Evaluation of cerebrospinal fluid levels of VAMP-2 and SNAP-25 in a dementia with Lewy bodies clinical cohort stratified by Alzheimer's pathophysiological biomarkers.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Alba Cervantes González, Julie Goossens, Elena Vera Campuzano, Isabel Sala, M Belén Sánchez-Saudinós, Íñigo Rodríguez-Baz, Laia Lidón, Danna Perlaza, Alexandre Bejanin, Annakaisa Haapasalo, Juan Fortea, Daniel Alcolea, Alberto Lleó, Eugeen Vanmechelen, Olivia Belbin
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引用次数: 0

Abstract

Background: Synaptic protein levels in cerebrospinal fluid (CSF) may represent much-needed objective biomarkers of cognitive impairment, disease progression and drug efficacy in patients with dementia with Lewy bodies (DLB). Soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) proteins, such as VAMP-2 and SNAP-25, are implicated in α-synuclein pathophysiology and CSF levels of these proteins are associated with pathophysiological biomarkers and cognitive decline in Alzheimer's disease (AD). The aim of the study was to compare CSF levels of VAMP-2 and SNAP-25 in patients with DLB to cognitively unimpaired controls and AD patients and study their association with cognitive performance and AD and neurodegeneration biomarkers.

Methods: VAMP-2 and SNAP-25 were quantified in CSF from cognitively normal controls (n = 62), DLB (n = 44) and AD (n = 114) patients from the Sant Pau Initiative for Neurodegeneration (SPIN) cohort using homebrew Single Molecule Array assays (Simoa). The DLB group was stratified into two groups with ("DLB + AD", n = 28) or without AD co-pathology ("pure DLB", n = 16) using our validated cut-off for the CSF phosphorylated tau (p-tau)/Aβ42 ratio. We used linear regression to test for group differences (adjusting for age) and association with AD biomarkers. We used standardized w-scores of the cognitive tests to analyze the association of the synaptic markers with cognitive performance.

Results: CSF VAMP-2 and SNAP-25 levels correlated across all groups (r = 0.71-0.9, p < 0.001). Both proteins were decreased in pure DLB (p < 0.001, p = 0.01) but increased in DLB + AD (p = 0.01, p = 0.02) compared to controls and showed good accuracy to discriminate pure DLB from DLB + AD (AUC = 0.84, 0.85). Both proteins were associated with CSF p-tau and total tau (t-tau) across all groups (r2 = 0.49-0.88, p < 0.001), with the Aβ42/40 ratio in DLB + AD (r2 = 0.29-0.36, p < 0.001) and in AD (r2 = 0.12-0.23, p < 0.001) and with CSF neurofilament-light chain (NfL) in controls (r²=0.10-0.11, p < 0.001-0.01) and AD patients (r²=0.01-0.08, p = 0.01 - 0.001). SNAP-25 was associated with CSF NfL in the DLB + AD group (r²=0.15, p = 0.02). CSF VAMP-2 and SNAP-25 were associated with phonemic fluency in pure DLB (r2 = 0.39 - 0.28, p = 0.01-0.03) and SNAP-25 with the Clock drawing test and the MMSE in DLB + AD (adj.r2 = 0.15 - 0.14, p = 0.03-0.03) and DLB (adj.r2 = 0.12 - 0.08, p = 0.02-0.04) groups.

Conclusions: CSF VAMP-2 and SNAP-25 are promising surrogate markers of synapse degeneration in DLB. However, care should be taken when interpreting CSF levels of these synaptic markers in DLB in light of the confounding effect of AD pathophysiological markers.

通过阿尔茨海默病病理生理生物标志物分层的路易体痴呆临床队列中VAMP-2和SNAP-25脑脊液水平的评估
背景:脑脊液(CSF)突触蛋白水平可能是认知障碍、疾病进展和路易体痴呆(DLB)患者疗效急需的客观生物标志物。可溶性n -乙基丙烯酰亚胺敏感因子附着蛋白受体(SNARE)蛋白,如VAMP-2和SNAP-25,与α-突触核蛋白病理生理有关,这些蛋白的CSF水平与阿尔茨海默病(AD)的病理生理生物标志物和认知能力下降有关。该研究的目的是比较DLB患者与认知功能未受损的对照组和AD患者脑脊液中VAMP-2和SNAP-25的水平,并研究它们与认知表现、AD和神经退行性变生物标志物的关系。方法:采用自制单分子阵列法(Simoa)对认知正常对照(n = 62)、DLB (n = 44)和AD (n = 114)患者脑脊液中的VAMP-2和SNAP-25进行定量分析。DLB组分为两组(“DLB + AD”,n = 28)或无AD共病理(“纯DLB”,n = 16),使用我们验证的脑脊液磷酸化tau (p-tau)/ a - β42比值的截止值。我们使用线性回归来检验组间差异(调整年龄)以及与AD生物标志物的关联。我们使用认知测试的标准w分数来分析突触标记与认知表现的关系。结果:各组脑脊液VAMP-2和SNAP-25水平相关(r = 0.71-0.9, p 2 = 0.49-0.88, p 2 = 0.29-0.36, p 2 = 0.12-0.23, p 2 = 0.39 - 0.28, p = 0.01-0.03), DLB + AD组(adj.r2 = 0.15 - 0.14, p = 0.03-0.03)和DLB组(adj.r2 = 0.12- 0.08, p = 0.02-0.04)的SNAP-25水平与Clock drawing试验和MMSE相关。结论:脑脊液VAMP-2和SNAP-25是有希望的DLB突触变性替代标志物。然而,在解释DLB中这些突触标记物的CSF水平时,考虑到AD病理生理标记物的混淆作用,应该小心。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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