Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

中文翻译：

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路易体痴呆大脑的网络蛋白质组学揭示了不同于阿尔茨海默病的突触前特征


路易体痴呆 （LBD） 是一类包括帕金森病痴呆 （PDD） 和路易体痴呆 （DLB） 的疾病，其特点是与阿尔茨海默病 （AD） 有很大的临床和病理重叠。鉴定 LBD 病理生理学特有的生物标志物可以有意义地推进其诊断、监测和治疗。使用定量质谱 （MS），我们测量了宾夕法尼亚大学尸检收藏中 138 个背外侧前额叶皮层 （DLPFC） 组织中的 9,000 多种蛋白质，包括对照、帕金森病 （PD）、PDD 和 DLB 诊断。然后，我们分析了 LBD 患者的共表达网络蛋白改变，在两个独立的 LBD 数据集中验证了这些疾病特征，并将这些发现与 AD 病例的网络分析中观察到的结果进行了比较。LBD 网络揭示了在 PDD 和 DLB 中显着改变的共表达蛋白的许多组或“模块”，代表突触、代谢和炎症病理生理学。将经过验证的 LBD 特征与 AD 特征进行比较，确定了两种疾病之间的明显差异。值得注意的是，突触核蛋白相关的突触前模块在 LBD 中升高，但在 AD 中相对于对照组减少。我们还发现，在 AD 中持续升高的神经胶质相关基质体特征在 LBD 中发生的变化更大，最终将那些同时承受 β-淀粉样蛋白沉积负担低与高负担的 LBD 病例分层。总之，无偏倚的网络蛋白质组学分析揭示了 LBD 额叶皮层的不同病理生理变化，不同于 AD 的变化。这些结果突出了 LBD 脑网络蛋白质组是可以增强临床识别和管理的生物标志物的有前途的来源。