Department of Neurology, Washington University School of Medicine St. Louis, Missouri ; Department of Developmental Biology, Washington University School of Medicine St. Louis, Missouri ; Hope Center for Neurological Disorders, Washington University School of Medicine St. Louis, Missouri.
Department of Neurology, Washington University School of Medicine St. Louis, Missouri.
Ann Clin Transl Neurol. 2015 Oct;2(10):949-59. doi: 10.1002/acn3.246. Epub 2015 Sep 12.
People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert.
High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested.
PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups.
These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.
帕金森病（PD）患者常发生痴呆，其与路易体中的α-突触核蛋白（α-syn）和路易神经突有关。此外，神经元丧失和聚集的α-syn 也发生在投射到大脑皮质、边缘和基底节区域的多个皮质下核中。因此，我们通过测量源自黑质致密部多巴胺能神经元、背侧中缝核 5-羟色胺能神经元、蓝斑核去甲肾上腺素能神经元和 Meynert 基底核胆碱能神经元投射的神经递质和神经递质转运蛋白，来量化这些受 PD 影响的皮质下核的区域性神经支配缺陷。
采用高效液相色谱法和新型酶联免疫吸附测定法，对死后脑组织中的多巴胺能、5-羟色胺能、去甲肾上腺素能和胆碱能神经支配进行定量分析。对 15 名 PD 患者（伴痴呆和 Braak 阶段 6α-syn 沉积）和 6 名年龄匹配的对照者的 8 个脑区进行了测试。
与对照组相比，PD 患者的尾状核、杏仁核、海马、下顶叶（IPL）、楔前叶和视觉联合皮质（VAC）中的多巴胺转运体广泛减少，超过了多巴胺的减少，而多巴胺仅在尾状核和杏仁核中显著减少。相比之下，PD 患者的尾状核、中额回、IPL 和 VAC 中 5-羟色胺和 5-羟色胺转运体的减少程度相当。PD 患者的所有 8 个脑区的去甲肾上腺素水平也显著降低。囊泡乙酰胆碱转运体水平仅在尾状核和海马中可定量，并且在 PD 和对照组之间没有差异。
这些结果表明，在伴有痴呆的晚期 PD 中，皮质、边缘和基底节区域的多巴胺能、5-羟色胺能和去甲肾上腺素能神经支配广泛受损。
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