Serum Alpha-Synuclein and Inflammatory Markers profile in an Egyptian Alzheimer’s and Parkinson’s Diseases patients: A Pilot Study

doi:10.21203/rs.3.rs-3893418/v1

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Serum Alpha-Synuclein and Inflammatory Markers profile in an Egyptian Alzheimer’s and Parkinson’s Diseases patients: A Pilot Study

https://doi.org/10.21203/rs.3.rs-3893418/v1

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Alzheimer’s and Parkinson's disease are the most common neurodegenerative diseases. In the current study, we explored the potential of blood-based markers to differentiate Alzheimer's disease (AD) and Parkinson's disease (PD) from healthy controls using ELISA assays via measuring the serum level of α-Syn and panels of inflammatory cytokines in the small pilot cohort of Egyptian volunteers. With the ongoing genetic studies, upcoming data suggest that it is not trivial to revisit the findings reported in specific populations to be tested in each ancestor of different genetic and environmental backgrounds. A total of 42 participants were recruited from the Neurology department, Suhag University Hospital, including 18 AD cases, 9 PD cases, and 15 healthy controls. Clinical and demographic characteristics were well-matched among the three groups. The current data is the first to provide evidence in an Egyptian cohort that aligns with earlier reports that serum level of α-synuclein can be a specific marker for distinguishing PD patients from healthy individuals but not AD patients. Both AD and PD, however, exhibited shared neuroinflammatory profiles with elevated IL-6 and decreased IL-10, hinting at a common inflammatory component despite their distinct etiologies. While trends toward increased IL-1β and TNF-α were observed in AD, the lack of statistical significance suggests a more limited role in its pathogenesis or the need to expand the sample size. These findings, although promising and the first of a kind to be conducted in Egyptian patients, necessitate further investigation with larger sample sizes to solidify these markers' potential for diagnosis and fully unravel the specific roles of individual cytokines in each disease.

Alzheimer’s Disease (AD)

Parkinson’s Disease (PD)

Alpha-Synuclein

Inflammation

Biomarkers

With the aging global population, the prevalence of neurodegenerative diseases, notably Alzheimer's disease (AD) and Parkinson's disease (PD), is on the rise (Reddy et al., 2015). Current diagnostic methods heavily rely on late-stage clinical assessments and neurophysiological evaluations, leading to delayed diagnosis until the clinical symptoms are already apparent (Tolosa et al., 2006, Dubois et al., 2007). The imperative for early detection and non-invasive, cost-effective biomarkers to reflect disease progression is now more pressing than ever (Chiu et al., 2013; Parnetti et al., 2019, Lin et al., 2020, Joo et al., 2023).

While various neuropathology-related markers have been explored in AD and PD, including amyloid-beta, Tau proteins, and α-Syn, inconsistent data and overlapping neuropathology necessitate a more comprehensive investigation in more inclusive cohorts (Parnetti et al., 2019, Lin et al., 2020). Traditionally, most of the data in the literature included patients from North America and Europe, but the recent advances in genetic studies have shown that it is inevitable to include other underrepresented populations that have not been studied earlier in the field of neurodegenerative diseases.

The protein α-synuclein (α-Syn), the main constituent of Lewy body, has been considered for a long time as a pathological hallmark of PD (Spillantini et al., 1997). However, growing data suggests that α-Syn can also be a promising candidate for exploring the commonalities and distinctions between AD and PD through the suggested interactions with key proteins in AD, including Amyloid-beta and Tau (Gold et al., 2013, Atik et al., 2016; C. Lin et al., 2017). Moreover, accumulating evidence highlights the involvement of neuroinflammation in the pathophysiology of both AD and PD. Pro-inflammatory cytokines, such as Interleukin 1β (IL-1β), interleukin 6 (IL6), and tumor necrosis factor α (TNFα), have been implicated as reviewed in (Kwon & Koh, 2020; Tansey et al., 2022; Zhang et al., 2023). Yet, limited investigations across diverse populations, including those not studied earlier, have hindered a comprehensive comparison and assessment of their diagnostic potentials(Kouli et al., 2020; Shateri et al., 2023)

Despite the scarce resources studying the potential biomarkers for AD and PD in Egyptian populations, our previous research provided evidence of the increased α-Syn autoantibodies level in Egyptian PD patients but not in AD, indicating its role in disease pathogenesis (Shalash et al., 2017). In addition, the available data reporting an increased prevalence of both PD and AD in Upper Egypt compared to other countries necessitated further investigation of this population for a clearer understanding of their characteristics. (Farrag et al., 1998; Khedr et al., 2012, 2015).

