Universität zu Köln

Pelzer, Esther Annegret, Melzer, Corina, Schoenberger, Anna, Hess, Martin, Timmermann, Lars, Eggers, Carsten and Tittgemeyer, Marc ORCID: 0000-0001-5072-2149 (2019). Axonal degeneration in Parkinson's disease - Basal ganglia circuitry and D2 receptor availability. NeuroImage-Clin., 23. OXFORD: ELSEVIER SCI LTD. ISSN 2213-1582

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Abstract

Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response. Included in the study were 24 parkinsonian patients [male, 62 years ( +/- 9.3 SD)] compared to 24 healthy controls [male, 63 years ( +/- 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI. We report a decline in nigro-striatal (p < .003) and dentato-pallidal (p < .0001) connectivity in the patients compared to controls, which is associated with increasing motor impairment (relating to nigro-striatal, r = -0.48; p < .001 and dentato-pallidal connectivity, r = -0.36; p = .035). Given, that variations of the ANKK1 Taq1 (rs 1,800,497) allele alters dopamine D2-dependent responses, all participants were genotyped respectively. By grouping patients (and controls) according to their ANKK1 genotype, we demonstrate a link between D2 receptor signalling and decline in connectivity in both investigated pathways for the A1- variant (nigro-striatal pathway: r = - 0.53; p = .012, dentato-pallidal pathway: r = - 0.62; p = .0012). In patients with the A1 + variant, we only found increased brain connectivity in the dentato-pallidal pathway (r = 0.71; p = .001) correlating with increasing motor impairment, suggesting a potentially compensatory function of the cerebellum. Related to medication response carriers of the A1 + variant had a better drug effect associated with stronger brain connectivity in the nigro-striatal pathway (r = 0.54; p < .02); the A1- group had a good medication response although nigro-striatal connectivity was diminished (r = -0.38; p < .05); these results underscore differences in receptor availability between both groups in the nigro-striatal pathway. No effect onto medication response was found in the dentato-pallidal pathway (p > .05). Interplay between basal ganglia connectivity and D2 receptor availability influence the clinical presentation and medication response of parkinsonian patients. Furthermore, while current models of basal-ganglia function emphasize that balanced activity in the direct and indirect pathways is required for normal movement, our data highlight a role of the cerebellum in compensating for physiological imbalances in this respect.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pelzer, Esther Annegret UNSPECIFIED UNSPECIFIED UNSPECIFIED Melzer, Corina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenberger, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggers, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Tittgemeyer, Marc UNSPECIFIED orcid.org/0000-0001-5072-2149 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-160645
DOI:	10.1016/j.nicl.2019.101906
Journal or Publication Title:	NeuroImage-Clin.
Volume:	23
Date:	2019
Publisher:	ELSEVIER SCI LTD
Place of Publication:	OXFORD
ISSN:	2213-1582
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DOPAMINE D2; SUBSTANTIA-NIGRA; ALLELIC ASSOCIATION; GENE POLYMORPHISMS; DENTATE NUCLEUS; DRD2; CONNECTIVITY; CEREBELLUM; MRI; TRACTOGRAPHY Multiple languages Neuroimaging Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16064