TY - JOUR
T1 - Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
AU - Droby, Amgad
AU - Artzi, Moran
AU - Lerman, Hedva
AU - Hutchison, R. Matthew
AU - Bashat, Dafna Ben
AU - Omer, Nurit
AU - Gurevich, Tanya
AU - Orr-Urtreger, Avi
AU - Cohen, Batsheva
AU - Cedarbaum, Jesse M.
AU - Sapir, Einat Even
AU - Giladi, Nir
AU - Mirelman, Anat
AU - Thaler, Avner
N1 - Funding Information:
A.D., M.A., H.L., D.B.B., N.O., A.O.U., B.C., E.E.S. report no competing interests. T. Gurevich reports no competing interests relevant to this work. She received advisory board membership with honoraria to her and her institution from Abbvie Israel, Neuroderm Ltd. and Allergan. She recieves research support from Phonetica Ltd., Israeli Innovation Authority, Sagol School of Neuroscience (Brain Boost), and Parkinson’s Foundation. She received travel support from Abbvie, Allergan, Medisson, and Medtronic. RM. Huchison is an employee of and owns stock in Biogen. J.M. Cedarbaum is a former employee of Biogen, and reports no competing interests relevant to this work. N. Giladi has no competing interests pertaining to this work. He serves as a member of the editorial board for the Journal of Parkinson’s Disease. He serves as consultant to Sionara, Accelmed, Teva, NeuroDerm, Intec Pharma, Pharma2B, Denali and Abbvie. He received royalties from Lysosomal Therapeutics (LTI) and payment for lectures at Teva, UCB, Abbvie, Sanofi-Genzyme, Bial, and Movement Disorder Society. He received research support from the Michael J Fox Foundation, the National Parkinson Foundation, the European Union 7th Framework Program, and the Israel Science Foundation as well as from Teva NNE program, Biogen, LTI, and Pfizer. A. Mirelman reports no competing interests relevant to this work. She reports serving as advisor to Neuroderm. A. Thaler reports receiving honoraria from Abbvie- Israel. He reports no competing interests relevant to this work.
Funding Information:
The authors wish to thank all study participants for their devoted participation in this study. We also thank Prof. Talma Hendler and Tal Koslovski for supporting this work. This study was funded by Biogen Inc. (grant #20416).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85126202241&partnerID=8YFLogxK
U2 - 10.1038/s41531-022-00285-z
DO - 10.1038/s41531-022-00285-z
M3 - Article
C2 - 35241697
AN - SCOPUS:85126202241
VL - 8
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
SN - 2373-8057
IS - 1
M1 - 20
ER -