Objective: To examine SDI across cognitive stages of Parkinson’s disease (PD) and its associations with cortical thickness (CTh), cognition, and cell-type transcriptomic signatures.

Background: Cognitive impairment is a prevalent non-motor manifestation of PD. The structural-functional decoupling index (SDI) quantifies deviation of regional functional activity from structural connectivity constraints. The spatial pattern, relationship with CTh, and transcriptomic basis of PD cognitive impairment remain unclear.

Method: We prospectively enrolled 309 patients with PD: 106 with normal cognition (PDNC), 125 with mild cognitive impairment (PDMCI), and 78 with dementia (PDD). Regional SDI and CTh were derived from multimodal MRI. After adjustment for age, sex, disease duration, and education, we performed group comparisons, clinical association analyses, and joint regression models. Imaging transcriptomics was performed using the Allen Human Brain Atlas with spatial permutation testing and gene set enrichment analysis (GSEA).

Results: Compared with PDNC, PDD showed increased SDI in higher-order association cortices, most prominently in the right middle orbitofrontal gyrus, left inferior orbitofrontal gyrus, and left inferior temporal gyrus (Cohen’s d=0.893, 0.642, and 0.990), and were associated with cognitive decline. PDD also showed cortical thinning in orbitofrontal and temporal regions. However, regional SDI was not directly associated with corresponding CTh (q>0.68; partial R²<0.004). After controlling for CTh, SDI remained significantly associated with cognition, supporting independent and complementary effects of SDI and CTh. GSEA showed oligodendrocyte-positive and microglia-negative enrichment in PDD vs PDMCI (NES=1.89 and -1.96). In PDD vs PDNC, microglial signatures remained negatively enriched (NES≈-1.98), whereas glutamatergic and immature neuronal signatures showed positive enrichment (NES≈1.9).

Conclusion: Structural-functional decoupling shows regional selectivity during cognitive decline in PD, predominantly involving orbitofrontal and temporal association cortices. These abnormalities increase with worsening cognitive impairment and remain relatively independent of cortical atrophy. Their spatial pattern shows stage-dependent cellular signatures, suggesting that SDI links macroscale network abnormalities to microscale molecular features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/structural-functional-decoupling-and-imaging-transcriptomics-in-cognitive-impairment-of-parkinsons-disease/