Neuroimaging and Transcriptomic Insights Into Iron Accumulation and Glymphatic Dysfunction in Olfactory Dysfunction

BACKGROUND: Olfactory dysfunction (OD) is clinically linked to inflammation and neurotoxin accumulation, yet the underlying neurobiological mechanisms remain largely unclear. Understanding how glymphatic function, iron dysregulation, and transcriptomic signatures contribute to OD may reveal new biomarkers and mechanisms of recovery. METHODS: A multimodal MRI framework integrating BOLD-CSF coupling, quantitative susceptibility mapping (QSM), and transcriptomic profiling was applied to post-viral (PVOD), post-traumatic (PTOD), and healthy control (HC) groups. Iron accumulation was quantified with QSM and linked to gene expression using partial least squares regression, followed by GO and protein-protein interaction analyses. RESULTS: PVOD showed significantly increased iron accumulation in the right inferior frontal and temporal cortices, regions related to olfactory memory and recognition. Transcriptomic associations indicated that iron deposition correlated with genes involved in neuronal organization, axon development, synapse formation, and intracellular signaling. PVOD also demonstrated enhanced glymphatic activity, reflected by stronger BOLD-CSF coupling compared to HC and PTOD. Patients with complete recovery exhibited the strongest coupling, suggesting improved neurotoxin clearance. CONCLUSION: OD is characterized by abnormal iron accumulation and altered glymphatic function, accompanied by transcriptional signatures supporting neuroplasticity. Enhanced glymphatic clearance and neuronal remodeling may facilitate recovery after viral injury, offering potential biomarkers for OD diagnosis and prognosis.