Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson’s disease

Ahmed Faraz Khan, Quadri Adewale, Sue-Jin Lin, Tobias R. Baumeister, Yashar Zeighami, Felix Carbonell, Nicola Palomero-Gallagher and Yasser Iturria-Medina ()
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Ahmed Faraz Khan: Montreal Neurological Institute, McGill University
Quadri Adewale: Montreal Neurological Institute, McGill University
Sue-Jin Lin: Montreal Neurological Institute, McGill University
Tobias R. Baumeister: Montreal Neurological Institute, McGill University
Yashar Zeighami: Montreal Neurological Institute, McGill University
Felix Carbonell: Biospective Inc
Nicola Palomero-Gallagher: Research Centre Jülich
Yasser Iturria-Medina: Montreal Neurological Institute, McGill University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Parkinson’s disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson’s disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson’s disease.

Date: 2023
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DOI: 10.1038/s41467-023-41677-w

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