Steinacker Petra, Werner Leonie, Tarabuko Alexander, Al-Ali Ilyas, Mechawar Naguib, Pryce Christopher R, Cattane Nadia, Poggi Giulia, Al Shweiki Mhd Rami, Graf Heiko, Großkopf Henning, Halbgebauer Steffen, Oeckl Patrick, Barba Lorenzo, Meier Laura, Abu-Rumeileh Samir, Marston Hugh, Bornemann Klaus D, Hengerer Bastian, Danzer Karin M, Schönfeldt-Lecuona Carlos, Otto Markus
Department of Neurology, Martin Luther University Halle Wittenberg, Halle (Saale), Germany.
Department of Neurology, Ulm University Hospital, Ulm, Germany.
BMJ Ment Health. 2025 Aug 21;28(1):e301752. doi: 10.1136/bmjment-2025-301752.
Decreased cerebrospinal fluid (CSF) levels of synaptic proteins, possibly reflecting impaired synaptic function, have been observed in major depressive disorder (MDD).
To investigate the diagnostic utility of the soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) complex protein, synaptosomal-associated protein of 25 kDa (SNAP-25), for MDD.
Overall, 208 participants with one of MDD, schizophrenia (SCZ) or bipolar disorder (BD), and healthy controls (HCs) were retrospectively enrolled. CSF levels of SNAP-25 were assessed relative to MDD characteristics and the diagnostic potential was analysed. In subgroups of patients, CSF levels of presynaptic neurexin 3 (NRXN3), postsynaptic neurogranin (NRGN) and Alzheimer's disease biomarkers were measured for comparison.
SNAP-25 levels, but not the levels of the other synaptic markers, were significantly decreased in MDD compared with HCs, allowing for discrimination with 68% sensitivity and 67% specificity. SNAP-25 was not associated with MDD severity or antidepressant medication. Compared with HCs, SCZ also displayed decreased SNAP-25 enabling discrimination with 64% sensitivity and 77% specificity. There were strong correlations between levels of synaptic proteins and established Alzheimer pathology markers, with subtle differences in the association pattern between disorders.
Our data suggest that SNAP-25, NRXN3 and NRGN versus beta-amyloid and phosphorylated tau protein 181 (ptau) are regulated differentially across psychiatric disorders and that SNAP-25 has a moderate diagnostic potential for MDD and SCZ. We propose that CSF SNAP-25 level might represent an integrated readout of reduced synaptic function, rather than of synaptic degeneration, in MDD. Further studies are needed to analyse whether this potential can be increased by using multimarker measurements and whether it will be possible to subtype psychiatric disorders according to synaptic involvement in pathophysiology.
SNAP-25 and other synaptic proteins in CSF might aid diagnosis and subtyping of MDD and SCZ. The current development of sensitive methods to also determine synaptic proteins in blood samples from patients will advance the validation of the biomarker potential and contribute to understanding of synaptic involvement in the pathophysiology of MDD and SCZ.
在重度抑郁症（MDD）中已观察到脑脊液（CSF）中突触蛋白水平降低，这可能反映了突触功能受损。
研究可溶性N - 乙基马来酰亚胺敏感因子附着受体（SNARE）复合体蛋白、25 kDa突触体相关蛋白（SNAP - 25）对MDD的诊断效用。
总体而言，回顾性纳入了208名患有MDD、精神分裂症（SCZ）或双相情感障碍（BD）之一的参与者以及健康对照（HCs）。相对于MDD特征评估了CSF中SNAP - 25的水平，并分析了其诊断潜力。在患者亚组中，测量了突触前神经连接蛋白3（NRXN3）、突触后神经颗粒素（NRGN）的CSF水平以及阿尔茨海默病生物标志物以作比较。
与HCs相比，MDD患者的SNAP - 25水平显著降低，而其他突触标志物水平未降低，其鉴别敏感度为68%，特异度为67%。SNAP - 25与MDD严重程度或抗抑郁药物无关。与HCs相比，SCZ患者的SNAP - 25水平也降低，鉴别敏感度为64%，特异度为77%。突触蛋白水平与已确立的阿尔茨海默病病理标志物之间存在强相关性，不同疾病之间的关联模式存在细微差异。
我们的数据表明，与β - 淀粉样蛋白和磷酸化tau蛋白181（ptau）相比，SNAP - 25、NRXN3和NRGN在不同精神疾病中的调节存在差异，且SNAP - 25对MDD和SCZ具有中等诊断潜力。我们提出，CSF中SNAP - 25水平可能代表MDD中突触功能降低而非突触退化的综合指标。需要进一步研究分析使用多标志物测量是否可以提高这种潜力，以及是否有可能根据病理生理学中的突触参与情况对精神疾病进行亚型分类。
CSF中的SNAP - 25和其他突触蛋白可能有助于MDD和SCZ的诊断及亚型分类。目前开发的用于测定患者血液样本中突触蛋白的灵敏方法将推进生物标志物潜力的验证，并有助于理解突触在MDD和SCZ病理生理学中的作用。
