Neuroimaging and Pathology Biomarkers in Parkinson's Disease and Parkinsonism

Abstract

The "Neuroimaging and Pathology Biomarkers in Parkinson's Disease" course held on 12-13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the "brain-first" versus "body-first" model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice.

Keywords: Parkinson’s disease biomarkers; Proteinopathies; co-pathology; multimodal neuroimaging; prodromal and atypical parkinsonism; translational precision medicine.

Figure 3

Cholinergic and Serotonergic Pathways in Parkinson’s Disease and Dementia with Lewy bodies. (A). Cholinergic pathways originating from the nucleus basalis of Meynert (NB) project to widespread cortical regions and are crucial for cognitive processing. These patterns are associated with progressive cognitive impairment and may also contribute to autonomic dysfunction. (B). Brainstem cholinergic pathways arising from the pedunculopontine nucleus (PPN) innervate subcortical motor structures and spinal locomotor circuits. (Adapted from Bohnen NI et al. [50]). (C). Serotonergic pathways. Ascending projections from the raphe nuclei modulate a wide range of non-motor symptoms (including depression [43], fatigue [47], sleep disturbances [48], visual hallucinations [46], and impulse control disorders [49]) and contribute to motor features (e.g., tremor [44] and levodopa-induced dyskinesias [45]), reflecting the interplay between 5HT and DA systems in PD pathophysiology (Modified from https://neurotorium.org/image/nt-serotonin-pw-normal/, accessed on 7 January 2026).

Figure 1

MRI of Dopaminergic System in PD. (A). NM-sensitive MRI axial slice passing by the midbrain showing the high signal intensity of the substantia nigra (red arrows) in a healthy subject (image on the left) and a patient with PD (image on the right). (B). Probability maps of the substantia nigra using NM signal intensity overlaid a brain template in a group of healthy subjects (controls) and patients with PD with 3.7-, 9.6- and 11.8-years disease duration. Percentages indicate the percent reduction in substantia nigra volume for each disease duration (adapted from Biondetti E. et al. Brain 2020 [13]). (C). (Left): Quantitative susceptibility map of the substantia nigra in the axial plane. (Right): Violin plots comparing the baseline distributions of QSM values in the posteroventral nigra between a group of healthy subjects (black), patients with isolated RBD (blue) and PD (red) (**, statistically significant difference) adapted from Gaurav R, et al. [20]). (D). (Left image): High-resolution axial 3D echo planar images showing the area of high signal intensity in the inferolateral part of the substantia nigra in a healthy control (swallow tail sign, red arrows). (Right image): This sign is not visible in a patient with PD).

Figure 2

MRI and Molecular Imaging of Noradrenergic System in PD. (A). NM-sensitive MRI sagittal representation of the Locus Coeruleus. Neuromelanin signal is reduced in patients with PD (image on the right) compared to healthy subjects (image on the left). (B). Molecular imaging of the NAT: areas of reduced updated and their association with motor and nonmotor clinical features (e.g., rest tremor, freezing of gait; sleep, orthostatic hypotension, cognitive dysfunction) are depicted.

Figure 4

α-Synuclein PET imaging in vivo. (A). Axial SUVR PET image of [¹⁸F]SPAL-T-06 overlaid on MRI in a patient with possible prodromal multiple system atrophy of cerebellar type (MSA-C). Shown at the level of the middle cerebellar peduncles, the tracer accumulates in regions characteristic of MSA (the pons, middle cerebellar peduncles, and cerebellar white matter), achieving high-contrast visualization of α-synuclein pathology (red arrowheads). (B) Concordance between striatal DAT-SPECT uptake reduction (upper panel) and [¹⁸F]-C05-05 accumulation in the midbrain (lower panel), both showing left-predominant changes contralateral to the right-dominant motor symptoms, in a patient with familial PD due to the A53T mutation in the SNCA gene.

Figure 5

Practical workflow for imaging and biomarker selection in PD and parkinsonism. The flowchart links common clinical scenarios (uncertain parkinsonism, prodromal high-risk states, cognitive impairment, suspected atypical parkinsonism, and advanced-therapy planning) to a stepwise selection of established and emerging biomarkers across neurotransmitter dysfunction imaging, pathology imaging, and peripheral/CSF assays. To facilitate implementation and to highlight research priorities for biomarker qualification, tools are color-coded by maturity level: clinically established (green) vs. emerging, ongoing validation (orange) vs. experimental and limited to research (red).