Dementia is a leading cause of death worldwide, with increasing prevalence as global life expectancy increases. The most common neurodegenerative disorders are Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). With this study, we took an in-depth look at the proteome of the (non-purified) cerebrospinal fluid (CSF) and the CSF-derived extracellular vesicles (EVs) of AD, PD, PD-MCI (Parkinson's disease with mild cognitive impairment), PDD and DLB patients analysed by label-free mass spectrometry. This has led to the discovery of differentially expressed proteins that may be helpful for differential diagnosis. We observed a greater number of differentially expressed proteins in CSF-derived EV samples (N = 276) compared to non-purified CSF (N = 169), with minimal overlap between both datasets. This finding suggests that CSF-derived EV samples may be more suitable for the discovery phase of a biomarker study, due to the removal of more abundant proteins, resulting in a narrower dynamic range. As disease-specific markers, we selected a total of 39 biomarker candidates identified in non-purified CSF, and 37 biomarker candidates across the different diseases under investigation in the CSF-derived EV data. After further exploration and validation of these proteins, they can be used to further differentiate between the included dementias and may offer new avenues for research into more disease-specific pharmacological therapeutics.

中文翻译：

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阿尔茨海默病、帕金森病和路易体痴呆患者的未纯化脑脊液和脑脊液来源的细胞外囊泡之间的蛋白质组比较

痴呆症是全球主要死亡原因，随着全球预期寿命的延长，其患病率也不断增加。最常见的神经退行性疾病是阿尔茨海默病（AD）、路易体痴呆（DLB）和帕金森病痴呆（PDD）。通过这项研究，我们深入研究了 AD、PD、PD-MCI（患有轻度认知障碍的帕金森病）的（未纯化的）脑脊液 (CSF) 和 CSF 衍生的细胞外囊泡 (EV) 的蛋白质组损伤），PDD 和 DLB 患者通过无标记质谱分析。这导致了差异表达蛋白的发现，可能有助于鉴别诊断。 与非纯化的 CSF ( N = 169) 相比，我们在 CSF 衍生的 EV 样本 ( N = 276)中观察到更多数量的差异表达蛋白 ，两个数据集之间的重叠最小。这一发现表明，脑脊液衍生的 EV 样本可能更适合生物标志物研究的发现阶段，因为去除了更丰富的蛋白质，导致动态范围更窄。作为疾病特异性标记物，我们总共选择了在未纯化的 CSF 中鉴定的 39 个候选生物标记物，以及在 CSF 衍生的 EV 数据中研究的不同疾病的 37 个候选生物标记物。经过对这些蛋白质的进一步探索和验证，它们可用于进一步区分所包括的痴呆症，并可能为研究更多疾病特异性药物治疗提供新途径。