Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis

Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis Yu-Hsien Chang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6581817/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Homocysteine, a key metabolite in one-carbon metabolism, has been implicated in neurodegeneration and cognitive decline. While its association with Alzheimer's disease has been extensively studied, its role in Parkinson’s disease (PD)-related cognitive impairment remains unclear. We conducted a systematic review and meta-analysis to examine the relationship between plasma homocysteine levels and cognitive dysfunction in PD patients. A systematic search of PubMed, Web of Science, CINAHL, and the Cochrane Library identified 12 eligible studies (n = 1,848). Random-effects meta-analysis showed that PD patients with cognitive impairment had significantly higher homocysteine levels compared to those with normal cognition (mean difference: 3.11 µmol/L; 95% CI: 2.13 to 4.10; p < 0.00001). Subgroup analysis indicated a stronger association in Eastern populations. Meta-regression revealed a positive correlation between disease duration and homocysteine levels but no significant association with L-dopa dosage. Sensitivity analyses supported the robustness of findings, and no major publication bias was detected. Our findings suggest that hyperhomocysteinemia may serve as a modifiable biomarker for cognitive decline in PD, offering potential avenues for early intervention. Moreover, these results highlight homocysteine metabolism as a broader therapeutic target across aging-related neurodegenerative diseases. This study provides translational insights into the systemic metabolic contributions to neurocognitive health. Health sciences/Biomarkers/Predictive markers Health sciences/Diseases/Neurological disorders/Parkinsons disease Health sciences/Neurology/Neurological disorders Homocysteine Parkinson Disease Cognitive Dysfunction Meta-Analysis Biomarkers Neurodegeneration Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms. However, cognitive impairment (CI) is a significant and often debilitating feature that exacerbates the disease's progression[ 1 ]. Parkinson’s disease dementia (PDD) and mild cognitive impairment (MCI) are common forms of cognitive decline observed in PD patients, with around 47% of PD patients developing dementia within 15 years of diagnosis[ 2 ] and 20% of patients with PD-MCI progressed to dementia within three years[ 3 ]. Therefore, early identification and prevention of cognitive dysfunction in PD are critical, as the progression to dementia or CI not only worsens disease outcomes but also significantly impacts the patient's quality of life, leading to increased dependence, caregiver burden, and loss of independence. Despite the growing recognition of cognitive decline, the underlying biomarkers that contribute to cognitive deterioration in PD remain unclear. One potential factor contributing to CI in PD is homocysteine (Hcy), an amino acid involved in methionine metabolism. Elevated levels of Hcy, known as hyperhomocysteinemia (HHcy), have been associated with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease[ 4 ]. Hcy has been shown to exert neurotoxic effects through mechanisms like vascular damage, neuroinflammation, and oxidative stress, all of which are implicated in cognitive dysfunction[ 5 ]. Furthermore, studies have suggested a relationship between elevated Hcy and cognitive decline in PD, but the findings have been inconsistent. This meta-analysis aims to clarify the relationship between Hcy and CI in Parkinson's disease by synthesizing data from multiple studies. We also investigate the potential role of other factors such as levodopa therapy, disease duration, and regional variations in Hcy metabolism across PD populations. By systematically analyzing existing studies, we aim to determine whether Hcy levels could serve as a reliable biomarker for cognitive decline in PD and inform future screening strategies or targeted interventions. Method Databases and search strategy We systematically searched four electronic databases: PubMed, Web of Science, CINAHL, and the Cochrane Library, from inception to March 25, 2025. All databases were last searched on March 25, 2025. No restrictions were placed on language or publication status. In addition to database searching, we manually screened the reference lists of all included full-text articles to identify additional eligible studies. No preprint servers, grey literature sources, or organizational websites were searched. We did not contact study authors or experts for unpublished data. The search strategy incorporated both keywords and Medical Subject Headings (MeSH) terms to maximize coverage. The following terms were used in various combinations using Boolean operators (AND/OR): ("Parkinson's disease" OR "Parkinson Disease") AND ("homocysteine" OR "hyperhomocysteinemia" OR "Homocysteine") AND ("cognition" OR "cognitive impairment" OR "Cognition Disorders"). There were no specific filters or limitations. Reference lists of eligible articles were also manually screened for additional studies. This study has been registered at PROSPERO (ID: CRD42025643475). A formal review protocol was not prepared beyond PROSPERO registration. All procedures were conducted according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) 2020 guidelines. Study screening and selection The articles were independently screened by Yu-Hsien Chang and Yo-Ning Chang. An initial review of titles and abstracts was conducted to exclude articles outside the scope of the meta-analysis. Review articles, meeting articles, and preclinical articles were also excluded. For the remaining articles, full-text versions were retrieved for further review. Any uncertainties were resolved through discussion. The flow diagram of this study is shown in Fig. 1 . Eligibility criteria for study inclusion: 1) Studies that include patients diagnosed with PD based on established criteria such as the UK Brain Bank criteria or MDS Clinical Diagnostic Criteria for Parkinson’s Disease. 2) Adequate documentation of case numbers and study findings such as Hcy levels and cognitive function outcomes, as evaluated using standardized neuropsychological assessments such as Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or the cognitive subscales of the Unified Parkinson’s Disease Rating Scale (UPDRS). 3) Studies that evaluate the possible relationship between Hcy and cognitive function of PD patients. The patients should include PD Cognitive Impairment group (PDCI group) and PD Normal Cognition group (PDNC group). In this meta-analysis, PD-CI was defined according to each study’s criteria, which were based on validated neuropsychological assessments. These included tools such as MMSE, MoCA, Parkinson’s Disease Cognitive Rating Scale, and Scales for Outcomes in Parkinson’s Disease-Cognition, etc. Only studies that clearly distinguished PD-CI from PD-NC using standardized diagnostic tools or cutoff values were included. Exclusion criteria:1) Preclinical studies, reviews and meta-analysis that don’t contain original data. 2) Studies with incomplete data or insufficient statistical information for quantitative synthesis. Assessment of reporting quality Two reviewers (Yu-Hsien Chang and Yo-Ning Chang) independently assessed study quality using the quality assessment tool proposed by Agency for Healthcare Research and Quality (AHRQ)[ 6 ] for cross-sectional studies. The AHRQ quality assessment tool consisted of 11 items, each evaluated with “yes”, “no” or “unclear”. The 11 items are shown as follows: 1. Define the source of information (survey, record review). 2. List inclusion and exclusion criteria for exposed and unexposed subjects (cases and controls) or refer to previous publications. 3. Indicate time period used for identifying patients. 4. Indicate whether or not subjects were consecutive if not population based. 5. Indicate if evaluators of subjective components of study were masked to other aspects of the status of the participants. 6. Describe any assessments undertaken for quality assurance purposes (e.g., test/retest of primary outcome measurements). 7. Explain any patient exclusions from analysis. 8. Describe how confounding was assessed and/or controlled. 9. If applicable, explain how missing data were handled in analysis 10. Summarize patient response rates and completeness of data collection. 11. Clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or follow-up was obtained. Discrepancies were resolved by consensus. No automation tools were used in the risk of bias assessment process. Data extraction and statistical analyses Two reviewers (Yu-Hsien Chang and Yo-Ning Chang) independently extracted data from each included study using a standardized data extraction form. Any discrepancies were resolved through discussion. We did not contact study authors for additional information, and no automation tools were used during the data extraction process. The primary outcome of this meta-analysis was the difference in peripheral Hcy levels between PD-CI and PD-NC individuals. Only cross-sectional or baseline Hcy data were included to ensure consistency. When studies employed multiple cognitive assessment tools or diagnostic definitions, we selected the classification most consistent with established diagnostic criteria. To determine eligibility for meta-analysis, we included only studies that reported group-level Hcy data (mean, standard deviation, and sample size) for both PD-CI and PD-NC groups. Studies that lacked key numerical data, used incompatible designs, or reported only correlational analyses were excluded from quantitative synthesis but retained for descriptive comparison. We tabulated study-level variables—including assessment tools, diagnostic thresholds, and population characteristics—to ensure comparability across studies. Extracted variables included study-level information such as author name, year of publication, participants’ age, sex, sample size, disease duration, L-dopa dosage, cognitive assessment tools, definitions of cognitive impairment, and Hcy measurement techniques, and geographic region. Data on folic acid and vitamin B12 levels were collected when reported. However, as these B-vitamin data were not part of the predefined search strategy and were inconsistently reported, their comparisons are presented descriptively and interpreted as exploratory findings rather than part of the formal quantitative synthesis. When outcome definitions or statistical reporting were unclear, assumptions were made based on contextual information within the original articles. No data imputation was performed for missing numerical values. When necessary, standard deviations were calculated from standard errors or confidence intervals using established formulas. No conversions or standardizations were required for Hcy values, as all studies reported results in µmol/L. Results were visually summarized using forest plots for meta-analyses, funnel plots for publication bias assessment, and bubble plots for meta-regression analyses. Mean difference (MD) with 95% confidence intervals (CI) was used as the effect measure for all quantitative syntheses. Meta-analyses were performed using Review Manager (RevMan) version 5.4. Between-study heterogeneity was assessed using the I² statistic. A random-effects model was adopted due to expected methodological and clinical variability; results were also compared to a fixed-effects model when heterogeneity was low. Meta-regression analyses were conducted in R version 4.4.2 to explore the effects of potential moderators such as disease duration and L-dopa dosage. Certainty of evidence was not assessed using formal frameworks such as the Grading of Recommendations Assessment, Development, and Evaluation, as all included studies were all observational and cross-sectional in design. Leave-one-out sensitivity analyses were conducted by sequentially removing one study at a time and recalculating the pooled effect size using inverse-variance weighting. This approach was used to assess the robustness and stability of the meta-analytic results. To assess potential reporting bias, we performed Egger’s regression test in addition to visual inspection of funnel plots. A p-value less than 0.05 was considered indicative of small-study effects or potential publication bias. For subgroup analyses by geographic region, studies were categorized into "Eastern" and "European" groups based on the geographic and cultural proximity. Eastern countries included East Asia such as China, Southeast Asian nations, and Middle Eastern regions such as Turkey, while European countries included Italy, Spain, and the Czech Republic, following precedent from prior meta-analyses. Results Study Selection and Characteristics A total of 256 articles were identified through database searches. After removing duplicates and screening titles and abstracts, 17 full-text articles were assessed for eligibility. Of these, 5 were excluded due to the absence of both PD-CI and PD-NC comparison groups or lack of group-level Hcy data. Ultimately, 12 studies[ 7 – 18 ] met the inclusion criteria and were included in the final meta-analysis. The study selection process and the reasons for exclusion are summarized in the flow diagram (Fig. 1 ). The majority of included studies were cross-sectional observational studies comparing peripheral Hcy levels between PD patients with and without cognitive impairment. One study conducted by Veselý et al.[ 14 ] was originally designed as a longitudinal cohort, following PD patients over a two-year period to evaluate progression from normal cognition to mild cognitive impairment. However, since Hcy was only measured at baseline, without follow-up data, the study was considered cross-sectional with respect to Hcy-related analysis in this meta-analysis. All other studies provided only cross-sectional or single time-point data for Hcy levels and cognitive status. These studies included 664 PD-CI and 1184 PD-NC participants. The characteristics of the included studies are summarized in Table 1 , which presents patient demographics, Hcy levels, folic acid levels, vitamin B12 levels, and disease characteristics. The studies assessed using the AHRQ quality assessment tool demonstrate generally good quality, with most providing clear information on inclusion/exclusion criteria, source of information, and confounding control. However, several areas of concern were identified, including unclear or missing follow-up data and inadequate explanation of how missing data were handled. Additionally, some studies did not specify if evaluators were masked, which could impact objectivity. Despite these issues, the majority of studies demonstrate robust methodology in key areas, though further transparency in reporting follow-up and data handling is recommended for improved study reliability. The results of the assessment of the quality are summarized in Table 2 . Table 2 Quality assessment of included studies using the Agency for Healthcare Research and Quality (AHRQ) assessment tool Study ID a 1 b 2 3 4 5 6 7 8 9 10 11 Zoccolella 2005 Y Y U U U U Y Y U Y N Rodriguez-Oroz 2009 Y Y U U Y U Y Y U Y N Liu 2019 Y Y Y Y U Y Y U U Y N Veselý 2019 Y Y U U U U U Y U Y Y Fu 2021 Y Y Y Y Y Y Y Y U Y N Martínez Horta 2021 Y Y Y N U U Y Y U Y N Periñán 2022 Y Y U U U Y Y Y U Y N Zhang 2023 Y Y Y Y U U Y Y U Y N Kobak Tur 2023 Y Y U U U U Y Y U Y N Ouyang 2024 Y Y Y Y U U Y Y U Y N Zhai 2024 Y Y Y U U U Y Y U Y N Xiao 2024 Y Y Y U U U U Y U Y N Abbreviations: Y, Yes; N, No; U, Unclear. a. The name of the first author and year of publication b. Items 1–11 refer to the specific AHRQ criteria, as described in the Methods section. Hcy Levels in PD-CI vs. PD-NC Patients The meta-analysis revealed a significant difference in Hcy levels between PD-CI and PD-NC patients. As shown in Fig. 2 , the mean Hcy level in the PD-CI group was 3.11 µmol/L higher than in the PD-NC group (95% CI: 2.13, 4.10, p < 0.0001). Moderate to high heterogeneity (I² = 71%) was observed across studies, indicating variability in the findings. The overall effect was statistically significant (Z = 6.19, p < 0.00001), suggesting that elevated Hcy could serve as a marker for CI in PD. Subgroup Analysis: Regional Variations in Hcy Levels Subgroup analyses by region (European vs. Eastern) revealed differences in Hcy levels between PD-CI and PD-NC patients (Fig. 2 ). The European subgroup showed a moderate difference in Hcy levels between PD-CI and PD-NC, with PD-CI patients exhibiting significantly higher Hcy levels (p = 0.02). However, moderate heterogeneity (I² = 52%) was observed, suggesting that factors like dietary habits, B-vitamin supplementation, or diagnostic criteria might explain some of the variability. The difference in Hcy levels was more pronounced in the Eastern subgroup, with PD-CI patients showing an average of 3.77 µmol/L higher Hcy levels compared to PD-NC patients (p < 0.00001). This finding was highly significant, though high heterogeneity (I² = 67%) indicated that regional variations in environmental, dietary, and genetic factors may contribute to the observed variability. The subgroup analysis highlights that while the association between elevated Hcy and CI in PD is consistent globally, regional differences should be taken into account in future research, particularly in understanding the effects of diet, genetic variation, and regional healthcare practices on Hcy metabolism. Folic