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Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy

Molecular Psychiatry volume 30, pages 2372–2380 (2025)Cite this article

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Abstract

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [18F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [18F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R2 = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R2 = 0.16, p = 0.01). Topographic correspondence analysis with the [18F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.

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Fig. 1: Associations between posterior cBF atrophy and cortical hypometabolism in PD.
Fig. 2: Mediation analysis of associations between cBF atrophy, cortical hypometabolism, and cognitive impairment.
Fig. 3: Topographic correspondence between patterns of cBF-associated cortical hypometabolism and cholinergic denervation in PD.

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Data availability

The data generated and analysed in the current study are available from the corresponding authors upon reasonable and formal request approved by the relevant local ethics committees.

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Acknowledgements

The authors would like to thank the participants in this study for their contribution to science and the Instituto de Biomedicina de Sevilla and the Hospital Universitario Virgen del Rocío for the research resources provided.

Funding

This work was supported by the Spanish Ministry of Science and Innovation (RTC2019-007150-1, PID2021-127034OA-I00), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) (PI16/01575, PI18/01898, PI19/01576, PI20/00613, PI21/01875, PI22/01704), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019), the Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucía (PY20_00896, P20_00903), and the Fundación Alicia Koplowitz. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project ID 739510). M.A.L.E. is supported by a PhD scholarship (VI-PPIT-US) from the University of Seville (USE-19094-G). J.S.R. is supported by the “Sara Borrell” program (CD21/00067) of the ISCIII-FEDER. M.J.G. is supported by the “Miguel Servet” program (CP19/00031) of the ISCIII-FEDER. N.O. is supported by the Danish Parkinson’s Disease Association and the Health Research Foundation of Central Denmark Region. L.M.D. is supported by the “Río Hortega” program (CM21/00051) of the ISCIII-FEDER. D.M.G. is supported by the “Juan Rodés” program (JR22/00073) of the ISCIII-FEDER.

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Author notes

  1. These authors contributed equally: Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez.

Authors and Affiliations

  1. Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Universidad de Sevilla/CSIC/CIBERNED, Sevilla, Spain

    Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Laura Muñoz-Delgado, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Elena Iglesias-Camacho, Manuela San-Eufrasio, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Fátima Carrillo, Juan Francisco Martín-Rodríguez, Pablo Mir & Michel J. Grothe

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Laura Muñoz-Delgado, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Juan Francisco Martín-Rodríguez, Pablo Mir & Michel J. Grothe

  3. Department of Psychiatry and Neurochemistry, Institute of Physiology and Neuroscience, University of Gothenburg, Gothenburg, Sweden

    Miguel A. Labrador-Espinosa

  4. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

    Miguel A. Labrador-Espinosa

  5. Reina Sofia Alzheimer Centre, CIEN Foundation, ISCIII, Madrid, Spain

    Jesús Silva-Rodriguez, Sandra Castro-Labrador & Michel J. Grothe

  6. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

    Niels Okkels

  7. Department of Neurology, Regional Hospital Viborg, Viborg, Denmark

    Niels Okkels

  8. Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark

    Jacob Horsager & Per Borghammer

  9. Unidad de Radiodiagnóstico, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    Florinda Roldan Lora

  10. Unidad de Medicina Nuclear, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    David García-Solís

  11. Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain

    Pablo Mir

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  1. Miguel A. Labrador-Espinosa
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Contributions

MJG and PM contributed to the study conceptualization and design. NO, LMD, JH, AMCG, EIC, MSE, DMG, SJ, AAG, EOL, FC, FRL, DGS, and PB contributed to the data collection and material preparation. MALE, JSR, NO, SCL, PFR, and JFMR were involved in pre-processing and preparing the data for the analysis. The analyses were performed by MALE and JSR. The first draft of the manuscript was written by MALE and JSR. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Pablo Mir or Michel J. Grothe.

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The authors declare no competing interests.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Hospital ‘Virgen del Rocío’ (approval number: 2158-N-20).

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Informed consent was obtained from all individual participants included in the study.

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Labrador-Espinosa, M.A., Silva-Rodriguez, J., Okkels, N. et al. Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy. Mol Psychiatry 30, 2372–2380 (2025). https://doi.org/10.1038/s41380-024-02842-9

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