In this study, we measured α-Syn and a panel of cytokines in the serum of AD and PD patients from Upper Egypt, using a commercially available ELISA assay and comparing their levels to healthy control in a cohort of Egyptian AD and PD patients.

Study Cohort:

A total of 42 participants were enrolled in the current study. Clinically confirmed cases of AD and PD (18 and 9) were recruited from Sohag University Hospital, and 15 healthy controls were recruited from New Giza Teaching Hospital. All participants were subjected to complete medical history taking, neurological examinations, and basic laboratory investigations and imaging to exclude any other possible causes serving their manifestations mainly dementia. PD patients were diagnosed according to the British Parkinson’s Disease Society Brain Bank criteria(Hughes et al., 1992) and were assessed using Hoehn and Yahr scale (H&Y). Patients with AD were diagnosis according to the NINCDS-ADRDA and DSM-IV criteria for dementia (McKhann et al., 2011) and assessed using the Arabic version of the Montreal Cognitive Assessment (MoCA) test (Rahman et al., 2009). Following confirmation of diagnosis and signing informed consent by all participants, blood samples were withdrawn, centrifuged immediately to collect serum, and stored at -20°C freezers before being transferred to The American University in Cairo to be stored at -80°C biobanks facility until the time of the analysis.

Enzyme-linked immunosorbent assay (ELISA)

Concentrations of human α-Syn, IL-6, IL-10, IL-1β, and TNF-α were measured in the serum samples using commercially available sandwich ELISA from ElabSceince (Cat # E-EL-H0983, Cat # E-EL-H6156, Cat # E-EL-H6154, Cat # E-EL-H0149 and Cat # E-EL-H0109).

Briefly, serum samples were diluted according to the manufacturer’s protocol, 100 µL of dilutions were used. Sample were done in duplicates. The protein concentrations were estimated based on the relevant standard calibration curve and expressed in pg/ml.

Statistical Analyses:

The collected data were revised, coded, and entered into GraphPad Prism 8.0.2. software for statistical analysis and visualization. All standard readings were used to develop a calibration curve for each marker that was used by the software to estimate the concentrations of samples based on the resulting ODs. Non-parametric Mann-Whitney statistical test was done to compare PD and AD cases, each versus the healthy controls. The analyses included histograms to show the levels of the marker in each group indicating the significance if available. For Patients’ characterization, median and range were used to describe the age of participants in the 3 cohorts. Means of different characteristic parameters were used for comparison.

1- Disease and demographic characteristics of the study cohort

A total of 42 Egyptian subjects were included (15 controls, 18 AD, and 9 PD). Table 1 shows the demographic characteristics of controls and patients. AD and PD patients had similar ranges of age, and age at onset, and most of them had slow progression of the disease.

Table 1

**Disease and Demographic Characteristics of Study Cohort.** All data is expressed in mean unless otherwise stated. CO: Controls, AD: Alzheimer’s Disease, PD: Parkinson’s Disease; n: number; y: year; NA: Not Applicable.
		CO	AD	PD
Number		15	18	9
Age	Median	55	70	70
	Max	59	89	75
	Min	50	58	56
Gender %	Males	9 (60.0)	5 (27.8)	8 (88.9)
Gender %	Females	6 (40.0)	13 (72.2)	1 (11.1)
Age at Onset		NA	67.89	64.89
Age at Diagnosis		NA	69.56	68.11
Onset Type		NA	(100.0) Insidious	(100.0) Gradual
Progress Speed		NA	(100.0) Slowly	(100.0) Slowly

2- α-Synuclein level in the serum can significantly differentiate PD from healthy controls more efficiently than AD patients.

To test if we can also use α-syn to differentiate PD and AD patients from healthy controls, we measured the α -syn level in the sera of our current cohort. The concentration of α-Syn was the highest in PD patients, with a median concentration of 5.4 ng/ml (2.3–17.9). The level was also elevated in AD patients at 3.2 ng/ml (4.9–9.4) compared to the healthy control but fell short of a statistical significance by a p-value of 0.0506 (Fig. 1).