Acid and Vitamin B12 Levels Although differences were not statistically significant, exploratory comparisons suggest a trend toward lower folate and B12 levels in PD-CI patients. Specifically, the MD in folic acid levels was − 0.76 ng/mL (p = 0.24; I² = 53%), while the MD in vitamin B12 levels was − 27.16 pg/mL (p = 0.21; I² = 72%) (Supplementary Fig. 1 and Fig. 2 ). These comparisons were based on a subset of studies and should be interpreted cautiously, as neither folic acid nor vitamin B12 were part of the original search strategy, and relevant data were not consistently reported across all included studies. The heterogeneity observed suggests that other factors like treatment effects, genetic influences, and dietary factors should be explored in future studies to clarify the role of folic acid and B12 in cognitive decline in PD. Meta-Regression Analysis The meta-regression analysis examining the relationship between L-dopa dosage and Hcy levels revealed no significant association (β = 0.0021, p = 0.6208) between L-dopa dosage and Hcy levels, with an R² value of 0.00% indicating that L-dopa does not explain the variability in Hcy levels (Fig. 3 ). The model showed substantial residual heterogeneity (I² = 94.52%), suggesting that other factors, such as disease duration and genetic variations in Hcy metabolism, may influence this relationship. Sensitivity analysis Given the moderate heterogeneity observed, we further assessed the robustness of results using sensitivity analysis, and a leave-one-out sensitivity analysis was performed using inverse-variance weighting. In this analysis, each individual study was sequentially excluded, and the pooled MD in Hcy levels between PD-CI and PD-NC groups was recalculated using the remaining studies. The resulting weighted MDs ranged from 2.79 to 3.02 µmol/L, indicating minimal fluctuation. This suggests that no single study exerted a disproportionate influence on the overall effect size, thereby supporting the stability and reliability of the pooled estimate. Publication Bias Publication bias was assessed using both visual inspection of the funnel plot and Egger’s regression test. The funnel plot (Fig. 5 ) appeared symmetrical, suggesting a low risk of publication bias. Egger’s test yielded an intercept of 1.185 with a p-value of 0.1379, indicating no statistically significant asymmetry. These findings suggest that the overall meta-analytic results were unlikely to have been substantially influenced by publication bias. Discussion This meta-analysis demonstrates a significant association between elevated Hcy levels and CI in PD, with PD-CI exhibiting consistently higher Hcy levels than PD-NC. These findings support the hypothesis that HHcy may play a pivotal role in the pathophysiology of cognitive decline in PD, consistent with previous studies linking elevated Hcy levels to various neurodegenerative conditions, including Alzheimer's disease and vascular dementia[ 19 ]. The underlying mechanisms through which elevated Hcy contributes to cognitive dysfunction are multifaceted. Hcy is known to induce vascular damage, neuroinflammation, and oxidative stress, all of which are implicated in neurodegeneration[ 12 , 20 – 22 ]. Furthermore, studies suggest that high Hcy levels may impair neurotransmitter metabolism and mitochondrial function, exacerbating the neurodegenerative process in PD [ 20 , 23 ]​​. Given that these mechanisms can accelerate cognitive decline, the role of Hcy as a biomarker for cognitive impairment in PD becomes more apparent. One of the key limitations of this meta-analysis lies in the heterogeneity of CI definitions across the included studies. Although all studies employed validated neuropsychological tools—such as MMSE, MoCA, and PD-CRS—the cutoff values, diagnostic criteria (e.g., MDS Level 1 vs. Level 2), and number of failed domains varied substantially. This variability may introduce measurement bias and reduce the comparability of CI classification between studies. Moreover, the included cohorts likely represented different stages of PD progression, which may independently affect both Hcy levels and cognitive outcomes. These methodological inconsistencies limit the ability to fully harmonize outcome definitions and could contribute to residual confounding. While meta-regression and subgroup analyses attempted to explore disease duration and L-dopa dosage as potential sources of heterogeneity, other unmeasured variables—such as nutritional status, comorbidities, or differential access to care—may also influence the observed associations. These factors should be considered when interpreting the findings and underscore the need for future longitudinal studies using standardized diagnostic criteria and comprehensive covariate adjustment. Despite the overall significant association between Hcy and cognitive decline, the high heterogeneity observed in this meta-analysis (I² = 71%) indicates that other factors may influence the relationship between Hcy and cognitive function. Regional differences were observed, with Eastern studies showing stronger associations between Hcy and cognitive dysfunction in PD patients compared to European studies. These discrepancies may be attributed to genetic factors, dietary habits, or environmental influences, all of which can significantly affect Hcy metabolism​. Integrating Hcy level monitoring in routine PD assessment could help identify individuals at higher risk for cognitive decline, particularly in regions with dietary or genetic susceptibility. This may be especially valuable in populations with limited access to advanced neuropsychological testing or in settings where preventive strategies could be deployed earlier. To further understand these regional differences, we examined key biological mechanisms that may underlie Hcy elevation in PD. For instance, the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, which reduces the efficiency of Hcy conversion to methionine, is associated with elevated Hcy levels and increased PD risk, particularly in European populations, but not significantly in Asian populations[ 24 ]. Dietary factors, including the intake of B-vitamins, play a role in one-carbon metabolism, which is crucial for Hcy regulation. Deficiencies in these nutrients may increase PD risk by affecting methylation processes and oxidative stress[ 23 ]. Certain dietary patterns, such as high consumption of dairy products, may increase PD risk, while others, like the intake of poly-unsaturated fatty acids, coffee, and tea, may offer protective effects, particularly in men[ 25 ]. Environmental exposures, such as pesticides and toxic substances, have been associated with increased PD risk. These factors may vary between regions, influencing the prevalence and progression of PD [ 26 ]. Lifestyle factors, including smoking and fish consumption, have been shown to decrease PD risk, highlighting the complex interplay between environment and genetic predispositions[ 27 ]. Another factor explored in our analysis was the potential impact of L-dopa therapy on Hcy levels. While previous studies have suggested that L-dopa treatment may elevate plasma Hcy levels through its metabolism by catechol-O-methyltransferase (COMT), which uses S-adenosylmethionine (SAM) as a methyl donor and converts L-dopa to S-adenosylhomocysteine (SAH) and subsequently to Hcy[ 28 ], this meta-regression analysis did not show a significant relationship between L-dopa dosage and Hcy levels. This suggests that while L-dopa may influence Hcy metabolism, disease progression, as indicated by the positive correlation between disease duration and Hcy levels, may be a more critical factor in Hcy-related cognitive dysfunction. This finding aligns with one observational study that indicates a positive correlation between elevated Hcy levels and increased disease duration and severity[ 29 ]. Exploratory comparisons revealed non-significant differences in folic acid and B12 levels between PD-CI and PD-NC groups, suggesting that these nutrients may still influence Hcy metabolism and cognitive function in PD. Future systematic reviews or interventional studies specifically designed to evaluate these nutrients are needed to clarify their roles. Both folate and vitamin B12 are essential for the remethylation of Hcy to methionine, a critical process in the methionine cycle. This reaction is necessary for producing methionine and generating SAM, a vital methyl donor for numerous cellular processes[ 30 , 31 ]. Deficiencies in these vitamins are known to exacerbate the toxic effects of elevated Hcy levels, contributing to cardiovascular, metabolic, and neuropsychiatric disorders[ 32 – 34 ]. While some studies suggest a protective effect of folate and B12 supplementation in reducing cognitive decline, the moderate