Most of us reach for DAT-SPECT or dopaminergic PET when we think about imaging biomarkers in PD. But a recent consensus paper from an international faculty assembled in Milan (Cilia et al., Brain Sciences, Jan 2026; https://doi.org/10.3390/brainsci16010110) synthesizes findings from four themed sessions spanning neurotransmitter dysfunction, protein pathology, and clinical translation. A few highlights that stood out:
Noradrenergic system: Neuromelanin-sensitive MRI of the locus coeruleus (LC) shows reduced signal in PD compared to healthy controls, and may detect changes even in prodromal stages such as iRBD. Molecular imaging of the noradrenaline transporter (NAT) links LC-NA dysfunction to rest tremor, freezing of gait, sleep disturbance, and orthostatic hypotension. The authors conclude that LC-NA imaging could be a robust complementary biomarker to DAT, particularly for non-motor symptom phenotyping.
Cholinergic system: MRI markers of nucleus basalis of Meynert (NBM) integrity correlate with cognitive impairment in PD. Importantly, white-matter connectivity of NBM projection pathways appears even more sensitive than structural NBM measures, and may serve as an earlier marker of dementia risk across the Lewy body continuum. Free-water imaging in the thalamic dorsomedial nucleus has also been linked to cognitive decline.
Multi-neurotransmitter framing: The overarching message is that PET, SPECT, and MRI offer complementary windows into dopaminergic, noradrenergic, cholinergic, and serotonergic dysfunction; and that combining these with clinical phenotyping and fluid biomarkers is where the field is headed.
This is directly relevant to how we use data available through the PPMI and other avaiable datasets. A few near-term analyses that seem tractable:
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NM-MRI in PPMI: The PPMI imaging protocol has included neuromelanin-sensitive sequences in a subset of participants. Has anyone extracted LC or SN NM-MRI features from PPMI and correlated them with non-motor outcomes (sleep, autonomic, cognitive scores)? This seems like a publishable gap worth filling.
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White-matter free-water analysis: Free-water corrected diffusion imaging is available in PPMI. A targeted analysis of thalamic dorsomedial nucleus or NBM projection tracts and their relationship to longitudinal cognitive trajectories (MOCA, HVLT, …) would map onto the cholinergic findings in this paper.
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DAT + MRI multimodal subtyping: Rather than using DAT-SPECT in isolation, combining it with NM-MRI or cholinergic white-matter metrics might reveal more biologically coherent subtypes than motor phenotype alone. The PPMI sample size should give reasonable statistical power for a clustering approaches.
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iRBD as a prodromal window: The PPMI prodromal cohort includes iRBD participants with longitudinal imaging. Tracking LC NM-MRI signal decline from prodromal to diagnosed PD would be a strong test of whether it outperforms or complements DAT as an early marker.
Open questions for community members
- Does anyone have preprocessing pipelines for NM-MRI (SN or LC) from PPMI they’d be willing to share?
- Is there appetite for a working group focused on non-dopaminergic imaging markers in PPMI?
- Are there other datasets (BioFIND, UK Biobank PD subsample) that could be used for replication?
Happy to hear your ideas on any of these to see if there’s overlap with what others are already working on. Please feel free to share your thoughts and ideas maybe that would open new oppurtunities for collaboration between members working on related topics! 