Advancing Understanding of Moyamoya Disease: A Comprehensive Progress Report on

Genetic and Inflammatory Markers

Riad Sankari

HMB496: Research Project in Human Biology

1007199719

November 16, 2023

Section 1:

Moyamoya disease is a distinctive cerebrovascular disorder, known for the progressive

narrowing of the distal internal carotid artery and the presence of a network or abnormal
collateral vessels, known as moyamoya vessels. The name “moyamoya” means “puff of smoke”
in Japanese, which describes the appearance of these tangled vessels on angiographic imaging.
The pathophysiology of MMD is not fully understood, and while it has been associated with
inflammation, the exact relationship between systemic immune-inflammatory markers an MMD
is still being elucidated.1,2

The etiology of Moyamoya disease is not completely understood, but it is known to be

associated with certain genetic mutations. The RNF213 gene, which encodes an unconventional
E3 ubiquitin ligase, is a major susceptibility gene for MMD, particularly in people from East
Asia3,4,5. This discovery has opened new avenues for research, but the low penetrance observed
in genetically susceptible individuals suggests that other factors also play a role in the
development of the disease4.

Inflammation plays a pivotal role in the progression of MMD. Studies are focusing on various
system immune-inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR),
platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII), to
understand their relationship with MMD. These markers are believed to reflect the state of
immune inflammation in the disease and have been used to investigate their potential link to
MMD6.

Moyamoya can lead to severe complications such as ischemic stroke or intracranial hemorrhage
in both children and adults, and its progression can significantly impact the quality of life 7.
Females and individuals of Asian descent are noted to have a higher prevalence of MDD 8. The
chronic progressive stenosis of the involved arteries and the risk of stroke necessitate a better
understanding of the disease mechanisms, including the role of systemic and cerebral
inflammation, to improve diagnostic and therapeutic approaches9,10

Researchers aim to clarify the association between these markers and the risk of MMD and its
subtypes, as understanding this relationship could contribute to better risk assessment,
diagnosis, and potential therapeutic strategies for MMD patients.11

Building on the established understanding that Moyamoya disease (MMD) is a progressive

cerebrovascular disorder marked by the narrowing of cerebral arteries and the development of
collateral networks, the scientific community is still grappling with the intricacies of its
pathophysiology. While the visualization of "puff of smoke" like moyamoya vessels on
angiographic imaging is characteristic, the lack of clarity on the inflammatory processes and
genetic predispositions underscores a critical gap in the current literature12.
One of the most significant findings in recent years is the association of MMD with the RNF213
gene, particularly in East Asian populations. However, the complexity of MMD is evidenced by
the low penetrance rate in genetically susceptible individuals, suggesting that genetic
predisposition alone does not account for the disease's manifestation. This points towards a
multifactorial etiology where other environmental or internal factors may play a pivotal role.13

Inflammation, a cornerstone in the pathogenesis of many vascular disorders, has emerged as a

key player in MMD progression. The exploration of systemic immune-inflammatory markers,
such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and the systemic
immune-inflammation index, represents a promising frontier in understanding the underlying
inflammatory processes in MMD14,15. However, the literature presents a dichotomy: while some
studies underscore the potential of these markers in reflecting the state of immune
inflammation in MMD, others call for caution, citing variability and lack of specificity. 16

The noted increased incidence of MMD-related complications such as ischemic stroke and
intracranial hemorrhage in females and individuals of Asian descent further complicates the
landscape. These demographic patterns suggest potential genetic and biological underpinnings
yet to be fully uncovered. The chronic nature of MMD, coupled with its severe implications on
patients' quality of life, highlights the urgency for a deeper understanding of the disease
mechanisms.

Current research endeavors are fragmented, with some focusing on the genetic components of
MMD while others explore the inflammatory markers separately. This disconnection reveals a
weakness in the literature: a lack of comprehensive studies that holistically examine the
interplay between genetic factors and inflammatory processes. Additionally, there is a dearth of
comparative studies that quantify the elevation of inflammatory markers in MMD patients
against healthy controls, which is crucial for establishing baseline values for clinical assessments
and therapeutic interventions.

Controversy also persists regarding the prognostic value of these inflammatory markers. While
some researchers advocate for their use in risk assessment and stratification, others question
their reliability due to the influence of concomitant diseases and individual variability.

Addressing these gaps, the proposed research aims to bridge the disconnect by systematically
evaluating the extent to which systemic and cerebral inflammatory markers are elevated in
MMD patients relative to healthy individuals. This investigation will not only provide insights
into the inflammatory nature of MMD but also assess the potential of these markers as
diagnostic and prognostic tools. By critically analyzing existing studies and synthesizing new
data, this research will endeavor to create a more coherent understanding of MMD, ultimately
contributing to the development of targeted therapeutic strategies and improved patient
outcomes.

