Is serum angiotensin-converting enzyme a suitable biomarker for differentiating idiopathic and demyelinating optic neuritis?

doi:10.21203/rs.3.rs-3587140/v1

Background: To measure serum angiotensin-converting enzyme (ACE) in patients diagnosed with idiopathic and demyelinating optic neuritis (ON) as well as heathy individuals and assess its viability as a biomarker

Methods: This case-control study involved patients with established acute ON as a study group and healthy controls aged between 18 and 50 years. After systemic and neurological evaluation, the study group was divided into two subgroups: idiopathic ON and demyelinating ON, including Multiple Sclerosis (MS), Neuromyelitis Optica (NMO) and clinically isolated syndrome (CIS). Using enzyme-linked immunosorbent assay, serum ACE levels were obtained and compared between groups.

Results: Fifty-one patients with acute optic neuritis (78.4% female, mean age 29.8 ± 8.4 years) and 51 controls (78.4% female, mean age 29.9 ± 6.9 years) were recruited. In the study group, 29 patients were diagnosed with idiopathic ON (56.9%), and 22 patients with demyelinating ON (43.1%) (MS-ON, n=16; NMO-ON, n=3; and clinically isolated syndrome, n=3). The median serum ACE levels were 33.50 U/L (range: 29.40–46.20) and 34.25 U/L (range: 29.30–46.10) for patients diagnosed with idiopathic ON and demyelinating ON, respectively (P>0.99). Mean serum ACE level for healthy individuals was 26.2 U/L (range: 24.80–20.50) and compared to other groups it was significantly different (P<0.001). A high level of serum ACE (defined as a serum ACE >65 U/L) was present in 3 (10.3%) patients with idiopathic ON and 2 (9.1%) patients with the demyelinating ON (P>0.99).

Conclusions: These results reveal that serum ACE levels are not significantly different in patients diagnosed with idiopathic ON and demyelinating ON. But serum ACE level in both groups is significantly higher compared to healthy subjects.

Optic neuritis

Multiple sclerosis

Neuromyelitis Optica

Angiotensin-Converting Enzyme

Optic Neuritis (ON), as an initial ocular manifestation in Multiple sclerosis (MS), is reported in up to one-third of the MS cases or may occur in up to 70% of patients during the clinical course of MS (1, 2). Typical ON, associated with MS, usually presents with subacute monocular vision loss accompanied by painful eye movements and dyschromatopsia, predominantly in young adult women (3, 4).

ON is identified by inflammatory neuropathy triggered by 1) a demyelinating process (e.g., MS-associated optic neuritis (MS-ON), optic neuritis associated with neuromyelitis optica (NMO-ON), 2) systemic disorders (e.g., infections, connective tissue diseases, and granulomatous disease), or 3) other idiopathic causes with no systemic involvement (e.g., recurrent or solitary isolated optic neuritis, and chronic relapsing inflammatory optic neuropathy (CRION)) (5–9).

Regardless of the traditional role of the renin-angiotensin system (RAS) in the regulation of cardiovascular homeostasis, many components of RAS have been identified in CNS (10, 11). It has been implied by several studies that Angiotensin II (Ang II) modulates various neurophysiological functions throughout two distinct axes, in addition to its vasoconstriction role. Signaling via Angiotensin type-1 receptor (AT1R) causes aberrant neural damage (12, 13). However, AT2R activation provides a neuroprotective effect by counteracting the Ang II/AT1R axis (14–17).

In an animal model of MS, oral administration of candesartan (angiotensin receptor blocker) drastically decreased demyelination of the optic nerve and retinal ganglion cell loss (13). In addition to that, Ang II up-regulation in astrocytes plays an important role in deteriorating the inflammatory pathogenesis of MS (14, 18, 19). A study has shown that Angiotensin-converting enzyme (ACE) level was higher in patients diagnosed with MS compared to healthy subjects (20). Moreover, our previous study demonstrated that the mean serum ACE level was remarkably increased in idiopathic acute ON patients compared to the control group (21). This shed light on the clinical implications of serum levels of ACE, as a component of risk profile, in terms of reflecting the ON prognosis (22–25). This study aimed to compare serum ACE level in patients diagnosed with idiopathic ON to ones diagnosed with demyelinating ON.

Study Design and Patients

In this case-control study, patients diagnosed with acute ON were evaluated for findings consistent with demyelination disorders at the Feiz Hospital, a referral ophthalmology center affiliated with Isfahan University of Medical Sciences, Isfahan, Iran. The study group was divided into two subgroups after systemic and neurological evaluation: idiopathic ON and demyelinating ON; the latter including Multiple sclerosis (MS-ON), Neuromyelitis Optica (NMO-ON), and clinically isolated syndrome (CIS). The healthy control group was equivalent to the patient group regarding age and gender, and it was selected from healthy subjects as candidates for refractive surgery.

