Jellinger K A
Institute of Clinical Neurobiology, Vienna, Austria.
J Neural Transm (Vienna). 2004 Oct;111(10-11):1219-35. doi: 10.1007/s00702-004-0138-7. Epub 2004 Apr 2.
To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging and various neurodegenerative disorders, its incidence and topographic pattern were examined in 260 brains of elderly patients, including 116 autopsy-proven cases of Alzheimer disease (AD), 71 cases of clinically and autopsy-proven Parkinson disease (PD), 38 of dementia with Lewy bodies (DLB), 8 patients with progressive supranuclear palsy (PSP), one with senile tremor, and 26 age-matched controls without neuropsychiatric disorders. Using immunohistochemistry, alpha-synuclein (AS) positive lesions were assessed semiquantitatively. For technical reasons, the olfactory system was not systematically studied. All PD-brains showed AS-positive lesions in medullary, pontine and mesencephalic nuclei, with involvement of the nucleus basalis (90.1%), limbic cortex (58.9%), cingulate cortex (46%), amygdala, CA 2/3 hippocampal region (36.2%), neocortex (28.8%), and striatum (11%). 88% of clinical PD cases corresponded to LB pathology stages 4-6, 12% to stage 3 according to Braak et al. (2003). 84% of DLB brains were PD stage 5 or 6 and 17% stage 4, without significant differences between DLB with and without neuritic AD pathology, suggesting morphologic similarities betwee these disorders. 6/8 PSP and senile tremor cases, 49.1% of AD and 69% of aged controls were negative. AS-positive lesions in AD showed decreasing incidence from midbrain (24-28%), limbic cortex and amygdala (17-18%), nucleus basalis and medullary nuclei (13-17%), cingulate cortex (12%), CA 2/3 region (8%) to neocortex (2%), without gender differences or relationship to the severity of AD pathology (mean Braak stage 5.1). AD cases with AS positive lesions, particularly those with AS pathology in the amygdala, were older at death than negative ones (86.6 vs 83.3 yrs), but this difference was not statistically significant. 15 AD cases (seven of them with mild PD symptoms) and 3 aged controls without parkinsonian signs but LB pathology stages 3 (n=5) and 4 (n=13) were considered "incidental LB disease". 16 AD brains without parkinsonian symptoms had AS positive lesions in various areas without medullary involvement, suggesting deviation from the proposed stereotypic expansion pattern. Located AS-pathology in the midbrain and limbic cortex was seen in 31% of asymptomatic aged controls. These data 1. largely confirm Braak's staging of LB-pathology in PD; 2. suggest morphologic and pathogenic relations between PD (brainstem type) and DLB with and without coexistent AD pathology; 3. the occurrence of LB-related alpha-synucleinopathy in about 50% of AD brains and about 30% of aged controls. However, the basic mechanisms of LB-related AS-pathology and their pathogenic and clinical relevance in aged brain and neurodegenerative disorders await further elucidation.
为阐明路易小体（LB）相关的α-突触核蛋白病在衰老及各种神经退行性疾病中的意义，我们在260例老年患者的大脑中研究了其发病率及分布模式，这些患者包括116例经尸检证实的阿尔茨海默病（AD）、71例经临床及尸检证实的帕金森病（PD）、38例路易体痴呆（DLB）、8例进行性核上性麻痹（PSP）患者、1例老年震颤患者以及26例年龄匹配且无神经精神疾病的对照者。采用免疫组织化学方法，对α-突触核蛋白（AS）阳性病变进行半定量评估。由于技术原因，未对嗅觉系统进行系统研究。所有PD患者的大脑在延髓、脑桥和中脑核中均显示AS阳性病变，基底核受累率为90.1%，边缘皮质为58.9%，扣带回皮质为46%，杏仁核、海马CA 2/3区为36.2%，新皮质为28.8%，纹状体为11%。根据Braak等人（2003年）的标准，88%的临床PD病例对应LB病理分期4 - 6期，12%对应3期。84%的DLB患者大脑处于PD分期5或6期，17%为4期，伴有或不伴有神经炎性AD病理改变的DLB之间无显著差异，提示这些疾病在形态学上具有相似性。8例PSP和老年震颤患者中有6例、49.1%的AD患者以及69%的老年对照者AS阳性病变为阴性。AD患者中AS阳性病变的发生率从中脑（24 - 28%）、边缘皮质和杏仁核（17 - 18%）、基底核和延髓核（13 - 17%）、扣带回皮质（12%）、CA 2/3区（8%）至新皮质（2%）逐渐降低，无性别差异，也与AD病理严重程度无关（平均Braak分期5.1）。AS阳性病变的AD患者，尤其是杏仁核有AS病理改变的患者，死亡时年龄比阴性患者大（86.6岁对83.3岁），但这种差异无统计学意义。15例AD患者（其中7例有轻度PD症状）以及3例无帕金森体征但LB病理分期为3期（n = 5）和4期（n = 13）的老年对照者被视为“偶发性LB病”。16例无帕金森症状的AD患者大脑在不同区域有AS阳性病变，未累及延髓，提示偏离了所提出的典型扩展模式。31%无症状老年对照者的中脑和边缘皮质存在AS病理改变。这些数据：1. 很大程度上证实了Braak对PD中LB病理的分期；2. 提示了PD（脑干型）与伴有或不伴有共存AD病理改变的DLB之间在形态学和发病机制上的关系；3. 约50%的AD患者大脑和约30%的老年对照者中存在LB相关的α-突触核蛋白病。然而，LB相关AS病理的基本机制及其在老年大脑和神经退行性疾病中的致病及临床相关性仍有待进一步阐明。
