Structural, functional and neurochemical imaging mapping of non-motor symptoms in Parkinson’s disease

Non-motor symptoms, including rapid eye movement sleep behavior disorder (RBD), depression, and anxiety, are common and often co-occurring in patients with Parkinson's disease (PD), suggesting a possible shared neurobiological vulnerability. This study aimed to characterize the structural, functional, and neurochemical correlates of these symptoms in a large PD cohort.

We analyzed data from 638 PD patients from the Parkinson's Progression Markers Initiative (PPMI) with 3T MRI. RBD, depression, and anxiety severity were assessed with the RBD Screening Questionnaire, Geriatric Depression Scale, and State-Trait Anxiety Inventory. Voxel-based morphometry (VBM) regression identified grey matter (GM) correlates of each symptom, controlling for age, sex, education, disease duration, MDS-UPDRS-III, MoCA, and total intracranial volume, with mutual adjustment across the three symptom scores (and antidepressant use in the RBD model). Coordinate-based network mapping (normative connectome, N=1000) characterized symptom-specific functional networks from VBM clusters, and spatial correlations with normative PET/SPECT neurotransmitter maps were assessed (JuSpace).

VBM revealed distinct GM atrophy patterns (pFWE<0.05), overlapping in the left middle temporal and right middle frontal gyri. Functional networks (pFWE<10⁻⁶) overlapped substantially across symptoms (Dice: anxiety–depression 0.49, depression–RBD 0.47, anxiety–RBD 0.29) and showed preferential spatial affinity with the Dorsal and Ventral Attention Networks. While depression- and anxiety-related networks correlated with multiple neurotransmitter systems, the noradrenaline transporter (NAT) was the only system significantly associated with all three symptom networks (z>0.2, pFDR<0.05).

These findings, consistent with prior evidence implicating noradrenergic/locus coeruleus dysfunction in PD non-motor symptoms, suggest a shared network vulnerability — rather than a deterministic shared mechanism — linking RBD, depression, and anxiety, that may help explain their frequent clinical co-occurrence. Cross-sectional design and reliance on normative connectome/PET data warrant cautious, correlational interpretation.