The ethics committee of the Isfahan University of Medical Sciences approved the study protocol (Registration number: IR.MUI.MED.REC.1399.1120). This study abides by the guidelines of the Helsinki Declaration, and subjects were provided with written informed consent to participate in the study.

Patients aged between 18-50 years, regardless of gender, diagnosed with acute ON of one eye in the setting of clinical examinations and MRI; in the absence of a known diagnosis of demyelination disorder were recruited.

The excluding criteria were defined as 1) any progressive known neurological disorder, medical condition, or limiting psychiatric disease that may impair the subject's capacity to participate and adhere to study; 2) other causes of optic neuropathy (e.g., intrinsic or extrinsic compression anywhere along the optic nerve, infections, ischemia, toxic and nutritional neuropathies); 3) medical comorbidities that may alter serum ACE level (e.g., hypertension, diabetes mellitus, renal parenchymal diseases, sarcoidosis, chronic liver diseases, moderate or severe cardiopulmonary disorders, and taking any medicines that may affect the RAS function); 4) inability to acquire magnetic resonance imaging (MRI) from the subject; 5) contraindications to MRI such as glomerular filtration rates less than 30 mL/min/1.73m², cardiac pacemaker, metal implants, and claustrophobia. This clinical report follows Strengthening the reporting of observational studies in epidemiology (STROBE) checklist for case-control studies.

Ocular examination

The diagnosis of ON was clinically determined for each eligible patient by a detailed history of periorbital pain with eye movement, subacute monocular vision loss developed over several days and confirmed by dyschromatopsia and relative afferent pupillary defect (RAPD) findings upon examination; accompanied by any pattern of visual field loss with or without disc oedema.

All patients had a thorough ophthalmological examination, including assessment of the best-corrected visual acuity (BCVA), pupillary response to light stimuli, Ishihara color blindness test, extraocular muscle function testing, ocular tonometry to define intraocular pressure (IOP), and dilated-pupil fundus examination using 78D lens and binocular slit-lamp examination of anterior segments. BCVA was converted to a logarithm of the minimum angle of resolution (logMAR) for statistical analysis.

Neurological examination

All the subjects underwent brain and orbital MRI, and a lumbar puncture was performed on any suspected individual. Cerebrospinal fluid (CSF) samples were collected to assess for MS or NMOSD. AQP4-IgG was measured by a live cell-based assay method. MS diagnosis was established according to the 2017 Mcdonald’s criteria (26).

Sample Storage and Biomarker Assessment

Venous blood samples of all participants were obtained from the cubital vein to measure the serum ACE level. Coagulated samples were centrifuged, and the sera were then frozen at -20°C. A standardized enzyme-linked immunosorbent assay (ELISA) method for ACE was used to quantify ACE concentration in the blood (R&D Systems, Minneapolis, Minnesota, USA). Healthy controls had their serum ACE levels measured using the same method as the ON subjects. The normal ACE reference range was considered 8–65 units.

Statistical Analysis

The Statistical Package for Social Sciences (version 26 SPSS, USA) was used to analyze the data. Means, standard deviations, medians, interquartile ranges, and box plots were utilized to explain and illustrate the numerical variables. Qualitative characteristics were quantified using numbers and percentages. Where appropriate, the Shapiro-Wilk test was performed to determine the normality of the distribution of numerical variables. Due to non-normal distribution of variables, comparisons between groups were conducted using the Mann-Whitney U and Kruskal-Wallis tests. Pairwise post-hoc testing with Bonferroni correction was used to make comparisons. The adjusted associations were assessed using a multinominal logistic regression model and reported as adjusted odds ratios. P-values less than 0.05 were considered significant.

Fifty-one patients with ON were enrolled as the study group (78.4% female, mean age 29.8 ± 8.4 years) and 51 healthy participants in the control group (78.4% female, mean age 29.9 ± 6.9 years). The study group was comprised of 29 patients (28.4%) diagnosed with idiopathic ON, 16 patients (15.7%) with MS-ON, 3 patients (2.9%) with NMO-ON, and 3 patients (2.9%) with CIS. Three preceding categories were considered to have a demyelinating disorder (n=22). The baseline demographics and clinical characteristics of the study group are summarized in Table 1 (Table 1).