heterogeneity observed in our analysis suggests that further studies are needed to clarify the role of these vitamins in PD-related cognitive impairment​. Although this review adhered to PRISMA guidelines and followed rigorous methodological standards, several limitations of the review process should be acknowledged. We did not include grey literature, dissertations, or conference proceedings, which may introduce publication bias. Moreover, despite dual independent screening and data extraction, subjective judgment in study selection and classification could not be entirely eliminated. The lack of a formal protocol beyond PROSPERO registration also limits reproducibility. Given the cross-sectional nature of the included studies, a causal link between Hcy and CI in PD cannot be established. Reverse causality and residual confounding factors (e.g., comorbidities, nutritional status) cannot be ruled out. Longitudinal studies are needed to assess how changes in Hcy levels over time correlate with the onset and progression of CI in PD. Additionally, B-vitamin data were included only in a subset of studies and were not part of the predefined literature search, limiting the generalizability of related findings. Future interventional trials evaluating B-vitamin supplementation in PD patients may help clarify whether correcting deficiencies could reduce Hcy levels and mitigate cognitive decline. Future studies should adopt standardized cognitive assessment criteria (e.g., MDS Level 2), harmonized thresholds for Hcy stratification, and longitudinal frameworks to establish causal relationships. Longitudinal tracking and interventional trials targeting Hcy reduction may clarify causality and therapeutic potential. The integration of Hcy measurement into routine clinical care may enable risk stratification. It may also serve as a bridge toward targeted nutritional or pharmacological interventions for cognitive preservation in PD. Given the regional heterogeneity in Hcy levels, population-specific thresholds and context-aware interpretation may be required before Hcy can be adopted in clinical decision-making. Declarations Data availability statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. Competing Interests Statement The author declares no competing interests. Author Contribution Y.H. Chang conceived and designed the study, developed the search strategy, conducted the literature screening and data extraction, performed the statistical analyses, interpreted the results, and drafted and revised the manuscript. The author approved the final version and takes full responsibility for the content of this work. Acknowledgement The author thanks Yo-Ning Chang for her assistance with literature screening and data extraction during the early stage of this study. References Todorović, Z. et al. Homocysteine serum levels and MTHFR C677T genotype in patients with Parkinson's disease, with and without levodopa therapy. J. Neurol. Sci. 248 (1–2), 56–61 (2006). Gallagher, J. et al. Long-Term Dementia Risk in Parkinson Disease. Neurology 103 (5), e209699 (2024). Saredakis, D., Collins-Praino, L. E., Gutteridge, D. S., Stephan, B. C. M. & Keage, H. A. D. 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S., Fowler, B. & Baumgartner, M. R. Vitamin B 12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. J. Inherit. Metab. Dis. 42 (4), 673–685 (2019). Mursleen, M. T. & Riaz, S. Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population. Diabetes Metab. Syndr. 11 (Suppl 1), S141–S146 (2017). Fenech, M., Aitken, C. & Rinaldi, J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19 (7), 1163–1171 (1998). Bottiglieri, T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr. Rev. 54 (12), 382–390 (1996). Setola, E. et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. Eur. J. Endocrinol. 151 (4), 483–489 (2004). Table 1 Table 1 is available in the Supplementary Files section. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6581817","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":457589473,"identity":"0e539edc-ace2-417a-9db6-965da46373f6","order_by":0,"name":"Yu-Hsien Chang","email":"data:image/png;base64,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","orcid":"","institution":"China Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yu-Hsien","middleName":"","lastName":"Chang","suffix":""}],"badges":[],"createdAt":"2025-05-03 04:38:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6581817/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6581817/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83047269,"identity":"e6c5d196-ec72-464c-bc16-24f1845c1bc2","added_by":"auto","created_at":"2025-05-19 11:55:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23314,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/e806a17171784bac1002ed7d.png"},{"id":83047628,"identity":"d10b136b-ac70-420f-a221-7ba215abbbf1","added_by":"auto","created_at":"2025-05-19 12:03:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":94483,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the mean difference in Hcy levels (μmol/L) between PD-CI and PD-NC patients across 12 studies. The studies are divided into European and Eastern subgroups to compare regional variations in Hcy levels.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/6078e42033b0e9eadcc01159.png"},{"id":83047626,"identity":"4c15a5ab-531f-480c-a7f1-bd1bd2f28484","added_by":"auto","created_at":"2025-05-19 12:03:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93111,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between L-dopa dosage (mg/day) and Hcy levels (μmol/L) in PD-CI patients. Each point represents an individual study's reported mean values for L-dopa dosage and homocysteine concentration. The blue line represents the meta-regression model.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/7d1eaadd3403359c642653a9.png"},{"id":83047288,"identity":"ae550363-7f37-47b5-9877-92c96c00729a","added_by":"auto","created_at":"2025-05-19 11:55:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":24015,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between disease duration and homocysteine levels in PD-CI patients. Each point represents a study's reported mean values for disease duration and homocysteine concentration, while the blue line represents the meta-regression model.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/7005e0100e58bf859c3ef2c5.png"},{"id":83047630,"identity":"ce9a0c0f-d332-4429-8873-7fb30c29f013","added_by":"auto","created_at":"2025-05-19 12:03:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":19823,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot assessing the presence of publication bias in the meta-analysis of Hcy levels in PD-CI and PD-NC patients.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/fb824b78ed6a0cddfcc707b6.png"},{"id":83048894,"identity":"0af7413b-68c1-4170-b124-74606009af19","added_by":"auto","created_at":"2025-05-19 12:19:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":942204,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/5d0133a3-bbb0-44f3-8d1d-ec0f5b850102.pdf"},{"id":83047627,"identity":"2de6e2ac-989e-4b4e-8d09-269ed2e86c5a","added_by":"auto","created_at":"2025-05-19 12:03:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":86525,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryscientific.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/6964e80b6760eb2b4e31d001.pdf"},{"id":83047625,"identity":"8cee468e-d5f8-46e9-9c22-ed87f890cb83","added_by":"auto","created_at":"2025-05-19 12:03:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27060,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6581817/v1/9bcd236f1e234daab62ced7f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms. However, cognitive impairment (CI) is a significant and often debilitating feature that exacerbates the disease's progression[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Parkinson\u0026rsquo;s disease dementia (PDD) and mild cognitive impairment (MCI) are common forms of cognitive decline observed in PD patients, with around 47% of PD patients developing dementia within 15 years of diagnosis[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and 20% of patients with PD-MCI progressed to dementia within three years[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, early identification and prevention of cognitive dysfunction in PD are critical, as the progression to dementia or CI not only worsens disease outcomes but also significantly impacts the patient's quality of life, leading to increased dependence, caregiver burden, and loss of independence. Despite the growing recognition of cognitive decline, the underlying biomarkers that contribute to cognitive deterioration in PD remain unclear.