Editorial: Advancing Personalized Diagnosis and Treatment in Parkinson's Disease: Integrating Biomarkers, Neuroimaging, and Artificial Intelligence

Alice Maria Giani^1*Steven Shafek²Elisa Tatti^2*

• ¹Icahn School of Medicine at Mount Sinai Claude D Pepper Older Americans Independence Center, New York, United States
• ²CUNY School of Medicine, New York, United States

Once viewed primarily as a late-onset movement disorder, Parkinson's disease (PD) is increasingly recognized as a multisystem syndrome with motor and non-motor symptoms arising from diverse genetic, molecular, neurological, and environmental factors.With the number of individuals affected more than doubled over the past three decades (Global Burden of Disease 2021) and the dramatic growing prevalence of early-onset forms (Li et al., 2025), researchers and clinicians are exploring how to integrate epidemiological insights, lifestyle determinants, and emerging biomarkers to identify PD pathophysiology and build personalized approaches to early diagnosis and treatment. Integrating Biomarkers, Neuroimaging, and Artificial Intelligence, brings together original studies and reviews that showcase innovative methodologies and clinical insights pointing the way toward integrated patient-specific care for PD. One of the biggest challenges in moving toward personalized care in PD lies in its clinical heterogeneity. Patients differ not only in the motor symptoms they display but also in the occurrence of non-motor symptoms, such as cognitive and mood disturbances. Neuroimaging approaches have been providing a deeper understanding of the neural basis of PD and several contributions to this Research Topic used such techniques to explore PD heterogeneity.Using MRI, Song and colleagues (Song et al. 2025) conducted the largest meta-analysis to date of regional homogeneity (ReHo) alterations, combining 72 datasets from over 2,000 patients with PD and 1,400 controls. This study revealed a distributed dysfunctional network, involving the visual, somatomotor, dorsal and ventral attention networks, confirming that PD pathology extends beyond dopaminergic circuits to large-scale networks.Another study (Xu T. et al. 2025) investigated hemispheric lateralization, a hallmark of asymmetric dopaminergic degeneration associated with distinct symptom profiles (Voruz Guéin and Péron, 2025). Compared to right-onset patients, left onset patients with PD (LPD) showed reduced cortical area in the right supramarginal gyrus, right precuneus, left inferior parietal lobule, and left lingual gyrus relative. In LPD, the right precuneus area positively correlated with MMSE cognitive scores, consistent with previous reports (Syrimi et al., 2017;Lee et al., 2016). At the network level, LPD patients exhibited altered topological organization, with increased path length and reduced small-world index, indicative of reduced efficiency.Building on this network-level approach, another study examined different stages of PD using resting-state fMRI and graph theory analysis (Wei et al., 2025). Both early-and middle-to-latestage patients with PD showed reduced clustering coefficients, indicating decreased local networks' specialization. More advanced patients showed an overall decline in network efficiency, both locally and across the whole brain. Importantly, centrality within the left middle frontal gyrus and right middle temporal pole correlated with clinical measures of motor severity and disease stage.Going beyond PD staging and subtyping, another critical challenge lies in distinguishing idiopathic PD from secondary conditions, such as drug-induced Parkinsonism (DIP). Zhou and colleagues (Zhou W. et al., 2025) found greater reduction in bilateral whole hippocampal volume and subfields atrophy in DIP patients compared to patients with PD and controls, which correlated with cognitive deficits, depressive and motor symptoms. However, DIP patients' lower MoCA cognitive scores may partially explain these volumetric differences, emphasizing the need to control for baseline cognitive functioning in future studies. Overall, these contributions highlight how neuroimaging techniques can capture several dimensions of PD heterogeneity, from volumetric changes to network dysfunction, lateralization, and EEG slowing. By linking structural and functional alterations to specific symptoms, these methods move beyond simple PD subtyping to identify patients at risk of rapid progression or cognitive decline, guide treatments, provide tools for monitoring disease trajectories, and enrich clinical trials with biologically defined subgroups, thereby accelerating the translation of precision medicine approaches into practice. Complementing this neuroimaging and electrophysiological evidence, other contributions in this Research Topic highlight how genetic, fluid, and metabolomic biomarkers can refine PD diagnosis, staging, and phenotyping, and how they can be combined or mapped onto brain networks for improved personalized care.A single-center longitudinal study (Xu H.L. et al. 2025) found that, compared to GG homozygotes, BST1 rs4698412 A-allele carriers had faster motor, but not cognitive, decline, mainly driven by rigidity and bradykinesia. This highlights a common PD-risk