70) and age (p=0.46).The mean of EDSS and duration of disease in the RRMS patients were 2.04±1.40 and 4.15±3.34 years, respectively (table 1).

 

The means of serum Aβ level were 192.75±125.65 and 128.11±85.20 pg/mL in the RRMS and control groups, respectively; it was significantly higher in the RRMS group compared with the controls (p=0.02) (figure 1).
In addition, a positive significant correlation was observed between EDSS and serum Aβ level (r= +0.85, p<0.01) (figure 2),
although there were no significant correlation between the serum Aβ level with age (p=0.81), gender (p=0.89), and duration of illness (p=49).

 
Discussion
According to the results of the current study, the serum Aβ level was above normal limits in MS patients. Also, the positive significant correlation between EDSS and serum Aβ level indicated that by increasing the severity of MS (increased EDSS or disability) the serum Aβ level also increases. As mentioned before, the level of Aβ decreases in the CSF of patients with MS (10). According to the study conducted by Augutis et al. (18) the levels of Aβ and sAPP in CSF were assessed in 87 patients with MS, including 54 RRMS and 33 SPMS cases, and 28 healthy controls using ELISA technique. The patients were also received natalizumab and mitoxantrone for 1-2 years. They indicated that the level of Aβ and sAPP in CSF of the patients with MS reduced, but the serum level of Aβincreased in patients with MS following the treatment with natalizumab.
They concluded that treatment with natalizumab may neutralize and make changes in the metabolism of APP in patients with MS. Also, they found an isoform distribution profile for Aβ in the CSF of the ones with SPMS, which differentiated them from the healthy controls. In another study by Pietroboni et al. (19) on 48 recently diagnosed MS subjects, the serum Aβ level was measured in the beginning of the study in all subjects; the test was also repeated after a 3-year follow-up and their EDSS scores were recorded at 6-month intervals. Results showed that the Aβ level in CSF was lower in MS patients compared with the healthy controls; based on the results of a 3-year follow-up, lower levels of Aβ in CSF of the patients with MS implied a prognostic factor for disability. In addition, they concluded that decrease of Aβ in CSF can be considered as adiagnostic marker for neurodegeneration in MS disease, which may occur prior to clinical symptoms; hence, Aβ can affect the prognosis of the disease.
In a study by Mai (20), the level of Aβ42 and the soluble form of αAPP or αsAPP in CSF were measured in 42 patients with MS, 10 subjects with neuromyelitisoptica, and 25 subjects with clinically isolated syndrome, as well as 21 healthy controls. Results of his study indicated no significant correlation between the patients and healthy controls in the level of Aβ42 and soluble form of αAPP in CSF. Also, the level of αsAPP in CSF of the patients undergone statin therapy was significantly higher than the ones not received such treatment; hence, the authors suggested a neuroprotective role for statin. Another study evaluated the association between cognitive disorder and cortical plasticity with the changes of Aβ level in CSF of patients with MS and the results indicated that the inflammation of CNS in MS disease makes changes in the metabolism of Aβ, which results in the reduction of Aβ in CSF as well as cognitive and synaptic plasticity impairments (21). Claner (22) in a study showed that APP particularly caused demyelination in MS studies in vitro; in addition, they indicated that astrocytes play a key role in the pathogenesis mechanism of demyelination. Some studies measured the serum level of amyloid A (AA) in patients with MS. For example, in a study by Yokote (23) who suggested AA as factor for T-helper 17 (Th17), which can participate in the pathogenesis of the disease in critical conditions and its amount was high in neuromyelitis optica cases compared with the patients with RRMS and healthy controls, respectively. He suggested the association between serum level of AA and clinical
phenotypes. In a study by Ristori et al. (24) the serum level of AA was measured in patients with RRMS. They concluded that the increase of serum AA level is attributed to the progressive peripheral inflammation; in fact, serum AA increase was one of the prognostic signs of progressive peripheral inflammation in their study. A case report also indicated the amyloid in the demyelinated plaques in MS (25).
 
Conclusion
Since according to the results of similar studies, the CSF level of Aβ decreases in patients with MS, which some studies attributed it to the inflammation of CNS or the progression of peripheral inflammation, based on the results of the current study, the serum level of Aβ increases in patients with MS compared with the healthy controls; serum Aβ level also increases in the ones with more severe MS or disabilities (higher scores of EDSS or critical inflammatory conditions following the demyelination) and play a pro-inflammatory role in the pathogenesis of MS disease, particularly RRMS. Owing to the limitations of the current study, such as small sample size and not including other types of MS to measure serum level of Aβ, further studies seems necessary. The current study was the first in Iran that evaluated the serum level of Aβ in patients with RRMS.

