Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.
Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, University Hospital Cologne, Cologne, Germany.
Lancet Neurol. 2018 Jul;17(7):618-628. doi: 10.1016/S1474-4422(18)30162-5. Epub 2018 Jun 1.
Accumulating evidence suggests that α-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease.
In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons.
Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), I-MIBG heart:mediastinum ratio (-0·508, -0·353 to -0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (-0·059, -0·019 to -0·099; p=0·0028), and putaminal F-DOPA uptake (Ki; -0·0023, -0·0009 to -0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to C-donepezil (p=0·39), I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001).
Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem.
Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.
越来越多的证据表明，α-突触核蛋白聚集——帕金森病的一个明确病理特征——表现出细胞间传递。α-突触核蛋白聚集的假说始于自主神经末梢，早在运动症状出现前数年，随后通过自主神经传播到脊髓和脑干。为了验证这一假说，我们研究了特发性快速眼动（REM）睡眠行为障碍患者的自主神经、副交感神经、去甲肾上腺素能和多巴胺能神经支配，特发性 REM 睡眠行为障碍是帕金森病的一种前驱表型。
在这项前瞻性、病例对照研究中，我们通过广告和丹麦的睡眠诊所招募了特发性 REM 睡眠行为障碍患者，这些患者通过多导睡眠图得到了确认，且没有帕金森病或痴呆的临床症状。我们使用 C-多奈哌齐 PET 和 CT 评估胆碱能（副交感）肠道神经支配，使用 I-间碘苄胍（MIBG）闪烁显像评估心脏交感神经支配，使用神经黑色素敏感 MRI 评估蓝斑色素神经元的完整性，使用 C-甲基麦角新碱（MeNER）PET 评估起源于蓝斑的去甲肾上腺素能神经末梢，使用 F-二羟苯丙氨酸（DOPA）PET 评估黑质纹状体多巴胺储存能力。对于每种成像方式，我们将特发性 REM 睡眠行为障碍患者与先前发表的无神经障碍或认知障碍的对照组以及有帕金森病症状的患者的参考数据进行了比较。我们使用单因素方差分析并校正了多重比较来评估成像数据。
在 2016 年 6 月 3 日至 2017 年 12 月 19 日期间，我们连续招募了 22 名特发性 REM 睡眠行为障碍患者参加这项研究。与对照组相比，特发性 REM 睡眠行为障碍患者的结肠 C-多奈哌齐摄取减少（-0.322，95%CI-0.112 至-0.531；p=0.0020），I-MIBG 心脏：纵隔比值降低（-0.508，-0.353 至-0.664；p<0.0001），神经黑色素敏感 MRI 蓝斑：桥脑比值降低（-0.059，-0.019 至-0.099；p=0.0028），以及纹状体 F-DOPA 摄取（Ki）减少（-0.0023，-0.0009 至-0.0037；p=0.0013）。在特发性 REM 睡眠行为障碍和帕金森病组之间，C-多奈哌齐（p=0.39）、I-MIBG（p>0.99）、神经黑色素敏感 MRI（p=0.96）和 C-MeNER（p=0.56）之间没有组间差异。相比之下，21 名特发性 REM 睡眠行为障碍患者中有 15 名（71%）的 F-DOPA Ki 值在正常范围内，而所有帕金森病患者的 F-DOPA Ki 值均显著低于特发性 REM 睡眠行为障碍患者（p<0.0001）。
特发性 REM 睡眠行为障碍患者的外周自主神经系统和蓝斑已经出现了完全发展的病理，与已诊断的帕金森病相同。这些患者还表现出去甲肾上腺素能丘脑神经支配缺失，但大多数患者的纹状体多巴胺储存能力正常。这种尾部向头部的功能障碍梯度支持了这样一种假说，即帕金森病中的α-突触核蛋白病理最初靶向外周自主神经，然后向脑干头部传播。
Lundbeck 基金会、Jascha 基金会和瑞士国家基金会。
