Implementing a novel, multimodal technique for monitoring cerebrovascular hemodynamics in mice as a diagnostic and prognostic tool for single and repeated mild TBI

实施一种新颖的多模式技术来监测小鼠脑血管血流动力学，作为单次和重复轻度 TBI 的诊断和预后工具

• 批准号: 10056044
• 负责人: KATHRYN E SAATMAN
• 金额: $ 42.08万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056044
• 关键词: Accounting; Acute; Acute Brain Injuries; Address; Amnesia; Anatomy; Animal Model; Athletic; Bioenergetics; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Brain Concussion; Cell Death; Cellular Structures; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Research; Closed head injuries; Cognitive deficits; Communication; Coupled; Craniocerebral Trauma; Detection; Development; Devices; Diagnosis; Diagnostic; Diffuse; Distress; Dizziness; Event; FDA approved; Fingerprint; Functional disorder; Goals; Guidelines; Headache; Health; Hippocampus (Brain); Human; Hyperemia; Image; Imaging Device; Impairment; Individual; Injury; Lead; Light; Maps; Mass Fragmentography; Measurement; Measures; Mediator of activation protein; Metabolic; Metabolism; Methods; Military Personnel; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Mus; Neurologic; Neurologic Dysfunctions; Neurosciences Research; Outcome; Outcome Measure; Pathway interactions; Persons; Photons; Physiological; Plasma; Play; Prognostic Marker; Public Health; Recovery; Reporting; Resolution; Rest; Risk; Rodent; Signal Transduction; Source; Structure; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Translating; Traumatic Brain Injury; brain tissue; cerebral hemodynamics; cerebrovascular; clinical application; clinical development; clinically translatable; cranium; diagnostic biomarker; disability; hemodynamics; high resolution imaging; innovation; insight; metabolic profile; metabolome; metabolomics; mild traumatic brain injury; multimodality; neuroimaging; neuron loss; neurophysiology; neurovascular coupling; novel; portability; potential biomarker; pre-clinical research; prevent; prognostic; prognostic tool; prototype; response; restoration; tissue oxygenation; tomography

Project Summary Traumatic brain injuries (TBIs) are a major societal and public health concern with over 2.8 million TBIs reported each year in the US. Mild TBIs (mTBIs), accounting for over 80% of TBIs, can be difficult to diagnose. Because no FDA-approved therapeutic intervention for mTBI exists, a period of rest to allow symptom resolution is the primary treatment approach. It is imperative that while symptomatic, a person recovering from mTBI avoid sustaining a second mTBI, as multiple mTBIs greatly increases the risk for prolonged disability. The period of brain vulnerability after mTBI, however, extends beyond the resolution of clinical symptoms, underscoring the vital need for accurate assessment of neurophysiological recovery in order to mitigate the risks associated with repeated head injury. Unlike moderate and severe TBI, which are typically associated with neuron death and vascular disruption, mTBI results in more subtle physiological and cellular changes, such as metabolic distress and alterations in cerebral blood flow (CBF). We hypothesize that mTBI induces acute, transient changes in CBF that, coupled with metabolic dysregulation, form the basis of the window of vulnerability to repeated mTBI. We predict, therefore, that a second injury induced during the period of acute CBF alteration will result in worsened outcome as reflected by greater perturbations in CBF and metabolism. Our group has developed a novel multiple-wavelength speckle contrast diffuse correlation tomography (MW- scDCT) technique that yields non-invasive, longitudinal, regional mapping of CBF and oxygenation in mice. We have validated our technique against established methods and demonstrated its utility in detecting CBF changes in rodents. In Aim 1, we will first use MW-scDCT to measure cortical and hippocampal CBF and oxygenation after single closed head injury (CHI) to monitor temporal changes and determine the time to recovery. We will then determine whether normalization of CBF is required to prevent synergistic effects of a second CHI on cerebral hemodynamics. Neurovascular coupling and cerebrovascular reactivity will be assessed at selected time points to inform potential mechanisms underlying CBF changes. Finally, quantitative analysis of cerebrovascular structure and communication will be performed to identify anatomical plasticity or damage. In Aim 2, a targeted metabolomics approach will be used to identify metabolite profiles in cortical tissue and plasma which are unique to mice with single or repeated mTBI. We will further test whether restoration of the metabolome coincides with normalization of CBF after mTBI. Such a finding would support a dual-pronged approach for assessing concussion recovery through noninvasive CBF monitoring and assessment of plasma metabolite biomarkers. These studies will pair metabolomics with our innovative MW- scDCT technique for monitoring cerebral hemodynamics to provide new insights into the neurophysiological determinants of the brain’s vulnerability to repeated mTBI and support the development of diagnostic and prognostic biomarkers for mTBI.

