Mapping White-Matter Alterations in Parkinson’s Disease: Tractography, Diffusion Models, and Neuroplasticity Across Subtypes

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Parkinson’s disease (PD) encompasses marked heterogeneity across motor, cognitive, and non-motor domains, reflecting variable balances of neurodegeneration and compensation across distributed brain circuits. Diffusion MRI tractography enables pathway-specific characterization of white matter alterations and offers a framework for linking clinical subtypes to patterns of degeneration and compensation along individual tracts that are often obscured by skeleton-based or connectomic averaging. Although several tract-specific correlational diffusion studies have linked individual pathways to clinical features and progression, much of the literature has relied on group-level skeleton or network representations, limiting generalizability and reproducibility across subtypes. Here, we synthesize tractography-based evidence across PD subtypes—including tremor-dominant, postural instability/gait difficulty, freezing of gait, and cognitive phenotypes—while situating these findings within a complementary multimodal imaging context. We review diffusion models ranging from diffusion tensor imaging to advanced free-water, neurite and fixel-based frameworks, highlighting how these approaches constrain and interpret tract-level findings and help distinguish degenerative processes from adaptive neuroplasticity. Emerging analytical approaches, including harmonization pipelines, radiomic tractometry (the extraction of along-tract microstructural and radiomic features), and machine learning classifiers, further enhance tract-level sensitivity and reproducibility. Cognitive subtypes illustrate how degeneration of posterior association and limbic tracts, in interaction with non-dopaminergic systems such as cholinergic and noradrenergic pathways, shapes clinical progression. Integrating tractography with molecular, genetic, and functional markers enables subtype-specific biomarkers for risk stratification, prognosis, and targeted therapeutic intervention. We propose a conceptual and methodological roadmap for leveraging tractography to refine PD subtype definitions and inform precision neuromodulation and rehabilitation strategies.

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