CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-02-11 DOI:10.1002/trc2.70051

Mihály Hajós, Kiran Pandey, Annabelle C. Singer, Duc Duong, Sara Bitarafan, Monika Shpokayte, Zach Malchano, Ralph Kern, James J. Lah, Allan I. Levey, Nicholas T. Seyfried

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引用次数: 0

Abstract

INTRODUCTION

Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.

METHODS

Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (n = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.

RESULTS

Differential expression analysis of proteins at baseline and after 8 weeks of treatment (N = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, P < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.

DISCUSSION

The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.

Highlights

We analyzed changes in cerebrospinal fluid (CSF) proteins in response to sensory-evoked gamma oscillations in individuals with mild cognitive impairment.
Sensory evoked steady-state gamma oscillations were evoked by Spectris medical device.
Changes in CSF proteins were observed after 8 weeks of daily 1 hour treatment.
Affected proteins were related to myelination, synaptic and neuroimmune functions, and regulation of cellular lipid transportation.
Proteomic changes support clinical outcomes and myelin preservation of Spectris treatment.

Abstract Image

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脑脊液蛋白质组学揭示了Spectris治疗后髓磷脂和突触生物学的变化

使用非侵入性医疗设备（Spectris）诱发的脑稳态伽马振荡在轻中度阿尔茨海默病（AD）患者中显示出潜在的临床益处，包括减少功能和认知能力下降，减少脑容量和髓鞘损失，以及增加脑功能连接。我们分析了轻度认知障碍（MCI）患者接受Spectris治疗后脑脊液（CSF）蛋白的变化及其与AD相关的既定生物学通路的关系。方法对来自淀粉样蛋白阳性MCI患者（n = 10）的脑脊液样本进行无偏蛋白质组学分析，这些样本来自FLICKER （NCT03543878）临床试验。参与者使用Cognito Therapeutics医疗设备（Spectris），证实可以唤起稳态伽马振荡。参与者被要求在试验期间每天使用该设备1小时。在刺激开始前和治疗4周和8周后收集脑脊液。蛋白质组分析采用串联质谱法。结果：基线和治疗8周后的蛋白差异表达分析（N = 5）显示，2951个蛋白中有110个符合显著性阈值(方差分析，P <；0.05，无错误发现率)。60个蛋白表达上调，50个蛋白表达下调。蛋白质表达的变化被映射到共识的人类AD蛋白网络，代表与细胞类型和生化途径相关的共表达和功能链接模块。治疗改变了与ad相关的脑蛋白质组模块相关的脑脊液蛋白，包括参与髓鞘形成（蛋白脂蛋白1，亲生态病毒整合位点2A）、突触和神经免疫功能以及细胞脂质运输调节的蛋白。生物通路分析显示，受影响最大的通路与脂蛋白、胆固醇、磷脂加工和磷脂酰胆碱生物合成有关。本研究中观察到的脑脊液蛋白质组学变化表明，阿尔茨海默病涉及多种途径，包括髓鞘形成、突触和神经免疫功能以及脂质转运。这些发现也与Spectris治疗AD后白质和髓鞘保存的观察结果一致。我们分析了轻度认知障碍患者的脑脊液（CSF）蛋白对感觉诱发的伽马振荡的反应。用Spectris医疗器械诱发感觉诱发稳态伽马振荡。每天1小时治疗8周后观察脑脊液蛋白的变化。受影响的蛋白与髓鞘形成、突触和神经免疫功能以及细胞脂质运输的调节有关。蛋白质组学变化支持Spectris治疗的临床结果和髓磷脂保存。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.