Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders
Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders
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多巴胺能回路的变性影响路易体障碍患者的抑郁症状
DOI：
10.1111/bpa.12697
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发表时间：
2019-07-01
期刊：
影响因子：
6.4
通讯作者：
Morris, Christopher M.
中科院分区：
文献类型：
--
作者：
Patterson, Lina;Rushton, Steven P.;Morris, Christopher M.
抑郁症是路易体病（Lewy body disorders，LBD）的前驱期常见症状，与认知功能障碍和认知功能下降速度加快有关。鉴于多巴胺在运动障碍发展中的作用，以及在动机和奖励中的作用，我们研究了帕金森病（PD）、PD伴痴呆（PDD）和路易体痴呆（DLB）患者多巴胺能回路中与抑郁症状相关的神经退行性病理学。方法对17例DLB、14例PDD和8例PD患者的纹状体和中脑亚区的α-突触核蛋白、过度磷酸化tau蛋白和淀粉样β蛋白病理进行了评估，并对黑质和腹侧被盖区的神经元细胞密度进行了评估。此外，我们使用了结构方程模型（SEM）的方法来研究大脑连接可能会影响多巴胺能通路内的病理蛋白质沉积的程度。结果LBD伴抑郁患者黑质（P = 0.006）、腹侧被盖区（P = 0.011）和延髓核（P = 0.031）的α-突触核蛋白负荷显著增加。黑质细胞密度与Lewy体（LB）Braak分期呈显著负相关（P = 0.013），腹侧被盖区细胞密度与LB Braak分期（P = 0.026）和神经元缠结Braak分期（P = 0.007）呈显著负相关。结论多巴胺能α-突触核蛋白病理学似乎驱动抑郁症。因此，选择性靶向多巴胺能通路可能为LBD患者的抑郁症状提供症状缓解。
Aims Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms. Methods alpha-synuclein, hyperphosphorylated tau and amyloid-beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modeling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways. Results A significantly higher alpha-synuclein burden was observed in the substantia nigra (P = 0.006), ventral tegmental area (P = 0.011) and nucleus accumbens (P = 0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in substantia nigra with Lewy body (LB) Braak stage (P = 0.013), whereas cell density in ventral tegmental area showed negative correlations with LB Braak stage (P = 0.026) and neurofibrillary tangle Braak stage (P = 0.007). Conclusions Dopaminergic alpha-synuclein pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.