Objective: This study elucidates spatiotemporal functional connectivity of pure fatigue in early Parkinson’s disease (PD) and uncovering underlying gene expression profiles.

Background: Fatigue is a prevalent, debilitating non-motor symptom in early PD, yet its CNS mechanisms remain unclear. Isolate “pure” fatigue mechanisms in PD remains a critical gap. This study addresses this by dissecting the neural circuitry and molecular landscape of fatigue while controlling for confounders.

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Method: Participants: 76 subjects: 31 early PD with pure fatigue (PD-F), 31 without fatigue (PD-NF), and 14 healthy controls (HC). Strict exclusion criteria removed depression, anxiety, sleep disorders, apathy, sarcopenia, and cognitive impairment.

Imaging: 3.0T rs-fMRI (medication-off/naïve). Calculated sFCD and dFCD.

Transcriptomics: Used JuSpace for neurotransmitter/cell-type correlation and Allen Human Brain Atlas for Gene Category Enrichment Analysis (GCEA).

Results: Clinical: PD-F showed greater motor/functional disability (MDS-UPDRS II/III) and higher FSS scores (5.58±0.95 vs 2.06±0.84, p<0.001) than PD-NF, with no significant differences in mood/cognition, confirming pure fatigue isolation.

Figure 1 illustrates reduced dFCD in left calcarine fissure and right precentral gyrus; shows negative correlation with FSS).

Molecular Correlations: Fatigue-related dFCD alterations spatially correlated with Dopamine D2 receptors (p=0.014), COX-1 (neuroinflammation, p=0.007), glucose metabolism (p=0.011), HDAC expression (epigenetics, p=0.027), and mitochondrial density (p=0.016).

Figure 2 visualizes spatial overlaps with D2, COX-1, glucose, HDAC, and mitochondria.

Gene Expression: GCEA revealed enrichment in protein modification/epigenetic regulation, RNA processing, glucose/lipid metabolism, neuroinflammation, blood-brain barrier function, and dopaminergic/cholinergic signaling.

Figure 3 Displays enriched GO categories: epigenetic regulation, RNA processing, energy metabolism, neuroinflammation, BBB function, receptor signaling.

Conclusion: Fatigue in early PD involves specific spatiotemporal connectivity abnormalities in visual/sensorimotor cortices, rooted in molecular pathologies like histone acetylation dysregulation, neuroinflammation (COX-1), and metabolic dysfunction.

Table 1: Clinical characteristics

Figure 1: Fatigue-related dFCD in PD

Figure 2

Figure 3: Gene categories

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