Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson’s disease
Open accessAbstract
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.
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Aberrant glutamatergic neurotransmission is a key contributing factor to neurodegeneration and Parkinson's disease.
“Aberrant glutamatergic neurotransmission represents a key contributing factor to neurodegeneration and PD.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [510]
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- Authors
- Khan, A. F., Adewale, Q., Lin, S.-J., Baumeister, T. R., Zeighami, Y., Carbonell, F., Palomero-Gallagher, N., & Iturria-Medina, Y.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- ORCID
- Venue
- Nature Communications
- Published
- 2023-09-26
- Volume
- 14
- Issue
- 1
- Pages
- 6009-6009
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10522603
- OpenAlex
- W4387041470
- Cited by
- 28
- References
- 114
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 10
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- JuSER Publikationsportal
- Funders
- Weston Brain Institute
- European Commission
- Canada First Research Excellence Fund
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, neurotransmitter receptors, gray matter atrophy, GABAergic system, glutamatergic system, cholinergic dysfunction, motor symptoms, visuospatial impairment, symptom severity
- MeSH terms
- Brain, Cerebral Cortex, Dopamine, Humans, Parkinson Disease, Receptors, Neurotransmitter, Neuroimaging
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