项目摘要 创伤性脑损伤（TBI）是一个主要的社会和公共卫生问题，超过280万TBI 每年在美国报告。轻度TBI（mTBI）占TBI的80%以上，可能难以诊断。 因为没有FDA批准的mTBI治疗干预存在，一段时间的休息，让症状 解决是主要的治疗方法。虽然有症状，但一个人从 mTBI避免持续第二次mTBI，因为多次mTBI会大大增加长期残疾的风险。 然而，mTBI后的大脑脆弱期超出了临床症状的解决， 强调了准确评估神经生理恢复的迫切需要，以减轻 与反复头部受伤有关的风险。与中度和重度TBI不同， 随着神经元死亡和血管破坏，mTBI导致更微妙的生理和细胞变化， 例如代谢性窘迫和脑血流（CBF）的改变。我们假设mTBI诱导 CBF的急性、短暂变化，加上代谢失调，形成了 易受反复mTBI的影响。因此，我们预测，在急性期， CBF改变将导致恶化的结果，反映在CBF和代谢的更大扰动。 我们的团队开发了一种新型的多波长散斑衬度漫相关层析成像（MW- scDCT）技术，其产生小鼠中CBF和氧合的非侵入性、纵向、区域映射。我们 我已经验证了我们的技术对建立的方法，并证明其实用性，在检测脑血流 啮齿动物的变化在目标1中，我们将首先使用MW-scDCT测量皮质和海马CBF， 单次闭合性颅脑损伤（CHI）后的氧合，以监测时间变化并确定 复苏然后我们将确定是否需要CBF正常化来防止A的协同效应 第二次CHI对脑血流动力学的影响。神经血管耦合和脑血管反应性将是 在选定的时间点进行评估，以告知CBF变化的潜在机制。最后， 将对脑血管结构和交通进行定量分析， 塑性或损伤。在目标2中，将使用靶向代谢组学方法来确定 皮质组织和血浆，这是单次或重复mTBI小鼠所特有的。我们将进一步测试 代谢组的恢复与mTBI后CBF的正常化一致。这一发现将支持一项 通过无创CBF监测评估脑震荡恢复的双管齐下的方法， 血浆代谢物生物标志物的评估。这些研究将把代谢组学与我们的创新MW- scDCT技术用于监测脑血流动力学，为神经生理学提供新的见解 大脑对反复mTBI的脆弱性的决定因素，并支持诊断和 mTBI的预后生物标志物。

项目成果

Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury.

• DOI: 10.3390/cells10030500
• 发表时间: 2021-02-26
• 期刊: Cells
• 影响因子: 6
• 作者: Hubbard WB;Banerjee M;Vekaria H;Prakhya KS;Joshi S;Wang QJ;Saatman KE;Whiteheart SW;Sullivan PG
• 通讯作者: Sullivan PG

Depth-sensitive diffuse speckle contrast topography for high-density mapping of cerebral blood flow in rodents.

• DOI: 10.1117/1.nph.10.4.045007
• 发表时间: 2023-10
• 期刊: NEUROPHOTONICS
• 影响因子: 5.3
• 作者: Mohtasebi, Mehrana;Singh, Dara;Liu, Xuhui;Fathi, Faraneh;Haratbar, Samaneh Rabienia;Saatman, Kathryn E.;Chen, Lei;Yu, Guoqiang
• 通讯作者: Yu, Guoqiang

Tissue factor release following traumatic brain injury drives thrombin generation.

• DOI: 10.1002/rth2.12734
• 发表时间: 2022-05
• 期刊: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
• 影响因子: 4.6
• 作者: Hubbard, W. Brad;Sim, Martha M. S.;Saatman, Kathryn E.;Sullivan, Patrick G.;Wood, Jeremy P.
• 通讯作者: Wood, Jeremy P.

The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants.

间歇性低氧血症对早产儿 1 型视网膜病变的影响。

• DOI: 10.1101/2023.09.25.23295922
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Haratbar,SamanehRabienia;Chen,Li;Cheng,Qiang;Singh,Dara;Fathi,Faraneh;Mohtasebi,Mehrana;Liu,Xuhui;Patwardhan,Abhijit;Bhandary,Prasad;Bada,HenriettaS;Yu,Guoqiang;AbuJawdeh,ElieG
• 通讯作者: AbuJawdeh,ElieG

Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets.

• DOI: 10.1002/jbio.202000366
• 发表时间: 2021-04
• 期刊: Journal of biophotonics
• 影响因子: 2.8
• 作者: Huang C;Mazdeyasna S;Mohtasebi M;Saatman KE;Cheng Q;Yu G;Chen L
• 通讯作者: Chen L