Parkinson’s disease (PD) research is advancing rapidly, driven by innovations in neuroimaging, biomarker science, and therapeutic development. The field is moving beyond symptom management toward biologically grounded strategies for early diagnosis, disease staging, and modification.

Biomarker-Driven Staging: The NSD-ISS Framework

A major shift is underway in how PD is diagnosed and staged. Inspired by biomarker frameworks in Alzheimer’s disease, the Neuronal α-Synuclein Disease–Integrated Staging System (NSD-ISS) offers a biologically based model to classify PD and related synucleinopathies. NSD-ISS combines clinical symptoms with biomarkers—especially α-synuclein seed amplification assays (SAA), DaT-SPECT imaging, and fluid markers of neurodegeneration—to define stages from preclinical to advanced disease. This supports earlier, more accurate diagnosis and better trial stratification.

A key enabler is the growing use of CSF-based α-synuclein SAA, which detects misfolded α-synuclein aggregates with high sensitivity and specificity. These assays are capable of identifying disease pathology even in the prodromal phase, enabling earlier enrolment into clinical trials and more targeted treatment approaches.

Advanced MRI Tools: Neuromelanin and QSM

Neuromelanin-sensitive MRI and quantitative susceptibility mapping (QSM) are gaining traction as non-invasive imaging biomarkers in PD. Neuromelanin MRI detects degeneration in the substantia nigra, where dopaminergic neurons rich in neuromelanin are lost in PD. QSM quantifies brain iron accumulation—a marker linked to oxidative stress and neurotoxicity.

Together, these techniques offer complementary insights into PD pathology and are now being integrated into clinical trials for diagnosis, monitoring progression, and evaluating treatment efficacy.

Toward Multimodal Biomarkers

Overall, PD biomarker strategies are increasingly multimodal, often integrating:

• Molecular assays (e.g., α-synuclein, neurofilament light)
• Imaging (e.g., PET/SPECT, neuromelanin-sensitive MRI, QSM)
• Genomic and proteomic profiling
• Digital and wearable sensor data

This approach supports a move toward precision medicine, allowing individualized disease classification, monitoring, and therapeutic targeting.

Therapeutic Development: Disease-Modifying and Symptomatic Trials

Recent trial results underscore the transition toward biomarker-informed, disease-modifying therapies:

• Roche’s prasinezumab (anti-α-synuclein mAb): Although the Phase IIb PADOVA trial did not meet its primary endpoint, exploratory and long-term data showed promising trends, especially in levodopa-treated patients. Imaging biomarkers, including neuromelanin MRI, supported reduced neurodegeneration. A Phase III trial is in progress.
• AbbVie’s tavapadon (D1/D5 partial agonist): Met primary motor endpoints in multiple Phase III studies, reducing “off” time; FDA submission is expected in 2025.
• Gain Therapeutics’ GT‑02287 (GCase modulator): Demonstrated safety and target engagement in Phase I; patient trials are underway.

Notable ongoing trials include:

• Ambroxol (GREAT trial): A GCase enhancer for GBA-PD with a biomarker-rich design.
• NLRP3 inflammasome inhibitors (e.g., Inzomelid, VTX3232): Targeting neuroinflammation.
• AAV2‑GDNF gene therapy: Phase I neuroprotective strategy via direct infusion.
• Solangepras (CVN-424): A GPCR6 inverse agonist in Phase III for motor fluctuations.
• UCB0022 (Glovadalen): A selective D1 receptor PAM in Phase II ATLANTIS trial, aiming to reduce “off” time; preclinical data suggests strong motor benefit with fewer dyskinesias.

Additional symptomatic therapies in development:

• Befiradol (NLX‑112): A 5‑HT₁A receptor agonist targeting levodopa-induced dyskinesia.
• Pirepemat (IRL‑752): In Phase II for treating apathy and motivational deficits.
• MAO-B inhibitors (e.g., rasagiline): Provide modest early-stage symptom relief.

Outlook: Precision Care in Parkinson’s Disease

These developments signal a future focused on:

• Individualized therapy based on molecular and imaging biomarkers
• Early detection and intervention in at-risk individuals
• True disease modification, not just symptom control

The integration of multimodal biomarkers and advanced imaging is accelerating a precision medicine era in PD, offering hope for more effective, targeted, and preventive care strategies.

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