3- Inflammatory cytokines are elevated in both AD and PD compared to healthy controls

Changes in the inflammatory profile of neurodegenerative disease patients are widely reported in many studies, to assess that in the current Egyptian cohort, a panel of cytokines (IL-6, IL-10, IL1B, and TNF-α) was measured. Not all assays were measured for all subjects in AD cohort due to limited sample availability. IL-6 was increased in both AD and PD patients with a median of 1.5 pg/ml (0.5–17.2) and 2.7 pg/ml (0.2–19.6), respectively (Table 2). Statistical comparisons between AD and PD groups vs. controls showed significant difference in both groups (p < 0.05, p < 0.01 respectively) (Fig. 2A). In contrast, IL-10 was significantly decreased in AD and PD patients with median concentrations 3.0 pg/ml (2.2–9.2) and 2.5 pg/ml (2.4–2.8) compared to controls 3.2 pg/ml (3.0-3.9) (Table 2) with (p < 0.0001) (Fig. 2B). A trend towards increased levels of TNF-α and IL-1β was also observed in AD patients but did not reach statistical significance (Fig. 2C and 2D).

Table 2

Detailed data description on measured α-Syn and Inflammatory cytokines values
		IL-6 (pg/ml)	IL-10 (pg/ml)	IL-1β (pg/ml)	TNF-α (pg/ml)	α-Syn (pg/ml)
CO	Median	0.71	3.18	57.26	32.99	2665.99
	Max	2.56	3.52	197.30	122.04	6701.54
	Min	0.13	2.98	13.68	1.17	555.91
AD	Median	2.34	2.55	95.20	67.25	5496.66
	Max	5.63	3.13	241.72	444.21	9427.30
	Min	0.47	2.22	3.25	18.36	2303.56
PD	Median	3.68	2.50	51.69	59.07	6263.64
	Max	19.62	2.83	163.26	146.41	17907.38
	Min	0.19	2.45	1.11	9.71	2339.31

As neurodegenerative diseases like AD and PD cast a growing shadow, the need for early-stage biomarkers intensifies. This study delves into the blood signatures of AD and PD of a small Egyptian cohort for the very first time as a pilot study, exploring α-Syn and inflammatory markers as potential keys to diagnosis and understand the pathophysiology of the diseases. This study provides the first evidence comparing the serum levels of α-Syn and a panel of inflammatory markers in Egyptian patients with AD and PD compared to healthy controls. Focusing on serum biomarkers, we aimed to contribute to the earlier efforts in the region aiming for a clearer understanding of the molecular landscape of the Egyptian population with neurodegenerative disease (Shalash et al., 2017).

The findings from the current cohort revealed a significant elevation of α-Syn in PD patients compared to healthy controls, underscoring its potential specificity to PD over AD and controls. This comes to no surprise and aligns with prior studies reporting increased α-Syn in both blood and cerebrospinal fluid (CSF) samples of PD patients (Gold et al., 2013; Salas-Leal et al., 2021; Shalash et al., 2017; Wang et al., 2020; Zubelzu et al., 2022). The level of α-Syn in AD was slightly increased in comparison to controls level but without reaching significance suggesting a potential role in disease pathogenesis that needs further investigation on a larger population. Still, as our data is generated from only small numbers of PD patients, there for caution needs to be practiced as other studies also reported decreased α-Syn levels in patients with PD which might be an attribute to the different populations of study, or the methodology used (Atik et al., 2016; Besong-Agbo et al., 2013; Laske et al., 2011; Parnetti et al., 2019; Vivacqua et al., 2016).

We observed an increase in IL-6 in the serum of both AD and PD patients and a reduction of IL-10 compared to healthy controls. This aligns with the earlier reports in the literature and suggests a shared pathophysiology involving neuroinflammation in both diseases (Scalzo et al., 2010; Karpenko et al., 2018; Kara et al., 2020; Porro et al., 2020; Lyra e Silva et al., 2021). The alterations in these markers in AD and PD, though non-specific, highlight their possible roles in the pathogenesis of neurodegenerative diseases. While a trend toward increased IL-1β and TNF-α in AD patients was observed, statistical significance was not reached, that is possibly due to the current small cohort, and further testing is required to test the hypothesis.