Table 1. Data characteristics of the study group with acute optic neuritis

Variables	Idiopathic ON (n=29)	Demyelinating ON (n=22)	P value*
*Sex*, n (%)
Male	8 (27.6)	3 (13.6)	0.31
Female	21 (72.4)	19 (86.4)	0.31
*Age*, years
Mean (SD)	30.9 (8.93)	28.86 (6.83)	0.38
Median (min-max)	30 (18-49)	27 (18-42)	0.38
*Eye*, n (%)
Right	14 (48.3)	9 (40.9)	0.60
Left	15 (51.7)	13 (59.1)	0.60
*RAPD*, n (%)
1+	1 (3.4)	0 (0.0)	0.64
2+	9 (31.0)	8 (36.4)
3+	19 (65.6)	14 (63.6)
*Visual acuity*, logMAR
Mean (SD)	1.69 (1.20)	1.61 (1.27)	0.82
Median (min-max)	1.4 (0-3.7)	1.5 (0.18-3.7)	0.82
*Disc swelling*, n (%)
Yes	6 (20.7)	2 (9.1)	0.44
No	23 (79.3)	20 (90.9)	0.44
*ACE level*, n (%)
Abnormal (>65)	3 (10.3)	2 (9.1)	> 0.99
Normal (≤65)	26 (89.7)	20 (90.9)	> 0.99
Mann-Whitney U test Abbreviations*: ON: optic neuritis, logMAR: logarithm of the minimum angle of resolution, SD: standard deviation, RAPD: relative afferent pupillary defect, ACE: angiotensin-converting enzyme

The median serum ACE levels were 33.50 U/L (range: 29.40–46.20), 34.25 U/L (range: 29.30–46.10), and 26.2 U/L (range: 24.80–20.50) for patients suffering from idiopathic ON, demyelinating ON and control group, respectively (P<0.001) (Table 2).

Table 2. Serum angiotensin-converting enzyme level in patients with idiopathic optic neuritis, demyelinating optic neuritis, and control groups.

		Serum ACE Level, U/L
		Mean (SD)	Median	Q1	Q3
Study groups	Idiopathic ON	66.47 (102.91)	33.50	29.40	46.20
Study groups	Demyelinating ON	44.37 (27.72)	34.25	29.30	46.10
Control group		30.87 (11.61)	26.2	24.80	29.50
P-Value (Kruskal-Wallis): < 0.001 Abbreviations: ACE: Angiotensin converting enzyme; ON: Optic neuritis; Q: Quantile; SD: Standard deviation

The median serum ACE level was higher in patients with idiopathic and demyelinating ON compared to the control group (P<0.001 and P<0.001, respectively); but there was no significant difference in serum ACE level between idiopathic and demyelinating ON groups (P>0.99) (Figure 1).

(Figure 1)

Also, abnormal levels of serum ACE (defined as a serum ACE >65 U/L) was present in 3 (10.3%) patients with idiopathic ON (ACE level: 540, 220 and 216) and 2 (9.1%) patients with the demyelinating ON (ACE level: 140 and 108) (P>0.99) (Table 1). It’s important to note that these outlier datapoints are not depicted in Figure 1.

According to multinominal logistic regression analysis, patients with idiopathic (OR: 1.057, 95% CI: 1.013–1.104) and demyelinating ON (OR: 1.054, 95% CI: 1.009 –1.100) had a greater chance of having increased serum ACE when compared to the control group (P=0.01 and P=0.02, respectively) (Table 3).

Table 3. Multinominal logistic regression analysis to show the association between ACE blood level and the diagnosis of each type of ON in comparison with the normal group by matching the effect of age and sex

Disease		Adjusted OR*	95% confidence interval		P
Disease		Adjusted OR*	Lower bound	Upper bound	P
Idiopathic ON	Age (year)	1.016	0.95	1.08	0.64
	ACE level	1.057	1.013	1.104	0.01
	Gender (male)	1.078	0.34	3.43	0.89
	Intercept	-	-	-	0.02
Demyelinating ON	Age (year)	0.989	0.92	1.06	0.75
	ACE level	1.054	1.009	1.100	0.02
	Gender (male)	0.505	0.12	2.15	0.35
	Intercept	-	-	-	0.10
The reference category is the normal group Abbreviations*: OR: odds ratio

In this study it was demonstrated that there’s no significant difference in terms of serum ACE levels in patients diagnosed with idiopathic ON compared to ones diagnosed with demyelinating ON. Therefore, our findings suggest that serum ACE levels can’t differentiate various types of ON.

The two receptors for RAS in CNS, AT1R and AT2R, are two components of this system that are most closely associated with neurodegenerative disorders. Previous studies have outlined the role of AT1R signaling which results in aberrant neurological damage (12,13). Underlying neurodegeneration mechanisms include the production of excessive reactive oxygen species (ROS), neuro-inflammation due to altered blood-brain barrier (BBB) permeability, and distorted regulation of neurotrophic factors (NFs). On the other hand, activation of the AT2R exerts neuroprotective effects by acting as a counterbalance to the Ang II/AT1R axis (12,13,15–17).