Conflict of Interest
The authors have no conflict of interest.

References
1. Steinman L. Immunology of Relapse and
Remission in Multiple Sclerosis. Annu Rev
Immunol 2014; 32:257-81. 

2. Frischer JM, Bramow S, Dal-Bianco A,
Lucchinetti CF, Rauschka H, Schmidbauer M,
et al. The Relation between Inflammation and
Neurodegeneration in Multiple Sclerosis
Brains. Brain 2009;132(5):1175-89.

3. Bjartmar C, Kidd G, Mörk S, Rudick R,
Trapp BD. Neurological Disability Correlates
with Spinal Cord Axonal Loss and Reduced
N‐acetyl Aspartate in Chronic Multiple
Sclerosis Patients. Ann Neurol
2000;48(6):893-901.

4. Kuhlmann T, Miron V, Cuo Q, Wegner C,
Antel J, Brück W. Differentiation Block of
Oligodendroglial Progenitor Cells as a Cause
for Remyelination Failure in Chronic Multiple
Sclerosis. Brain 2008;131(7):1749-58.

5. Lucchinetti CF, Brueck W, Rodriguez M,
Lassmann H. Multiple Sclerosis: Lessons
from Neuropathology. Semin Neurol
1998;18(3):337-49.

6. Blennow K, Hampel H, Weiner M, Zetterberg
H. Cerebrospinal Fluid and Plasma
Biomarkers in Alzheimer Disease. Nat Rev
Neurosci 2010;6(3):131-44.

7. Gisslén M, Krut J, Andreasson U, Blennow K,
Cinque P, Brew BJ, et al. Amyloid and tau
Cerebrospinal Fluid Biomarkers in HIV
Infection. BMC Neurol 2009;9(1):63.

8. Sjögren M, Gisslén M, Vanmechelen E,
Blennow K. Low Cerebrospinal Fluid β-
amyloid 42 in Patients with Acute Bacterial
Meningitis and Normalization after
Treatment. Neurosci Lett 2001;314(1):33-6.

9. Trysberg E, Höglund K, Svenungsson E,
Blennow K, Tarkowski A. Decreased Levels
of Soluble Amyloid β-protein Precursor and
β-amyloid Protein in Cerebrospinal Fluid of
Patients with Systemic Lupus Erythematosus.
Arthritis Res Ther 2004;6(2):R129- R36.

10. Mattsson N, Axelsson M, Haghighi S,
Malmeström C, Wu G, Anckarsäter R, et al.
Reduced Cerebrospinal Fluid BACE1
Activity in Multiple Sclerosis. Mult Scler J
2009;15(4):448-54.

11. Mattsson N, Bremell D, Anckarsäter R,
Blennow K, Anckarsäter H, Zetterberg H, et
al. Neuroinflammation in Lyme
Neuroborreliosis Affects Amyloid
Metabolism. BMC Neurol 2010;10(1):51.

12. Gehrmann J, Banati RB, Cuzner ML,
Kreutzberg GW, Newcombe J. Amyloid
Precursor Protein (APP) Expression in
Multiple Sclerosis Lesions. Glia
1995;15(2):141-51.

13. Trapp BD, Peterson J, Ransohoff RM, Rudick
R, Mörk S, Bö L. Axonal Transection in the
Lesions of Multiple Sclerosis. N Engl J Med
1998;338(5):278-85.

14. Ferguson B, Matyszak MK, Esiri MM, Perry
VH. Axonal Damage in Acute Multiple
Sclerosis Lesions. Brain 1997;120(3):393-9.

15. Grant JL, Ghosn EEB, Axtell RC, Herges K,
Kuipers HF, Woodling NS, et al. Reversal of
Paralysis and Reduced Inflammation from
Peripheral Administration of β-amyloid in
TH1 and TH17 Versions of Experimental
Autoimmune Encephalomyelitis. Sci Transl
Med 2012;4(145):145ra05.

16. Polman CH, Reingold SC, Banwell B, Clanet
M, Cohen JA, Filippi M, et al. Diagnostic
Criteria for Multiple Sclerosis: 2010
Revisions to the McDonald Criteria. Ann
Neurol 2011;69(2):292-302.

17. Ziemssen T. Multiple Sclerosis Beyond
EDSS: Depression and Fatigue. J Neurol Sci
2009; 277 Suppl 1:S37-41.

18. Augutis K, Axelsson M, Portelius E,
Brinkmalm G, Andreasson U, Gustavsson
MK, et al. Cerebrospinal Fluid Biomarkers of
β-amyloid Metabolism in Multiple Sclerosis.
Mult Scler J 2013;19(5):543-52.

