Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 synaptic proteins with postmortem global tau and TDP-43 burden and cognitive performance and to assess their diagnostic capacity in a neuropathological FTLD cohort. We included patients with a neuropathological confirmation of FTLD-Tau (n = 24, mean age-at-CSF 67 years ± 11), FTLD-TDP (n = 25, 66 years ± 9) or AD (n = 25, 73 years ± 6) as well as cognitively normal controls (n = 35, 69 years ± 7) from the Penn FTD Center and ADRC. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance, ordinal regression, step-wise multiple linear regression and receiver-operating characteristic curves. CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (rs = .55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p = .001, .77-fold, p = .04, respectively) and controls (.80-fold, p = .02, .78-fold, p = .02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r2 = .56, p = .007 and r2 = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r2 = .69, p = .003) and MMSE score (r2 = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r2 = .49, p = .04) and improved diagnostic performance to discriminate FTLD-Tau and FTLD-TDP neuropathologic subtypes (AUC = .83). These synaptic panels have potential in the differential diagnosis of FTLD neuropathologic subtypes and as surrogate markers of cognitive performance in future clinical trials targeting TDP-43 or tau.

中文翻译：

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多标记突触蛋白脑脊液面板反映了额颞叶变性病理队列中的 TDP-43 病理学和认知表现

突触变性是病理性额颞叶变性 (FTLD) 的早期事件。因此，突触缺失的替代标志物可用于监测潜在 FTLD 患者的早期病理变化。本研究的目的是评估 8 种突触蛋白的生前脑脊液 (CSF) 水平与死后整体 tau 和 TDP-43 负荷以及认知表现的关系，并评估它们在神经病理学 FTLD 队列中的诊断能力。我们纳入了经神经病理学证实为 FTLD-Tau（n = 24，脑脊液平均年龄 67 岁 ± 11）、FTLD-TDP（n = 25、66 岁 ± 9）或 AD（n = 25、73 岁）的患者± 6) 以及宾夕法尼亚 FTD 中心和 ADRC 的认知正常对照（n = 35、69 岁 ± 7）。我们使用 tau 和 TDP-43 内含物的半定量测量来量化 16 个大脑区域的病理负担。统计方法包括 Spearman 等级相关性、协方差的单向分析、有序回归、逐步多元线性回归和接受者操作特征曲线。CSF Calsyntenin-1 和 neurexin-2a 在所有患者组中均相关（rs = .55 至 .88）。在 FTLD-TDP 中，我们观察到与 AD（分别为 0.72 倍，p = 0.001、0.77 倍，p = 0.04）和对照（0.80 -fold, p = .02, .78-fold, p = .02, respectively), which are inversely associated with post-mortem global TDP-43 burden (regression r2 = .56, p = .007 and r2 = .57 , p = .006，分别）。包括 Calsyntenin-1 在内的多标记组合与 TDP-43 负荷相关（r2 = .69，p = . 003) 和 MMSE 分数 (r2 = .19, p = .03) 在 FTLD 中。第二个多标记突触组，也包括 Calsyntenin-1，与 FTLD-tau 的 MMSE 评分相关（r2 = .49，p = .04）并提高了区分 FTLD-Tau 和 FTLD-TDP 神经病理学亚型的诊断性能（AUC = .83). 这些突触面板在 FTLD 神经病理学亚型的鉴别诊断中具有潜力，并在未来针对 TDP-43 或 tau 的临床试验中作为认知表现的替代标志物。