RAS dysregulation in the brain significantly contributes to aging-related alterations and neurodegeneration by intensifying neuroinflammation. Hence, serum ACE, which converts angiotensin I to angiotensin II, or any other components of RAS can be targeted through pharmacological methods in acute ON (e.g. blocking or deactivating enzymes or receptors)(16).

In previous reports, it was surmised that variations in serum ACE activity are correlated with the total plaque volume in the brains of MS patients measured by brain MRI (20). Also, there was a substantial difference in cerebral fluid ACE levels between people with MS and those without the disease. Kawajiri et al. (27) found that CSF ACE levels of patients diagnosed with MS were significantly higher than healthy individuals. Similarly, previous data from idiopathic acute ON patients suggests that RAS may play a role in ON (21). These findings suggest that ACE may be involved in the pathophysiology of ON. Previously, Razazian and colleagues (20) reported no statistically significant difference in serum ACE levels between 30 MS patients and 30 healthy controls in their investigation. Our findings did suggest a significantly elevated serum ACE levels in MS patients compared to healthy individuals, however elevations were observed in idiopathic ON patients as well. Considering the non-significant differences noted in serum ACE levels of idiopathic and demyelinating ON, it seems that serum ACE level elevation is not associated with demyelinating disorders.

As far as we are aware, this is the first study to quantify and compare the serum ACE levels of idiopathic and demyelinating ON patients.

As with any study, this study has several limitations to be considered. In our study, all individuals were recruited from a particular ethnic group from a single center, which limits the generalizability of the results. Moreover, future studies should also prioritize other components of the renin-angiotensin system such as renin, angiotensin, and aldosterone as well as a multicenter study design with larger sample size.

Continued investigation, especially prospective cohort study of long-term data, remains critical for determining the correlation between serum ACE level and either development of demyelinating disorders or conversion of idiopathic types to demyelinating disease. According to the Optic Neuritis Treatment Trial (ONTT), 25% of patients with no lesion and 72% of patients with at least 1 lesion can convert to MS within the first 5 years (5).

In conclusion, we did not find serum ACE level a suitable biomarker for differentiating idiopathic ON from demyelinating ON. Improved understanding of RAS in the brain would enable the development of novel strategies, unique methodologies, and risk assessment tools for predicting a patient's individual MS risk after the onset of acute ON. Validation of serum or CSF biomarkers used to estimate risk of developing a demyelinating disorder, requires additional research with large, well-designed cohorts that include various components of RAS and other associated risk factors with a more extended period of follow-ups.

ACE: Angiotensin-Converting Enzyme

ON: Optic Neuritis

MS: Multiple Sclerosis

NMO: Neuromyelitis Optica

CIS: Clinically Isolated Syndrome

CRION: Chronic Relapsing Inflammatory Optic Neuropathy

RAS: Renin-Angiotensin System

Ang II: Angiotensin II

AT1R: Angiotensin Type-1 Receptor

AT2R: Angiotensin Type-2 Receptor

BCVA: Best-Corrected Visual Acuity

IOP: Intraocular Pressure

LogMAR: Logarithm of the Minimum Angle Of Resolution

CSF: Cerebrospinal Fluid

ELISA: Enzyme-Linked Immunosorbent Assay

ROS: Reactive Oxygen Species

NF: Neurotrophic Factors

Ethics approval and consent to participate:

Ethics approval for this report was obtained from the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran. (Registration number: IR.MUI.MED.REC.1399.1120). All patients completed a written informed consent form as a requirement of participation in the study.

Consent for publication:

Not applicable

Availability of data and materials:

The data supporting the findings of this study are accessible upon request from the corresponding authors.

Competing interests:

The authors verified that they had no conflicts of interest in line with the research objectives, authorship, or publication of this article.

Funding:

The authors received no financial support for the research, authorship, or publication of this article.

Authors’ contributions:

A. Dehghani and M. Pourazizi: Involved in conceptualization and designing the study method. Revised the manuscript and approved the final version. M. Irajpour: Reviewed the literature and revised the final version of manuscript. NS. Hosseini.: Reviewed the literature and wrote the initial draft; M. Mirmoahammadkhani.: Analyzed the data and involved in designing the study method; A. Amirkhani.: Involved in data gathering and revised the manuscript; M. Moayeri and F. Esfahanian: Reviewed the literature and revised the manuscript. All authors have approved the final version to be published. All authors committed to being accountable for all aspects of the work, including investigating and resolving any issues regarding the accuracy or integrity of any section of the work.

Acknowledgements:

Not applicable

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No competing interests reported.

Is serum angiotensin-converting enzyme a suitable biomarker for differentiating idiopathic and demyelinating optic neuritis?

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Abstract

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Background

Methods

Results

Discussion

Conclusion

Abbreviations

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