19. Pietroboni AM, Schiano di Cola F, Scarioni
M, Fenoglio C, Spanò B, Arighi A, et al. CSF
β-amyloid as a Putative Biomarker of Disease
Progression in Multiple Sclerosis. Mult Scler
2016;23(8):1085-91.

20. Mai W, Hu X, Lu Z, Peng F, Wang Y.
Cerebrospinal Fluid Levels of Soluble
Amyloid Precursor Protein and β-amyloid 42
in Patients with Multiple Sclerosis,
Neuromyelitis Optica and Clinically Isolated
Syndrome. J Int Med Res 2011;39(6):2402-
13.

21. Mori F, Rossi S, Sancesario G, Codecà C,
Mataluni G, Monteleone F, et al. Cognitive
and Cortical Plasticity Deficits Correlate with
Altered Amyloid-β CSF Levels in Multiple
Sclerosis. Neuropsychopharmacology
2011;36(3):559-68.

22. Clarner T, Buschmann JP, Beyer C, Kipp M.
Glial Amyloid Precursor Protein Expression
Is Restricted to Astrocytes in an Experimental 
Toxic Model of Multiple Sclerosis. J Mol
Neurosci 2011;43(3):268-74.

23. Yokote H, Yagi Y, Watanabe Y, Amino T,
Kamata T, Mizusawa H. Serum Amyloid A
Level Is Increased in Neuromyelitisoptica and
Atypical Multiple Sclerosis with Smaller T2
Lesion Volume in Brain MRI. J
Neuroimmunol 2013;259(1):92-5.

24. Ristori G, Laurenti F, Stacchini P, Gasperini
C, Buttinelli C, Pozzilli C, et al. Serum
Amyloid A Protein Is Elevated in Relapsing–
remitting Multiple Sclerosis. J Neuroimmunol
1998;88(1):9-12.

25. Schroder R, Nennesmo I, Linke RP. Amyloid
in a Multiple Sclerosis Lesion Is Clearly of A
Lambda Type. Acta Neuropathol
2000;100(6):709-11.
Type of Study: Research | Subject: Special
Received: 2017/11/30 | Accepted: 2017/11/30 | Published: 2017/11/30

