The Association Between Neural Biomarkers and Olfactory Dysfunction in the Prodromal Stage of Parkinson’s Disease: A Systematic Review

Background: Parkinson’s disease (PD) is preceded by a prolonged prodromal phase marked by non-motor symptoms such as olfactory dysfunction (OD). Early identification of at-risk individuals remains challenging due to the lack of validated biomarkers. This systematic review evaluates the association between neural biomarkers and OD in prodromal PD, focusing on diagnostic accuracy and clinical utility. Methods: Following PRISMA guidelines, we searched PubMed, Scopus, Web of Science, and Embase (۲۰۰۰–۲۰۲۵) for studies assessing neural biomarkers (neuroimaging, molecular, genetic) and OD in prodromal PD. Risk of bias was evaluated using the Newcastle-Ottawa Scale. Results: Twenty-four studies (n=۳۷۲۱) met inclusion criteria. Analysis of DAT-SPECT imaging revealed significant deficits in striatal dopamine transporter binding in individuals with OD who later developed PD [Hazard Ratio (HR) ۷.۳, ۹۵% CI ۴.۱–۱۲.۹, p۰.۰۰۱]. Reduced striatal binding correlated with OD severity (r=-۰.۵۳, p=۰.۰۰۲). Skin and CSF α-synuclein aggregates, measured by RT-QuIC, showed high specificity (۸۹%, ۹۵% CI: ۸۲–۹۴%) for prodromal PD. Genetic analyses indicated that LRRK۲ G۲۰۱۹S carriers had higher OD prevalence (۵۵% vs. ۳۶%, p=۰.۰۰۰۳) and significant DAT deficits. Combining DAT-SPECT and olfactory testing substantially improved diagnostic accuracy [Area Under the Curve (AUC)=۰.۸۸]. Conclusion: Olfactory dysfunction in prodromal PD is strongly linked to nigrostriatal degeneration, α-synuclein pathology, and genetic susceptibility. Multimodal biomarker panels, particularly combining DAT imaging and olfactory testing, enhance early diagnosis and risk stratification. Standardization of protocols and longitudinal validation are critical for clinical translation. Keywords: Parkinson's Disease, Olfactory Dysfunction, Neural Biomarkers

کلیدواژه ها:

Parkinson's Disease ، Olfactory Dysfunction ، Neural Biomarkers