\u003c/p\u003e \u003cp\u003eOne potential factor contributing to CI in PD is homocysteine (Hcy), an amino acid involved in methionine metabolism. Elevated levels of Hcy, known as hyperhomocysteinemia (HHcy), have been associated with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Hcy has been shown to exert neurotoxic effects through mechanisms like vascular damage, neuroinflammation, and oxidative stress, all of which are implicated in cognitive dysfunction[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, studies have suggested a relationship between elevated Hcy and cognitive decline in PD, but the findings have been inconsistent.\u003c/p\u003e \u003cp\u003eThis meta-analysis aims to clarify the relationship between Hcy and CI in Parkinson's disease by synthesizing data from multiple studies. We also investigate the potential role of other factors such as levodopa therapy, disease duration, and regional variations in Hcy metabolism across PD populations. By systematically analyzing existing studies, we aim to determine whether Hcy levels could serve as a reliable biomarker for cognitive decline in PD and inform future screening strategies or targeted interventions.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDatabases and search strategy\u003c/h2\u003e \u003cp\u003eWe systematically searched four electronic databases: PubMed, Web of Science, CINAHL, and the Cochrane Library, from inception to March 25, 2025. All databases were last searched on March 25, 2025. No restrictions were placed on language or publication status. In addition to database searching, we manually screened the reference lists of all included full-text articles to identify additional eligible studies. No preprint servers, grey literature sources, or organizational websites were searched. We did not contact study authors or experts for unpublished data. The search strategy incorporated both keywords and Medical Subject Headings (MeSH) terms to maximize coverage.\u003c/p\u003e \u003cp\u003eThe following terms were used in various combinations using Boolean operators (AND/OR): (\"Parkinson's disease\" OR \"Parkinson Disease\") AND (\"homocysteine\" OR \"hyperhomocysteinemia\" OR \"Homocysteine\") AND (\"cognition\" OR \"cognitive impairment\" OR \"Cognition Disorders\"). There were no specific filters or limitations. Reference lists of eligible articles were also manually screened for additional studies. This study has been registered at PROSPERO (ID: CRD42025643475). A formal review protocol was not prepared beyond PROSPERO registration. All procedures were conducted according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) 2020 guidelines.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy screening and selection\u003c/h3\u003e\n\u003cp\u003eThe articles were independently screened by Yu-Hsien Chang and Yo-Ning Chang. An initial review of titles and abstracts was conducted to exclude articles outside the scope of the meta-analysis. Review articles, meeting articles, and preclinical articles were also excluded. For the remaining articles, full-text versions were retrieved for further review. Any uncertainties were resolved through discussion. The flow diagram of this study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eEligibility criteria for study inclusion: 1) Studies that include patients diagnosed with PD based on established criteria such as the UK Brain Bank criteria or MDS Clinical Diagnostic Criteria for Parkinson\u0026rsquo;s Disease. 2) Adequate documentation of case numbers and study findings such as Hcy levels and cognitive function outcomes, as evaluated using standardized neuropsychological assessments such as Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or the cognitive subscales of the Unified Parkinson\u0026rsquo;s Disease Rating Scale (UPDRS). 3) Studies that evaluate the possible relationship between Hcy and cognitive function of PD patients. The patients should include PD Cognitive Impairment group (PDCI group) and PD Normal Cognition group (PDNC group). In this meta-analysis, PD-CI was defined according to each study\u0026rsquo;s criteria, which were based on validated neuropsychological assessments. These included tools such as MMSE, MoCA, Parkinson\u0026rsquo;s Disease Cognitive Rating Scale, and Scales for Outcomes in Parkinson\u0026rsquo;s Disease-Cognition, etc. Only studies that clearly distinguished PD-CI from PD-NC using standardized diagnostic tools or cutoff values were included.\u003c/p\u003e \u003cp\u003eExclusion criteria:1) Preclinical studies, reviews and meta-analysis that don\u0026rsquo;t contain original data. 2) Studies with incomplete data or insufficient statistical information for quantitative synthesis.\u003c/p\u003e\n\u003ch3\u003eAssessment of reporting quality\u003c/h3\u003e\n\u003cp\u003eTwo reviewers (Yu-Hsien Chang and Yo-Ning Chang) independently assessed study quality using the quality assessment tool proposed by Agency for Healthcare Research and Quality (AHRQ)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] for cross-sectional studies. The AHRQ quality assessment tool consisted of 11 items, each evaluated with \u0026ldquo;yes\u0026rdquo;, \u0026ldquo;no\u0026rdquo; or \u0026ldquo;unclear\u0026rdquo;. The 11 items are shown as follows: 1. Define the source of information (survey, record review). 2. List inclusion and exclusion criteria for exposed and unexposed subjects (cases and controls) or refer to previous publications. 3. Indicate time period used for identifying patients. 4. Indicate whether or not subjects were consecutive if not population based. 5. Indicate if evaluators of subjective components of study were masked to other aspects of the status of the participants. 6. Describe any assessments undertaken for quality assurance purposes (e.g., test/retest of primary outcome measurements). 7. Explain any patient exclusions from analysis. 8. Describe how confounding was assessed and/or controlled. 9. If applicable, explain how missing data were handled in analysis 10. Summarize patient response rates and completeness of data collection. 11. Clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or follow-up was obtained. Discrepancies were resolved by consensus. No automation tools were used in the risk of bias assessment process.\u003c/p\u003e\n\u003ch3\u003eData extraction and statistical analyses\u003c/h3\u003e\n\u003cp\u003eTwo reviewers (Yu-Hsien Chang and Yo-Ning Chang) independently extracted data from each included study using a standardized data extraction form. Any discrepancies were resolved through discussion. We did not contact study authors for additional information, and no automation tools were used during the data extraction process.\u003c/p\u003e \u003cp\u003eThe primary outcome of this meta-analysis was the difference in peripheral Hcy levels between PD-CI and PD-NC individuals. Only cross-sectional or baseline Hcy data were included to ensure consistency. When studies employed multiple cognitive assessment tools or diagnostic definitions, we selected the classification most consistent with established diagnostic criteria.\u003c/p\u003e \u003cp\u003eTo determine eligibility for meta-analysis, we included only studies that reported group-level Hcy data (mean, standard deviation, and sample size) for both PD-CI and PD-NC groups. Studies that lacked key numerical data, used incompatible designs, or reported only correlational analyses were excluded from quantitative synthesis but retained for descriptive comparison. We tabulated study-level variables\u0026mdash;including assessment tools, diagnostic thresholds, and population characteristics\u0026mdash;to ensure comparability across studies.\u003c/p\u003e \u003cp\u003eExtracted variables included study-level information such as author name, year of publication, participants\u0026rsquo; age, sex, sample size, disease duration, L-dopa dosage, cognitive assessment tools, definitions of cognitive impairment, and Hcy measurement techniques, and geographic region. Data on folic acid and vitamin B12 levels were collected when reported. However, as these B-vitamin data were not part of the predefined search strategy and were inconsistently reported, their comparisons are presented descriptively and interpreted as exploratory findings rather than part of the formal quantitative synthesis.\u003c/p\u003e \u003cp\u003eWhen outcome definitions or statistical reporting were unclear, assumptions were made based on contextual information within the original articles. No data imputation was performed for missing numerical values. When necessary, standard deviations were calculated from standard errors or confidence intervals using established formulas. No conversions or standardizations were required for Hcy values, as all studies reported results in \u0026micro;mol/L. Results were visually summarized using forest plots for meta-analyses, funnel plots for publication bias assessment, and bubble plots for meta-regression analyses.