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Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers

Non-manifesting carriers (NMCs) of Parkinson’s disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. Howev...

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Autores principales: Droby, Amgad, Artzi, Moran, Lerman, Hedva, Hutchison, R. Matthew, Bashat, Dafna Ben, Omer, Nurit, Gurevich, Tanya, Orr-Urtreger, Avi, Cohen, Batsheva, Cedarbaum, Jesse M., Sapir, Einat Even, Giladi, Nir, Mirelman, Anat, Thaler, Avner
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894349/
https://www.ncbi.nlm.nih.gov/pubmed/35241697
http://dx.doi.org/10.1038/s41531-022-00285-z
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author Droby, Amgad
Artzi, Moran
Lerman, Hedva
Hutchison, R. Matthew
Bashat, Dafna Ben
Omer, Nurit
Gurevich, Tanya
Orr-Urtreger, Avi
Cohen, Batsheva
Cedarbaum, Jesse M.
Sapir, Einat Even
Giladi, Nir
Mirelman, Anat
Thaler, Avner
author_facet Droby, Amgad
Artzi, Moran
Lerman, Hedva
Hutchison, R. Matthew
Bashat, Dafna Ben
Omer, Nurit
Gurevich, Tanya
Orr-Urtreger, Avi
Cohen, Batsheva
Cedarbaum, Jesse M.
Sapir, Einat Even
Giladi, Nir
Mirelman, Anat
Thaler, Avner
author_sort Droby, Amgad
collection PubMed
description Non-manifesting carriers (NMCs) of Parkinson’s disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease. Resting-state fMRI (rs-fMRI) has been proposed as a mode for assessing functional alterations associated with PD, but its relation to dopaminergic deficiency remains unclear. We aimed to study the association between presynaptic striatal dopamine uptake and functional connectivity (FC) patterns among healthy first-degree relatives of PD patients with mutations in LRRK2 and GBA genes. N = 85 healthy first-degree subjects were enrolled and genotyped. All participants underwent DaT and rs-fMRI scans, as well as a comprehensive clinical assessment battery. Between-group differences in FC within striatal regions were investigated and compared with striatal binding ratios (SBR). N = 26 GBA-NMCs, N = 25 LRRK2-NMCs, and N = 34 age-matched nonmanifesting noncarriers (NM-NCs) were included in each study group based on genetic status. While genetically-defined groups were similar across clinical measures, LRRK2-NMCs demonstrated lower SBR in the right putamen compared with NM-NCs, and higher right putamen FC compared to GBA-NMCs. In this group, higher striatal FC was associated with increased risk for PD. The observed differential SBR and FC patterns among LRRK2-NMCs and GBA-NMCs indicate that DaTscan and FC assessments might offer a more sensitive prediction of the risk for PD in the pre-clinical stages of the disease.
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spelling pubmed-88943492022-03-08 Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers Droby, Amgad Artzi, Moran Lerman, Hedva Hutchison, R. Matthew Bashat, Dafna Ben Omer, Nurit Gurevich, Tanya Orr-Urtreger, Avi Cohen, Batsheva Cedarbaum, Jesse M. Sapir, Einat Even Giladi, Nir Mirelman, Anat Thaler, Avner NPJ Parkinsons Dis Article Non-manifesting carriers (NMCs) of Parkinson’s disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease. Resting-state fMRI (rs-fMRI) has been proposed as a mode for assessing functional alterations associated with PD, but its relation to dopaminergic deficiency remains unclear. We aimed to study the association between presynaptic striatal dopamine uptake and functional connectivity (FC) patterns among healthy first-degree relatives of PD patients with mutations in LRRK2 and GBA genes. N = 85 healthy first-degree subjects were enrolled and genotyped. All participants underwent DaT and rs-fMRI scans, as well as a comprehensive clinical assessment battery. Between-group differences in FC within striatal regions were investigated and compared with striatal binding ratios (SBR). N = 26 GBA-NMCs, N = 25 LRRK2-NMCs, and N = 34 age-matched nonmanifesting noncarriers (NM-NCs) were included in each study group based on genetic status. While genetically-defined groups were similar across clinical measures, LRRK2-NMCs demonstrated lower SBR in the right putamen compared with NM-NCs, and higher right putamen FC compared to GBA-NMCs. In this group, higher striatal FC was associated with increased risk for PD. The observed differential SBR and FC patterns among LRRK2-NMCs and GBA-NMCs indicate that DaTscan and FC assessments might offer a more sensitive prediction of the risk for PD in the pre-clinical stages of the disease. Nature Publishing Group UK 2022-03-03 /pmc/articles/PMC8894349/ /pubmed/35241697 http://dx.doi.org/10.1038/s41531-022-00285-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Droby, Amgad
Artzi, Moran
Lerman, Hedva
Hutchison, R. Matthew
Bashat, Dafna Ben
Omer, Nurit
Gurevich, Tanya
Orr-Urtreger, Avi
Cohen, Batsheva
Cedarbaum, Jesse M.
Sapir, Einat Even
Giladi, Nir
Mirelman, Anat
Thaler, Avner
Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title_full Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title_fullStr Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title_full_unstemmed Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title_short Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
title_sort aberrant dopamine transporter and functional connectivity patterns in lrrk2 and gba mutation carriers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894349/
https://www.ncbi.nlm.nih.gov/pubmed/35241697
http://dx.doi.org/10.1038/s41531-022-00285-z
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