Local synchronicity in dopamine-rich caudate nucleus influences Huntington’s disease motor phenotype

Author:

Kasper Jan12ORCID,Eickhoff Simon B12,Caspers Svenja34,Peter Jessica5,Dogan Imis678,Wolf Robert Christian9ORCID,Reetz Kathrin678ORCID,Dukart Juergen12ORCID,Orth Michael510ORCID

Affiliation:

1. Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich , 52428 Jülich , Germany

2. Institute of Systems Neuroscience, Medical Faculty & University Hospital Düsseldorf, Heinrich Heine University Düsseldorf , 40225 Düsseldorf , Germany

3. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich , 52428 Jülich , Germany

4. Institute of Anatomy I, Medical Faculty & University Hospital Düsseldorf, Heinrich Heine University Düsseldorf , 40225 Düsseldorf , Germany

5. University Hospital of Old Age Psychiatry and Psychotherapy, University of Bern , 3000 Bern 60 , Switzerland

6. Department of Neurology, RWTH Aachen University , 52056 Aachen , Germany

7. JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Jülich GmbH , 52425 Jülich Germany

8. RWTH Aachen University , 52056 Aachen , Germany

9. Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University , 69047 Heidelberg , Germany

10. Neurozentrum Siloah , 3073 Gümligen , Switzerland

Abstract

Abstract Structural grey and white matter changes precede the manifestation of clinical signs of Huntington’s disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure–function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington’s disease close to onset and very early manifest Huntington’s disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington’s disease phase despite clear evidence of brain atrophy. In manifest Huntington’s disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington’s disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington’s disease or motor manifest Huntington’s disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington’s disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable.

Funder

European Union’s Horizon 2020

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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