\u003c/p\u003e \u003cp\u003eMean difference (MD) with 95% confidence intervals (CI) was used as the effect measure for all quantitative syntheses. Meta-analyses were performed using Review Manager (RevMan) version 5.4. Between-study heterogeneity was assessed using the I\u0026sup2; statistic. A random-effects model was adopted due to expected methodological and clinical variability; results were also compared to a fixed-effects model when heterogeneity was low. Meta-regression analyses were conducted in R version 4.4.2 to explore the effects of potential moderators such as disease duration and L-dopa dosage. Certainty of evidence was not assessed using formal frameworks such as the Grading of Recommendations Assessment, Development, and Evaluation, as all included studies were all observational and cross-sectional in design.\u003c/p\u003e \u003cp\u003eLeave-one-out sensitivity analyses were conducted by sequentially removing one study at a time and recalculating the pooled effect size using inverse-variance weighting. This approach was used to assess the robustness and stability of the meta-analytic results. To assess potential reporting bias, we performed Egger\u0026rsquo;s regression test in addition to visual inspection of funnel plots. A p-value less than 0.05 was considered indicative of small-study effects or potential publication bias.\u003c/p\u003e \u003cp\u003eFor subgroup analyses by geographic region, studies were categorized into \"Eastern\" and \"European\" groups based on the geographic and cultural proximity. Eastern countries included East Asia such as China, Southeast Asian nations, and Middle Eastern regions such as Turkey, while European countries included Italy, Spain, and the Czech Republic, following precedent from prior meta-analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Selection and Characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 256 articles were identified through database searches. After removing duplicates and screening titles and abstracts, 17 full-text articles were assessed for eligibility. Of these, 5 were excluded due to the absence of both PD-CI and PD-NC comparison groups or lack of group-level Hcy data. Ultimately, 12 studies[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e] met the inclusion criteria and were included in the final meta-analysis. The study selection process and the reasons for exclusion are summarized in the flow diagram (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe majority of included studies were cross-sectional observational studies comparing peripheral Hcy levels between PD patients with and without cognitive impairment. One study conducted by Vesel\u0026yacute; et al.[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e] was originally designed as a longitudinal cohort, following PD patients over a two-year period to evaluate progression from normal cognition to mild cognitive impairment. However, since Hcy was only measured at baseline, without follow-up data, the study was considered cross-sectional with respect to Hcy-related analysis in this meta-analysis. All other studies provided only cross-sectional or single time-point data for Hcy levels and cognitive status. These studies included 664 PD-CI and 1184 PD-NC participants. The characteristics of the included studies are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, which presents patient demographics, Hcy levels, folic acid levels, vitamin B12 levels, and disease characteristics.\u003c/p\u003e\n \u003cp\u003eThe studies assessed using the AHRQ quality assessment tool demonstrate generally good quality, with most providing clear information on inclusion/exclusion criteria, source of information, and confounding control. However, several areas of concern were identified, including unclear or missing follow-up data and inadequate explanation of how missing data were handled. Additionally, some studies did not specify if evaluators were masked, which could impact objectivity. Despite these issues, the majority of studies demonstrate robust methodology in key areas, though further transparency in reporting follow-up and data handling is recommended for improved study reliability. The results of the assessment of the quality are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eQuality assessment of included studies using the Agency for Healthcare Research and Quality (AHRQ) assessment tool\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy ID\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZoccolella 2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRodriguez-Oroz 2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiu 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVesel\u0026yacute; 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFu 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMart\u0026iacute;nez Horta 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeri\u0026ntilde;\u0026aacute;n 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhang 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKobak Tur 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOuyang 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZhai 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eXiao 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003eAbbreviations: Y, Yes; N, No; U, Unclear.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003ea. The name of the first author and year of publication\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003eb. Items 1\u0026ndash;11 refer to the specific AHRQ criteria, as described in the Methods section.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eHcy Levels in PD-CI vs. PD-NC Patients\u003c/h3\u003e\n\u003cp\u003eThe meta-analysis revealed a significant difference in Hcy levels between PD-CI and PD-NC patients. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the mean Hcy level in the PD-CI group was 3.11 \u0026micro;mol/L higher than in the PD-NC group (95% CI: 2.13, 4.10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Moderate to high heterogeneity (I\u0026sup2; = 71%) was observed across studies, indicating variability in the findings. The overall effect was statistically significant (Z\u0026thinsp;=\u0026thinsp;6.19, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001), suggesting that elevated Hcy could serve as a marker for CI in PD.\u003c/p\u003e \n\u003ch3\u003eSubgroup Analysis: Regional Variations in Hcy Levels\u003c/h3\u003e\n\u003cp\u003eSubgroup analyses by region (European vs. Eastern) revealed differences in Hcy levels between PD-CI and PD-NC patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The European subgroup showed a moderate difference in Hcy levels between PD-CI and PD-NC, with PD-CI patients exhibiting significantly higher Hcy levels (p\u0026thinsp;=\u0026thinsp;0.02). However, moderate heterogeneity (I\u0026sup2; = 52%) was observed, suggesting that factors like dietary habits, B-vitamin supplementation, or diagnostic criteria might explain some of the variability.\u003c/p\u003e \u003cp\u003eThe difference in Hcy levels was more pronounced in the Eastern subgroup, with PD-CI patients showing an average of 3.77 \u0026micro;mol/L higher Hcy levels compared to PD-NC patients (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). This finding was highly significant, though high heterogeneity (I\u0026sup2; = 67%) indicated that regional variations in environmental, dietary, and genetic factors may contribute to the observed variability.\u003c/p\u003e \u003cp\u003eThe subgroup analysis highlights that while the association between elevated Hcy and CI in PD is consistent globally, regional differences should be taken into account in future research, particularly in understanding the effects of diet, genetic variation, and regional healthcare practices on Hcy metabolism.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eFolic Acid and Vitamin B12 Levels\u003c/h2\u003e \u003cp\u003eAlthough differences were not statistically significant, exploratory comparisons suggest a trend toward lower folate and B12 levels in PD-CI patients. Specifically, the MD in folic acid levels was \u0026minus;\u0026thinsp;0.76 ng/mL (p\u0026thinsp;=\u0026thinsp;0.24; I\u0026sup2; = 53%), while the MD in vitamin B12 levels was \u0026minus;\u0026thinsp;27.16 pg/mL (p\u0026thinsp;=\u0026thinsp;0.21; I\u0026sup2; = 72%) (Supplementary Fig.