Personalized brain models identify neurotransmitter receptor changes in Alzheimer's disease

Brain, vol. 145, pp. 1785–1804

Abstract

Alzheimer's disease involves many neurobiological alterations from molecular to macroscopic spatial scales, but we currently lack integrative, mechanistic brain models characterizing how factors across different biological scales interact to cause clinical deterioration in a way that is subject-specific or personalized. As important signalling molecules and mediators of many neurobiological interactions, neurotransmitter receptors are promising candidates for identifying molecular mechanisms and drug targets in Alzheimer's disease. We present a neurotransmitter receptor-enriched multifactorial brain model, which integrates spatial distribution patterns of 15 neurotransmitter receptors from post-mortem autoradiography with multiple in vivo neuroimaging modalities (tau, amyloid-β and glucose PET, and structural, functional and arterial spin labelling MRI) in a personalized, generative, whole-brain formulation. In a heterogeneous aged population (n = 423, ADNI data), models with personalized receptor-neuroimaging interactions showed a significant improvement over neuroimaging-only models, explaining about 70% (±20%) of the variance in longitudinal changes to the six neuroimaging modalities. In Alzheimer's disease patients (n = 25, ADNI data), receptor-imaging interactions explained up to 39.7% (P < 0.003, family-wise error-rate-corrected) of inter-individual variability in cognitive deterioration, via an axis primarily affecting executive function. Notably, based on their contribution to the clinical severity in Alzheimer's disease, we found significant functional alterations to glutamatergic interactions affecting tau accumulation and neural activity dysfunction and GABAergic interactions concurrently affecting neural activity dysfunction, amyloid and tau distributions, as well as significant cholinergic receptor effects on tau accumulation. Overall, GABAergic alterations had the largest effect on cognitive impairment (particularly executive function) in our Alzheimer's disease cohort (n = 25). Furthermore, we demonstrate the clinical applicability of this approach by characterizing subjects based on individualized 'fingerprints' of receptor alterations. This study introduces the first robust, data-driven framework for integrating several neurotransmitter receptors, multimodal neuroimaging and clinical data in a flexible and interpretable brain model. It enables further understanding of the mechanistic neuropathological basis of neurodegenerative progression and heterogeneity, and constitutes a promising step towards implementing personalized, neurotransmitter-based treatments.

Authors 7

1. Ahmed Faraz Khan

   Montreal Neurological Institute and Hospital · Ludmer Centre for Neuroinformatics and Mental Health · McGill University

   Affiliation as printed

   Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montreal H3A 2B4 , Canada

   Ludmer Centre for Neuroinformatics and Mental Health , Montreal H3A 2B4 , Canada

   McConnell Brain Imaging Center, Montreal Neurological Institute , Montreal H3A 2B4 , Canada

2. Quadri Adewale

   Montreal Neurological Institute and Hospital · Ludmer Centre for Neuroinformatics and Mental Health · McGill University

   Affiliation as printed

   Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montreal H3A 2B4 , Canada

   Ludmer Centre for Neuroinformatics and Mental Health , Montreal H3A 2B4 , Canada

   McConnell Brain Imaging Center, Montreal Neurological Institute , Montreal H3A 2B4 , Canada

3. Tobias R. Baumeister

   Montreal Neurological Institute and Hospital · Ludmer Centre for Neuroinformatics and Mental Health · McGill University

   Affiliation as printed

   Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montreal H3A 2B4 , Canada

   Ludmer Centre for Neuroinformatics and Mental Health , Montreal H3A 2B4 , Canada

   McConnell Brain Imaging Center, Montreal Neurological Institute , Montreal H3A 2B4 , Canada

4. Félix Carbonell
   Affiliation as printed

   Biospective Inc ., Montreal H3B 2T9 , Canada

5. Karl Zilles

   Forschungszentrum Jülich

   Affiliation as printed

   Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich , 52425 Jülich , Germany

6. Nicola Palomero‐Gallagher Aachen Department of Psychiatry, Psychotherapy and Psychosomatics Medical Faculty

   Forschungszentrum Jülich · Jülich Aachen Research Alliance · Heinrich Heine University Düsseldorf · RWTH Aachen University

   Affiliation as printed

   Cécile and Oskar Vogt Institute of Brain Research, Medical Faculty, Heinrich-Heine University , 40225 Düsseldorf , Germany

   Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical Faculty, RWTH Aachen , 52074 Aachen , Germany

   Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich , 52425 Jülich , Germany

   JARA, Translational Brain Medicine , 52074 Aachen , Germany

7. Yasser Iturria‐Medina corresponding

   Montreal Neurological Institute and Hospital · Ludmer Centre for Neuroinformatics and Mental Health · McGill University

   Affiliation as printed

   Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montreal H3A 2B4 , Canada

   Ludmer Centre for Neuroinformatics and Mental Health , Montreal H3A 2B4 , Canada

   McConnell Brain Imaging Center, Montreal Neurological Institute , Montreal H3A 2B4 , Canada