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
Movement Disorders Unit, Neurological Institute, Tel Aviv Medical Center, Tel Aviv, Israel.
Laboratory for Early Markers of Neurodegeneration, Neurological Institute, Tel Aviv Medical Center, Tel Aviv, Israel.
NPJ Parkinsons Dis. 2022 Mar 3;8(1):20. doi: 10.1038/s41531-022-00285-z.
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.
帕金森病（PD）相关突变（如LRRK2和GBA）的非显性携带者（NMCs）患PD的风险增加。多巴胺转运体（DaT）-光谱正电子发射计算机断层扫描被广泛用于捕捉黑质纹状体多巴胺能功能活动。然而，它并不能反映其他正在进行的神经元过程；尤其是在疾病的前驱阶段。静息态功能磁共振成像（rs-fMRI）已被提议作为评估与PD相关的功能改变的一种方式，但其与多巴胺能缺乏的关系仍不清楚。我们旨在研究携带LRRK2和GBA基因突变的PD患者健康一级亲属中突触前纹状体多巴胺摄取与功能连接（FC）模式之间的关联。招募了N = 85名健康一级受试者并进行基因分型。所有参与者均接受了DaT和rs-fMRI扫描，以及全面的临床评估。研究了纹状体区域内FC的组间差异，并与纹状体结合率（SBR）进行比较。根据基因状态，每个研究组纳入N = 26名GBA-NMCs、N = 25名LRRK2-NMCs和N = 34名年龄匹配的非显性非携带者（NM-NCs）。虽然各基因定义组在临床指标上相似，但与NM-NCs相比，LRRK2-NMCs右侧壳核的SBR较低，与GBA-NMCs相比，右侧壳核的FC较高。在该组中，较高的纹状体FC与患PD的风险增加相关。在LRRK2-NMCs和GBA-NMCs中观察到的不同SBR和FC模式表明，DaT扫描和FC评估可能为疾病临床前期PD风险提供更敏感的预测。