variant as a potential progression biomarker, useful for refining prognosis and optimizing trials for accelerated motor decline.In the WPBLC cohort, He and colleagues found that elevated plasma Parkin in patients with PD had moderate diagnostic accuracy. Combining Parkin with homocysteine, total protein, and urea improved discrimination. Parkin correlated with blood α-synuclein oligomers and phosphorylated α-synuclein, but not with motor severity. Mediation analyses suggested partial effects via albumin and carcinoembryonic antigen, and transcriptomics pointed to PINK1-PRKN mitophagy and related metabolic pathways. Together, these data support a minimally invasive multi-analyte blood panel for PD (He H. et al. 2025).Another study integrated plasma neurofilament light (NfL) with cortical morphometry and connectivity and observed that patients with PD with excessive daytime sleepiness (EDS) show higher NfL, focal parietal thinning (left supramarginal gyrus; right postcentral gyrus), and reduced parietal-frontal coupling. NfL partially mediated the link between supramarginal thickness and EDS severity. These results support combined neuroimaging and plasma NfL biomarkers to clarify EDS mechanisms and track non-motor progression (Chen J. et al. 2025).Finally, blood metabolomics identified seven molecules distinguishing PD from controls and a distinct three-metabolite pattern specific to PD with REM sleep behavior disorder (PD-RBD). PPAR signaling in PD-RBD, supporting these metabolites as candidate (Chen H. et al. 2025). Beyond neuroimaging and molecular markers, population-based studies have also identified systemic biomarkers of PD. In a cross-sectional analysis of NHANES 2005-2020 data, Zhao and colleagues (2025) found that higher systemic immune-inflammation index (SII) values, derived from routine blood counts, were linked to greater PD prevalence, particularly at higher SII levels.These findings highlight PD's multisystem nature and support immune-inflammatory markers as useful indicators.Similarly, Zhou and collaborators reported that cardiovascular health, reflected by higher Life's Essential 8 (LE8), correlated with lower PD risk, suggesting that maintaining cardiometabolic health may help reducing disease risk (Zhou C. et al. 2025).Digital and AI-based tools are also advancing PD diagnostics. In a cross-sectional study, a digital clock drawing test (dCDT) was implemented to differentiate PD patients with mild cognitive impairment (MCI) from Alzheimer's disease (AD) (Wang et al., 2025). Combined metrics separated AD-MCI from PD-MCI with high accuracy and the overall drawing score correlated with the MoCA visuospatial/executive subtest score, supporting dCDT's value in cognitive assessment.Eye-tracking, increasingly integrated with machine learning (ML) and virtual reality (VR), is further refining PD phenotyping. In their systematic review, Culicetto and colleagues reported that oculomotor metrics, such as saccade velocity, fixation duration, and pupil size, correlated with disease severity, and that integrating these metrics with ML/VR pipelines improve diagnostic accuracy and scalability (Culicetto et al., 2025). Together, these advances position eye-tracking as a promising biomarker platform for motor and cognitive dysfunction in PD, though standardization across devices and protocols remains essential before clinical adoption. Huang and colleagues demonstrated that galangin mitigated MPTP-induced dopaminergic neurodegeneration in mice, restoring striatal dopamine levels, reducing neuroinflammatory cytokines and α-synuclein accumulation, increasing antioxidant enzymes and improving motor performance. Mechanistically, galangin activated PI3K/AKT/CREB-BDNF signaling, inhibited Beclin-1-dependent autophagy, and preserved TH-positive neurons, indicative of its diseasemodifying efficacy in preclinical models (Huang et al., 2025).Taking another innovative approach, Deng and colleagues reported the first documented case of combining posterior subthalamic area (PSA) and globus pallidus internus (GPi) deep brain stimulation (DBS) in a single PD patient with pronounced left-right asymmetry. The PSA is a tremor-responsive target, whereas the GPi is favored for treating rigidity and dyskinesia. A left PSA lead suppressed right-sided tremor, and a right GPi lead treated left-sided rigidity and dyskinesia. Over six months of this dual-target DBS, motor status improved and tremor frequency decreased, while cognition remained intact with no significant adverse effects. As a single case with short follow-up, these findings support feasibility of symptom specific dual-target neuromodulation for individualized therapy, while larger controlled studies are needed to establish effectiveness (Deng Q. et al. 2025). As PD emerges as a multifaceted disorder extending beyond dopaminergic degeneration, progress in care will depend on closer integration of technology and neurobiologically informed clinical practice. Collectively, the studies in this Research Topic show that combining biomarkers, advanced neuroimaging, and AI-driven analytics enables earlier diagnosis, personalized treatment, and improved monitoring of disease progression, indicating an ongoing shift toward precision care.