Abstract
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.
Highlights
Dopamine transporter (DaT)-single-photon emission computed tomography (DaTscan) is a sensitive imaging biomarker for early disease detection in Parkinson’s disease (PD)[1], quantifying a membrane protein expressed exclusively in dopaminergic neurons[2]
Demographic and clinical characteristics of the study participants Genetic phenotyping resulted in three study groups that consist of; N = 34 nonmanifesting noncarriers (NM-NC), N = 26 GBA-non-manifesting carriers (NMCs), and N = 25 LRRK2-NMCs
No significant differences were observed between the study groups in age, gender, H&Y, handedness, UPDRS-III, UPDRS-total, Montreal Cognitive Assessment (MOCA), Beck Depression Inventory (BDI), SCOPA-AUT, REM sleep Behavior Disorder Questionnaire (RBDq), NMS scores, and University of Pennsylvania Smell Identification Test (UPSIT) scores (p > 0.05; in all cases) (Table 1)
Summary
Dopamine transporter (DaT)-single-photon emission computed tomography (DaTscan) is a sensitive imaging biomarker for early disease detection in Parkinson’s disease (PD)[1], quantifying a membrane protein expressed exclusively in dopaminergic neurons[2]. In PD, a dorso-posterior to a ventro-anterior gradient of striatal dopamine depletion occurs, with dopamine depletion in the premotor phase starting in the posterior putamen prior to changes in the caudate nucleus[2]. While DaTscans are sensitive to striatal presynaptic DaT density, its spatio-temporal resolution remains rather limited[4,5]. Resting-state functional MRI (rs-fMRI) enables the assessment of the inter-regional temporal correlations (functional connectivity [FC]) patterns reflecting spontaneous neural activity[6,7]. Previous rsfMRI studies reported patterns of FC changes within cortical and subcortical functional networks of the brain in both PD patients and non-manifesting carriers (NMCs) of mutations in the LRRK2 genes[8–14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
