Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson’s disease into this case-control PET study. Patients with Parkinson’s disease were divided into 24 RBD-negative (PD^RBD−) and 13 RBD-positive cases (PD^RBD+) and a comparator group of 22 iRBD patients. We used ¹¹C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and ¹⁸F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PD^RBD− and PD^RBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10⁻¹³, ANOVA). When compared to the PD^RBD− patients, the PD^RBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10⁻⁵, ANOVA) and colon ¹¹C-donepezil standard uptake values (P = 0.008, ANOVA). The PD^RBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PD^RBD− (P = 0.07, t-test). In comparison to the other groups, the PD^RBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PD^RBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and ¹¹C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PD^RBD− data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and ¹¹C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson’s disease.

中文翻译：

---

脑优先性与身体优先性帕金森氏病：多模式影像病例对照研究。

帕金森氏病的特征在于存在异常的神经内神经α-突触核蛋白聚集体，其可能以a病毒样方式在细胞间传播。然而，仍不确定初始α-突触核蛋白聚集体起源于何处。我们假设帕金森氏病包括两种亚型。脑优先（自上而下）类型，其中α-突触核蛋白病理最初出现在大脑中，然后扩散到周围的自主神经系统。以及身体优先（自下而上）类型，其中病理起源于肠或周围的自主神经系统，然后扩散到大脑。我们还假设孤立的REM睡眠行为障碍（iRBD）是机体优先型的前驱表型。使用多模态成像 我们通过量化在三个不同患者组中对应于Braak I，II和III期的结构中的神经元功能障碍来检验假设。我们连续纳入了37个帕金森氏病患者从头进入这项病例对照PET研究。帕金森氏病患者分为24例RBD阴性（PD ^RBD-）和13例RBD阳性（PD ^{RBD +}），并比较22例iRBD患者。我们使用¹¹ C-donepezil PET / CT评估胆碱能（副交感神经）的神经支配能力，¹²³ I-甲代蛋氨酸苄基胍（MIBG）闪烁显像法测量心脏的交感神经支配能力，神经黑色素敏感的MRI来测量蓝斑色素性神经元的完整性，以及¹⁸F-二羟基苯丙氨酸（FDOPA）PET评估put胺多巴胺的储存能力。用CT扫描和不透射线标志物评估结肠体积和通过时间。使用ANOVA和三项校正后的Kruskal-Wallis测试对三组的影像数据进行了询问。PD ^RBD-和PD ^{RBD +}组显示出类似的显着降低的腹腔FDOPA特异性摄取，而三分之二的iRBD患者扫描正常（P  <  10 ^-13，ANOVA）。与PD ^RBD-患者相比，PD ^{RBD +}和iRBD患者的平均MIBG心脏：纵隔比率（P  <  10 ^-5，ANOVA）降低¹¹ C-多奈哌齐标准摄取值（P  =  0.008，ANOVA）。与PD ^RBD-相比，PD ^{RBD +}组趋向于平均MRI轨迹^蓝光：脑桥比率^降低（P  =  0.07，t-检验）。与其他组相比，PD ^{RBD +}组的结肠体积也有所增加（P  <  0.001，ANOVA），结肠的转运时间也有所延迟（P  =  0.01，Kruskal-Wallis）。结合的iRBD和PD ^{RBD +}患者数据与身体优先轨迹兼容，其特征在于心脏MIBG信号的初始丧失和¹¹C结肠多奈哌齐信号，随后失去了肠壁FDOPA摄取。相比之下，PD ^RBD-数据与脑优先轨迹兼容，其特征是先天性谷氨酸FDOPA摄取减少，然后继发心脏MIBG信号和¹¹ C-多奈哌齐信号继发性丢失。这些发现支持了帕金森氏病脑优先和机体优先亚型的存在。