References
1. Steinman L. Immunology of Relapse and Remission in Multiple Sclerosis. Annu Rev Immunol 2014; 32:257-81 [DOI:10.1146/annurev-immunol-032713-120227] [PMID]
2. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The Relation between Inflammation and Neurodegeneration in Multiple Sclerosis Brains. Brain 2009;132(5):1175-89. [DOI:10.1093/brain/awp070] [PMID] [PMCID]
3. Bjartmar C, Kidd G, Mörk S, Rudick R, Trapp BD. Neurological Disability Correlates with Spinal Cord Axonal Loss and Reduced N‐acetyl Aspartate in Chronic Multiple Sclerosis Patients. Ann Neurol 2000;48(6):893-901. https://doi.org/10.1002/1531-8249(200012)48:6<893::AID-ANA10>3.0.CO;2-B [DOI:10.1002/1531-8249(200012)48:63.0.CO;2-B]
4. Kuhlmann T, Miron V, Cuo Q, Wegner C, Antel J, Brück W. Differentiation Block of Oligodendroglial Progenitor Cells as a Cause for Remyelination Failure in Chronic Multiple Sclerosis. Brain 2008;131(7):1749-58. [DOI:10.1093/brain/awn096] [PMID]
5. Lucchinetti CF, Brueck W, Rodriguez M, Lassmann H. Multiple Sclerosis: Lessons from Neuropathology. Semin Neurol 1998;18(3):337-49. [DOI:10.1055/s-2008-1040885] [PMID]
6. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal Fluid and Plasma Biomarkers in Alzheimer Disease. Nat Rev Neurosci 2010;6(3):131-44. [DOI:10.1038/nrneurol.2010.4]
7. Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, et al. Amyloid and tau Cerebrospinal Fluid Biomarkers in HIV Infection. BMC Neurol 2009;9(1):63. [DOI:10.1186/1471-2377-9-63] [PMID] [PMCID]
8. Sjögren M, Gisslén M, Vanmechelen E, Blennow K. Low Cerebrospinal Fluid β-amyloid 42 in Patients with Acute Bacterial Meningitis and Normalization after Treatment. Neurosci Lett 2001;314(1):33-6. [DOI:10.1016/S0304-3940(01)02285-6]
9. Trysberg E, Höglund K, Svenungsson E, Blennow K, Tarkowski A. Decreased Levels of Soluble Amyloid β-protein Precursor and β-amyloid Protein in Cerebrospinal Fluid of Patients with Systemic Lupus Erythematosus. Arthritis Res Ther 2004;6(2):R129- R36. [DOI:10.1186/ar1040] [PMID] [PMCID]
10. Mattsson N, Axelsson M, Haghighi S, Malmeström C, Wu G, Anckarsäter R, et al. Reduced Cerebrospinal Fluid BACE1 Activity in Multiple Sclerosis. Mult Scler J 2009;15(4):448-54. [DOI:10.1177/1352458508100031] [PMID]
11. Mattsson N, Bremell D, Anckarsäter R, Blennow K, Anckarsäter H, Zetterberg H, et al. Neuroinflammation in Lyme Neuroborreliosis Affects Amyloid Metabolism. BMC Neurol 2010;10(1):51. [DOI:10.1186/1471-2377-10-51] [PMID] [PMCID]
12. Gehrmann J, Banati RB, Cuzner ML, Kreutzberg GW, Newcombe J. Amyloid Precursor Protein (APP) Expression in Multiple Sclerosis Lesions. Glia 1995;15(2):141-51. [DOI:10.1002/glia.440150206] [PMID]
13. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal Transection in the Lesions of Multiple Sclerosis. N Engl J Med 1998;338(5):278-85. [DOI:10.1056/NEJM199801293380502] [PMID]
14. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal Damage in Acute Multiple Sclerosis Lesions. Brain 1997;120(3):393-9. [DOI:10.1093/brain/120.3.393] [PMID]
15. Grant JL, Ghosn EEB, Axtell RC, Herges K, Kuipers HF, Woodling NS, et al. Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of β-amyloid in TH1 and TH17 Versions of Experimental Autoimmune Encephalomyelitis. Sci Transl Med 2012;4(145):145ra05.
16. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Ann Neurol 2011;69(2):292-302. [DOI:10.1002/ana.22366] [PMID] [PMCID]
17. Ziemssen T. Multiple Sclerosis Beyond EDSS: Depression and Fatigue. J Neurol Sci 2009; 277 Suppl 1:S37-41. [DOI:10.1016/S0022-510X(09)70011-5]
18. Augutis K, Axelsson M, Portelius E, Brinkmalm G, Andreasson U, Gustavsson MK, et al. Cerebrospinal Fluid Biomarkers of β-amyloid Metabolism in Multiple Sclerosis. Mult Scler J 2013;19(5):543-52. [DOI:10.1177/1352458512460603] [PMID]
19. Pietroboni AM, Schiano di Cola F, Scarioni M, Fenoglio C, Spanò B, Arighi A, et al. CSF β-amyloid as a Putative Biomarker of Disease Progression in Multiple Sclerosis. Mult Scler 2016;23(8):1085-91. [DOI:10.1177/1352458516674566] [PMID]
20. Mai W, Hu X, Lu Z, Peng F, Wang Y. Cerebrospinal Fluid Levels of Soluble Amyloid Precursor Protein and β-amyloid 42 in Patients with Multiple Sclerosis, Neuromyelitis Optica and Clinically Isolated Syndrome. J Int Med Res 2011;39(6):2402-13. [DOI:10.1177/147323001103900641] [PMID]
21. Mori F, Rossi S, Sancesario G, Codecà C, Mataluni G, Monteleone F, et al. Cognitive and Cortical Plasticity Deficits Correlate with Altered Amyloid-β CSF Levels in Multiple Sclerosis. Neuropsychopharmacology 2011;36(3):559-68. [DOI:10.1038/npp.2010.187] [PMID] [PMCID]
22. Clarner T, Buschmann JP, Beyer C, Kipp M. Glial Amyloid Precursor Protein Expression Is Restricted to Astrocytes in an Experimental Toxic Model of Multiple Sclerosis. J Mol Neurosci 2011;43(3):268-74. [DOI:10.1007/s12031-010-9419-9] [PMID]
23. Yokote H, Yagi Y, Watanabe Y, Amino T, Kamata T, Mizusawa H. Serum Amyloid A Level Is Increased in Neuromyelitisoptica and Atypical Multiple Sclerosis with Smaller T2 Lesion Volume in Brain MRI. J Neuroimmunol 2013;259(1):92-5. [DOI:10.1016/j.jneuroim.2013.03.004] [PMID]
24. Ristori G, Laurenti F, Stacchini P, Gasperini C, Buttinelli C, Pozzilli C, et al. Serum Amyloid A Protein Is Elevated in Relapsing–remitting Multiple Sclerosis. J Neuroimmunol 1998;88(1):9-12. [DOI:10.1016/S0165-5728(98)00037-X]
25. Schroder R, Nennesmo I, Linke RP. Amyloid in a Multiple Sclerosis Lesion Is Clearly of A Lambda Type. Acta Neuropathol 2000;100(6):709-11. [DOI:10.1007/s004010000244] [PMID]

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