Several prior studies reported increased levels of IL-10 as well as IL-1β and TNF- α in neurodegenerative patients ((Bessler et al., 1999; Hall et al., 2018; Ng et al., 2018; de Almeida et al., 2022, Shateri et al., 2023) Yet, the available information is inconsistent as many studies reported no change in the levels of cytokines specifically IL-1β and TNF- α (Ng et al., 2018 Leal et al., 2013;). The discrepancies may stem from variations in population characteristics or testing durations,

This study has several limitations including the small sample size due to the limited access to patients as a starting piloting cohort, and the limited parameters measured by relying solely on commercially available ELISA kits that can be delivered to Egypt. Although many studies are currently using more sensitive assays like SIMOA or seeding amplification assays, we have opted for the commercially available ELISA in blood samples due to the availability and accessibility to low-income countries like Egypt.

Replicating the study on a larger sample size in the upcoming studies would help validate the the current results and further understand the mechanism of neurodegeneration in the pathophysiology of both diseases, specifically in Egyptian populations. The wider geographical representation of included patients is also necessary in future setups, to consider the possible impact of differences in demographic characteristics and environmental factors. In addition, studying more inflammatory mediators and their change in AD and PD along the course of the disease progression is essential to help understand the role of neuroinflammation throughout the diseaase progression.

However, despite the fact of above-mentioned limitation, it’s the first study to evaluate the inflammatory cytokines in Egyptian populations. This is very important in a region where the reported pollution and environmental factors like agricultural industries can heavily participate in the pathophysiology of neurodegenerative diseases that cannot be replicated in other areas of different cultures and demography (Rösler et al., 2018).

In conclusion, the current study investigated several blood biomarkers in AD and PD patients, reporting elevation of α-Syn in PD patients compared to AD and healthy controls indicating its potential role as a biomarker for PD. In addition, the study reported significant changes in IL-6 and IL-10 in AD and PD compared to healthy controls indicating their role in understanding the pathogenesis of neurodegenerative diseases and neuronal damage.

Funding Declaration

This study was supported by the American University in Cairo (Bartlett Fund for Critical Challenges − 2021 and Faculty Support Grants-2023 [MS]) and Mansoura University competitive grant (Mu-Med-20-31) to SE.

Ethics Statement

The study was conducted after receiving approval from the American University in Cairo Institutional Review Board (AUC-IRB). All patients signed an informed consent before enrollment in the study. All procedures were done in accordance with the Declaration of Helsinki

Funding Declaration

This study was supported by the American University in Cairo (Bartlett Fund for Critical Challenges -2021 and Faculty Support Grants-2023 [MS]) and Mansoura University competitive grant (Mu-Med-20-31) to SE.

Ethics Statement

Author Contributions
Conceptualization: [Shimaa Heikal], [Sara Elfarrash], [Mohamed Salama]; Data Collection: [Gharib Fawi], [Gafaar Ragab], [Mohamed Hegazi]; Methodology [Shimaa Heikal], [Mai Barakat]; Formal analysis and investigation: [Shimaa Heikal], [Sara Elfarrash], [Mohamed Salama]; Writing - original draft preparation: [Shimaa Heikal, Sara Moustafa]; Writing - review and editing: [Sara ElFarrash, Mohamed Salama]; Funding acquisition: [Sara Elfarrash, Mohamed Salama]; Supervision: [Sara ElFarrash, Mohamed salama]. All authors reviewed and approved the final draft.

Competing Interests

All authors declare no financial or non-financial competing interests.

Data Availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Code availability

Not Applicable

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not Applicable

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Serum Alpha-Synuclein and Inflammatory Markers profile in an Egyptian Alzheimer’s and Parkinson’s Diseases patients: A Pilot Study

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Abstract

Figures

Introduction

Materials and Methods

Study Cohort:

Enzyme-linked immunosorbent assay (ELISA)

Statistical Analyses:

Results

1- Disease and demographic characteristics of the study cohort

3- Inflammatory cytokines are elevated in both AD and PD compared to healthy controls

Discussion

Conclusion

Ethics Statement

Declarations

References

Additional Declarations

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