A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

中文翻译：

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一组 CSF 蛋白可将遗传性额颞叶痴呆与症状前突变携带者区分开来：一项 GENFI 研究

详细了解遗传性额颞叶痴呆的病理过程对于为患者提供最佳的未来治疗至关重要。脑脊液中的蛋白质水平有可能反映大脑中不同的病理生理过程。我们的目的是识别和评估脑脊液蛋白组，这些蛋白组有可能将有症状的个体与无临床症状的个体（未受影响）以及症状前的个体与突变非携带者区分开。使用基于多重抗体的悬浮珠阵列分析了来自遗传性额颞叶痴呆家族的 221 名个体的脑脊液样本中 111 种蛋白质的水平。使用 LASSO 和随机森林探索数据。当将受影响的个体与未受影响的个体进行比较时，发现 14 种蛋白质对于分离具有潜在的重要作用。其中，有四种被认为是最重要的，即神经丝介质多肽（NEFM）、神经元正五聚蛋白2（NPTX2）、神经分泌蛋白VGF（VGF）和水通道蛋白4（AQP4）。这四种蛋白质的组合谱成功地将两组分开，与未受影响的个体相比，受影响个体的 NEFM 和 AQP4 水平较高，而 NPTX2 水平较低。VGF 对模型有贡献，但受影响个体的水平并没有显着降低。接下来，当将症状出现附近的症状前 GRN 和 C9orf72 突变携带者与突变非携带者进行比较时，发现了六种可能有助于分离的蛋白质，包括颗粒体蛋白前体 (GRN)。总之，我们鉴定了几种具有将受影响个体与未受影响个体分开的综合潜力的蛋白质，以及有可能有助于区分症状前个体和突变非携带者的蛋白质。需要进一步的研究来继续研究这些蛋白质及其与遗传 FTD 病理生理机制的潜在关联。