Therefore, the central research question of this study is: "To what extent are systemic and
cerebral inflammatory markers elevated in patients diagnosed with Moyamoya disease
compared to healthy controls?" To tackle this query, we will employ a meta-analysis framework,
synthesizing data from a range of clinical studies to quantify the differences in inflammatory
markers. This methodology will allow for a robust comparative analysis that accounts for
variability across individual studies and patient demographics. The justification for this research
stems from the need to elucidate the inflammatory underpinnings of Moyamoya disease, which
may inform more precise diagnostic criteria and pave the way for targeted therapeutic
interventions, addressing a critical gap in the current understanding of this debilitating
condition.

Section 2:

This study will apply a meta-analysis approach, leveraging established techniques from prior
research within our lab to comprehensively evaluate systemic and cerebral inflammatory
markers in Moyamoya disease. Drawing from the methodology used in a previous lab project
analyzing the cognitive effects of doxorubicin17. The following strategies will be adapted for this
analysis:

2.1. Publication Search

A systematic search will be conducted using electronic databases, specifically PubMed and
MedLine, with search terms tailored to Moyamoya disease and related inflammatory markers.
The search parameters will include publications up to the current month and year, restricted to
English language studies.

2.2. Publication Selection

Criteria for inclusion will require that studies report original data on human patients diagnosed
with Moyamoya disease, detailing objective measures of systemic and cerebral inflammation.
Studies will be selected based on their methodological rigor and relevance to the research
question, excluding reviews and prior meta-analyses.

2.3. Data Extraction

Key data points will be extracted, including mean values and standard deviations of
inflammatory markers, sample size, demographic details, and study design specifics. This
extraction process will mirror the rigor of the doxorubicin study, ensuring consistency and
reliability in data handling.

2.4. Statistical Analysis

Statistical analysis will be performed using a software package suited for meta-analysis, such as
Revman5.3 or a comparable tool, to calculate effect sizes and evaluate the significance of
differences in inflammatory markers between Moyamoya patients and healthy controls. The
analysis will employ a random effects model to account for study heterogeneity, and
significance will be set at a two-tailed P < 0.05.

2.5. Publication Bias Assessment

Consistent with the previous lab methodology, publication bias will be assessed using funnel
plots to visualize the relationship between effect size and study precision, providing insights into
the potential for systemic error within the gathered literature.

By adhering to a structured and proven methodological framework, this meta-analysis will

provide robust insights into the inflammatory profile of Moyamoya disease, offering a valuable
contribution to the field's understanding of this condition's pathophysiology.

Section 3:

Progress in the meta-analysis of systemic and cerebral inflammatory markers in Moyamoya

disease has been substantial to date. The preliminary search strategy has been executed,
yielding a total of 121 records from PubMed and 21 from Ovid Medline. After a meticulous
process of removing duplicates, 83 unique studies remained from PubMed, with no additional
unique records from Ovid Medline. A focused screening further narrowed these articles down
to 17 studies that met the specific inclusion criterion of measuring inflammatory markers in
Moyamoya patients against healthy controls.

The selection process has been guided by a structured research question aiming to discern the
extent of elevation in inflammatory markers in patients diagnosed with Moyamoya disease
compared to healthy individuals. This process of distillation ensures that the ensuing meta-
analysis is founded on rigorously selected studies, providing a robust basis for synthesizing data
and deriving meaningful insights into the inflammatory landscape of Moyamoya disease. The
next phase will involve a detailed evaluation and synthesis of the selected studies to construct a
comprehensive picture of the inflammatory profile characteristic of this condition.

Section 4:

With the initial literature search and selection phases successfully completed, the project is well
on its way to meeting its objectives. The next steps to ensure the completion of the meta-
analysis before the course deadline in April 2024 will involve detailed data extraction, quality
assessment of studies, statistical analysis, and interpretation of results.

November-December 2023: Begin detailed data extraction from the 17 studies identified,
cataloging inflammatory marker levels, patient demographics, and study characteristics.
Develop a coding manual for consistent data handling.

January 2024: Complete data extraction. Start the quality assessment of the included studies
using standardized assessment tools to ensure the validity of the meta-analysis.

February 2024: Conduct statistical analysis. Employ software for meta-analysis, such as RevMan
or a similar tool, to perform effect size calculations, heterogeneity assessments, and sensitivity
analyses.
March 2024: Interpret the results, including subgroup analyses if applicable. Begin drafting the
discussion section of the report, considering the implications of the findings, limitations of the
study, and suggestions for future research.

April: Finalize the draft of the meta-analysis report. Ensure that the results, discussion, and
conclusion sections are cohesively written and that the report includes all necessary
components, such as abstract, introduction, methods, results, discussion, and references. Peer-
review and revision period. Submit the draft for feedback from colleagues and advisors, and
make necessary revisions based on their critiques, then finalize the meta-analysis report,
incorporating all feedback and ensuring that the document is formatted according to the course
requirements. Prepare for the presentation of the findings, developing visual aids and a clear
narrative for the results.

Word Count: 1717

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