\u0026nbsp;1 and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These comparisons were based on a subset of studies and should be interpreted cautiously, as neither folic acid nor vitamin B12 were part of the original search strategy, and relevant data were not consistently reported across all included studies. The heterogeneity observed suggests that other factors like treatment effects, genetic influences, and dietary factors should be explored in future studies to clarify the role of folic acid and B12 in cognitive decline in PD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMeta-Regression Analysis\u003c/h2\u003e \u003cp\u003eThe meta-regression analysis examining the relationship between L-dopa dosage and Hcy levels revealed no significant association (β\u0026thinsp;=\u0026thinsp;0.0021, p\u0026thinsp;=\u0026thinsp;0.6208) between L-dopa dosage and Hcy levels, with an R\u0026sup2; value of 0.00% indicating that L-dopa does not explain the variability in Hcy levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The model showed substantial residual heterogeneity (I\u0026sup2; = 94.52%), suggesting that other factors, such as disease duration and genetic variations in Hcy metabolism, may influence this relationship.\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eGiven the moderate heterogeneity observed, we further assessed the robustness of results using sensitivity analysis, and a leave-one-out sensitivity analysis was performed using inverse-variance weighting. In this analysis, each individual study was sequentially excluded, and the pooled MD in Hcy levels between PD-CI and PD-NC groups was recalculated using the remaining studies. The resulting weighted MDs ranged from 2.79 to 3.02 \u0026micro;mol/L, indicating minimal fluctuation. This suggests that no single study exerted a disproportionate influence on the overall effect size, thereby supporting the stability and reliability of the pooled estimate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias\u003c/h2\u003e \u003cp\u003ePublication bias was assessed using both visual inspection of the funnel plot and Egger\u0026rsquo;s regression test. The funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003e) appeared symmetrical, suggesting a low risk of publication bias. Egger\u0026rsquo;s test yielded an intercept of 1.185 with a p-value of 0.1379, indicating no statistically significant asymmetry. These findings suggest that the overall meta-analytic results were unlikely to have been substantially influenced by publication bias.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis demonstrates a significant association between elevated Hcy levels and CI in PD, with PD-CI exhibiting consistently higher Hcy levels than PD-NC. These findings support the hypothesis that HHcy may play a pivotal role in the pathophysiology of cognitive decline in PD, consistent with previous studies linking elevated Hcy levels to various neurodegenerative conditions, including Alzheimer's disease and vascular dementia[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The underlying mechanisms through which elevated Hcy contributes to cognitive dysfunction are multifaceted. Hcy is known to induce vascular damage, neuroinflammation, and oxidative stress, all of which are implicated in neurodegeneration[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, studies suggest that high Hcy levels may impair neurotransmitter metabolism and mitochondrial function, exacerbating the neurodegenerative process in PD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]​​. Given that these mechanisms can accelerate cognitive decline, the role of Hcy as a biomarker for cognitive impairment in PD becomes more apparent.\u003c/p\u003e \u003cp\u003eOne of the key limitations of this meta-analysis lies in the heterogeneity of CI definitions across the included studies. Although all studies employed validated neuropsychological tools\u0026mdash;such as MMSE, MoCA, and PD-CRS\u0026mdash;the cutoff values, diagnostic criteria (e.g., MDS Level 1 vs. Level 2), and number of failed domains varied substantially. This variability may introduce measurement bias and reduce the comparability of CI classification between studies. Moreover, the included cohorts likely represented different stages of PD progression, which may independently affect both Hcy levels and cognitive outcomes. These methodological inconsistencies limit the ability to fully harmonize outcome definitions and could contribute to residual confounding. While meta-regression and subgroup analyses attempted to explore disease duration and L-dopa dosage as potential sources of heterogeneity, other unmeasured variables\u0026mdash;such as nutritional status, comorbidities, or differential access to care\u0026mdash;may also influence the observed associations. These factors should be considered when interpreting the findings and underscore the need for future longitudinal studies using standardized diagnostic criteria and comprehensive covariate adjustment.\u003c/p\u003e \u003cp\u003eDespite the overall significant association between Hcy and cognitive decline, the high heterogeneity observed in this meta-analysis (I\u0026sup2; = 71%) indicates that other factors may influence the relationship between Hcy and cognitive function. Regional differences were observed, with Eastern studies showing stronger associations between Hcy and cognitive dysfunction in PD patients compared to European studies. These discrepancies may be attributed to genetic factors, dietary habits, or environmental influences, all of which can significantly affect Hcy metabolism​. Integrating Hcy level monitoring in routine PD assessment could help identify individuals at higher risk for cognitive decline, particularly in regions with dietary or genetic susceptibility. This may be especially valuable in populations with limited access to advanced neuropsychological testing or in settings where preventive strategies could be deployed earlier. To further understand these regional differences, we examined key biological mechanisms that may underlie Hcy elevation in PD.\u003c/p\u003e \u003cp\u003eFor instance, the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, which reduces the efficiency of Hcy conversion to methionine, is associated with elevated Hcy levels and increased PD risk, particularly in European populations, but not significantly in Asian populations[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Dietary factors, including the intake of B-vitamins, play a role in one-carbon metabolism, which is crucial for Hcy regulation. Deficiencies in these nutrients may increase PD risk by affecting methylation processes and oxidative stress[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Certain dietary patterns, such as high consumption of dairy products, may increase PD risk, while others, like the intake of poly-unsaturated fatty acids, coffee, and tea, may offer protective effects, particularly in men[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Environmental exposures, such as pesticides and toxic substances, have been associated with increased PD risk. These factors may vary between regions, influencing the prevalence and progression of PD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Lifestyle factors, including smoking and fish consumption, have been shown to decrease PD risk, highlighting the complex interplay between environment and genetic predispositions[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother factor explored in our analysis was the potential impact of L-dopa therapy on Hcy levels. While previous studies have suggested that L-dopa treatment may elevate plasma Hcy levels through its metabolism by catechol-O-methyltransferase (COMT), which uses S-adenosylmethionine (SAM) as a methyl donor and converts L-dopa to S-adenosylhomocysteine (SAH) and subsequently to Hcy[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], this meta-regression analysis did not show a significant relationship between L-dopa dosage and Hcy levels. This suggests that while L-dopa may influence Hcy metabolism, disease progression, as indicated by the positive correlation between disease duration and Hcy levels, may be a more critical factor in Hcy-related cognitive dysfunction. This finding aligns with one observational study that indicates a positive correlation between elevated Hcy levels and increased disease duration and severity[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExploratory comparisons revealed non-significant differences in folic acid and B12 levels between PD-CI and PD-NC groups, suggesting that these nutrients may still influence Hcy metabolism and cognitive function in PD. Future systematic reviews or interventional studies specifically designed to evaluate these nutrients are needed to clarify their roles. Both folate and vitamin B12 are essential for the remethylation of Hcy to methionine, a critical process in the methionine cycle. This reaction is necessary for producing methionine and generating SAM, a vital methyl donor for numerous cellular processes[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Deficiencies in these vitamins are known to exacerbate the toxic effects of elevated Hcy levels, contributing to cardiovascular, metabolic, and neuropsychiatric disorders[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. While some studies suggest a protective effect of folate and B12 supplementation in reducing cognitive decline, the moderate heterogeneity observed in our analysis suggests that further studies are needed to clarify the role of these vitamins in PD-related cognitive impairment​.\u003c/p\u003e \u003cp\u003e Although this review adhered to PRISMA guidelines and followed rigorous methodological standards, several limitations of the review process should be acknowledged. We did not include grey literature, dissertations, or conference proceedings, which may introduce publication bias. Moreover, despite dual independent screening and data extraction, subjective judgment in study selection and classification could not be entirely eliminated. The lack of a formal protocol beyond PROSPERO registration also limits reproducibility.\u003c/p\u003e \u003cp\u003eGiven the cross-sectional nature of the included studies, a causal link between Hcy and CI in PD cannot be established. Reverse causality and residual confounding factors (e.g., comorbidities, nutritional status) cannot be ruled out. Longitudinal studies are needed to assess how changes in Hcy levels over time correlate with the onset and progression of CI in PD. Additionally, B-vitamin data were included only in a subset of studies and were not part of the predefined literature search, limiting the generalizability of related findings. Future interventional trials evaluating B-vitamin supplementation in PD patients may help clarify whether correcting deficiencies could reduce Hcy levels and mitigate cognitive decline. Future studies should adopt standardized cognitive assessment criteria (e.g., MDS Level 2), harmonized thresholds for Hcy stratification, and longitudinal frameworks to establish causal relationships. Longitudinal tracking and interventional trials targeting Hcy reduction may clarify causality and therapeutic potential. The integration of Hcy measurement into routine clinical care may enable risk stratification. It may also serve as a bridge toward targeted nutritional or pharmacological interventions for cognitive preservation in PD. Given the regional heterogeneity in Hcy levels, population-specific thresholds and context-aware interpretation may be required before Hcy can be adopted in clinical decision-making.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\u003c/p\u003e \n\u003ch2\u003eCompeting Interests Statement\u003c/h2\u003e \u003cp\u003eThe author declares no competing interests.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eY.H. Chang conceived and designed the study, developed the search strategy, conducted the literature screening and data extraction, performed the statistical analyses, interpreted the results, and drafted and revised the manuscript. The author approved the final version and takes full responsibility for the content of this work.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe author thanks Yo-Ning Chang for her assistance with literature screening and data extraction during the early stage of this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTodorović, Z. et al. Homocysteine serum levels and MTHFR C677T genotype in patients with Parkinson's disease, with and without levodopa therapy. \u003cem\u003eJ. Neurol. Sci.\u003c/em\u003e \u003cb\u003e248\u003c/b\u003e (1\u0026ndash;2), 56\u0026ndash;61 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallagher, J. et al. 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Association of MTHFR C677T with total homocysteine plasma levels and susceptibility to Parkinson's disease: a meta-analysis. \u003cem\u003eNeurol. Sci.\u003c/em\u003e \u003cb\u003e36\u003c/b\u003e (6), 945\u0026ndash;951 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoulos, C., Yaghi, N., El Hayeck, R., Heraoui, G. N. \u0026amp; Fakhoury-Sayegh, N. Nutritional Risk Factors, Microbiota and Parkinson's Disease: What Is the Current Evidence? \u003cem\u003eNutrients\u003c/em\u003e ;11(8):1896. (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeorgiou, A. et al. Genetic and Environmental Factors Contributing to Parkinson's Disease: A Case-Control Study in the Cypriot Population. \u003cem\u003eFront. Neurol.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e, 1047 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellou, V., Belbasis, L., Tzoulaki, I., Evangelou, E. \u0026amp; Ioannidis, J. P. 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Vitamin B\u003csub\u003e12\u003c/sub\u003e, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. \u003cem\u003eJ. Inherit. Metab. Dis.\u003c/em\u003e \u003cb\u003e42\u003c/b\u003e (4), 673\u0026ndash;685 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMursleen, M. T. \u0026amp; Riaz, S. Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population. \u003cem\u003eDiabetes Metab. Syndr.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e (Suppl 1), S141\u0026ndash;S146 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFenech, M., Aitken, C. \u0026amp; Rinaldi, J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. \u003cem\u003eCarcinogenesis\u003c/em\u003e \u003cb\u003e19\u003c/b\u003e (7), 1163\u0026ndash;1171 (1998).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBottiglieri, T. Folate, vitamin B12, and neuropsychiatric disorders. \u003cem\u003eNutr. Rev.\u003c/em\u003e \u003cb\u003e54\u003c/b\u003e (12), 382\u0026ndash;390 (1996).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSetola, E. et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. \u003cem\u003eEur. J. Endocrinol.\u003c/em\u003e \u003cb\u003e151\u003c/b\u003e (4), 483\u0026ndash;489 (2004).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Homocysteine, Parkinson Disease, Cognitive Dysfunction, Meta-Analysis, Biomarkers, Neurodegeneration","lastPublishedDoi":"10.21203/rs.3.rs-6581817/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6581817/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHomocysteine, a key metabolite in one-carbon metabolism, has been implicated in neurodegeneration and cognitive decline. While its association with Alzheimer's disease has been extensively studied, its role in Parkinson\u0026rsquo;s disease (PD)-related cognitive impairment remains unclear. We conducted a systematic review and meta-analysis to examine the relationship between plasma homocysteine levels and cognitive dysfunction in PD patients. A systematic search of PubMed, Web of Science, CINAHL, and the Cochrane Library identified 12 eligible studies (n\u0026thinsp;=\u0026thinsp;1,848). Random-effects meta-analysis showed that PD patients with cognitive impairment had significantly higher homocysteine levels compared to those with normal cognition (mean difference: 3.11 \u0026micro;mol/L; 95% CI: 2.13 to 4.10; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Subgroup analysis indicated a stronger association in Eastern populations. Meta-regression revealed a positive correlation between disease duration and homocysteine levels but no significant association with L-dopa dosage. Sensitivity analyses supported the robustness of findings, and no major publication bias was detected. Our findings suggest that hyperhomocysteinemia may serve as a modifiable biomarker for cognitive decline in PD, offering potential avenues for early intervention. Moreover, these results highlight homocysteine metabolism as a broader therapeutic target across aging-related neurodegenerative diseases. This study provides translational insights into the systemic metabolic contributions to neurocognitive health.\u003c/p\u003e","manuscriptTitle":"Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-19 11:55:52","doi":"10.21203/rs.3.rs-6581817/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ae1543ec-cf41-4b9f-8df7-460b1dfcd7f3","owner":[],"postedDate":"May 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48632164,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":48632165,"name":"Health sciences/Diseases/Neurological disorders/Parkinsons disease"},{"id":48632166,"name":"Health sciences/Neurology/Neurological disorders"}],"tags":[],"updatedAt":"2025-05-19T11:55:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-19 11:55:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6581817","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6581817","identity":"rs-6581817","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}