Improving CBF through direct control of CSF pulsations

描述（由申请人提供）：许多神经系统疾病，包括脑积水，部分通过减少脑血流量（CBF）导致脑损伤和功能障碍。来自临床和实验研究的证据表明，脑血流减少可能部分是由于血管和脑脊液（CSF）顺应性受损以及由此产生的异常颅内压（ICP）脉搏。因此，血管-脑脊液顺应性耦合和重要的脑脊液空间可能在调节脑血流中发挥重要作用。据推测，脑脊液可能在将脉动性、非连续性的血流转移到非脉动性、连续的毛细血管血流中起重要作用，这被称为大脑的Windkessel机制。我们假设脑脊液空间顺应性和脉动性的变化导致血管顺应性、脉动性和CBF的变化。此外，我们假设通过脑脊液容量与心脏周期同步的直接变化，我们可以在不改变平均体压或颅内压的情况下改变CBF。本研究的目的是通过直接、可控的脑脊液空间操作来改善脑血流。目前的研究采用慢性脑积水的实验动物模型，模拟相同的临床情况，减少CBF和CSF顺应性。一种可手术植入和可调节的颅球囊装置和振荡泵系统，专门设计用于与心脏周期同步，具有改变幅度、频率、相位和充气/收缩率的能力，以直接控制（增加或减少）CBF。气球膨胀/收缩将与人体自身的生理特性（即收缩/舒张）一致，因此与潜在的Windkessel机制密切匹配。这种振荡球囊装置的目的是：(1)通过改善脑脊液顺应性来增加脑血流，(2)保护大脑免受未吸收的动脉脉冲进入封闭的颅腔所造成的创伤。在本研究中，我们将使用颅球囊装置在正常生理条件下，在急性（通气过度/通气不足，脑脊液移除/输注）变化期间，以及慢性脑积水后，增强或减少脑脊液脉动。主要终点是CBF，通过组织和血流探针以及SPECT成像定量测量，脑脊液脉搏变化。次要终点将包括脑氧输送，以及使用免疫组织化学、ELISA和Western blot方法评估神经元特异性烯醇化酶（NSE）、星形细胞蛋白S100B和缺血标志物血管内皮生长因子（VEGF）受体2的实质和血管损伤。本研究的意义在于通过心脏同步的脑脊液容量操作来改善CBF。如果这种方法有效，那么我们对脑积水病理生理的认识将从传统的脑脊液积聚的观点转变为动态脉动异常的观点。基于这一认识的新疗法可应用于各种CBF减少的神经系统疾病，包括阿尔茨海默病和血管性痴呆，血管痉挛、淀粉样变性、动脉粥样硬化、静脉高压等血管疾病，脑脊液流体动力学障碍，如脑积水和假性脑瘤。此外，该方法也可有效地用于控制其他临床疾病中观察到的脑脊液异常脉动，包括中风、闭合性颅脑损伤和充血性心力衰竭，这些疾病可能存在与CBF降低和脑脊液脉动异常相关的进一步神经损伤风险。公共卫生相关性：当前研究的目标是通过直接控制脑脊液（CSF）操作来改善脑血流量（CBF）。在慢性脑积水的动物模型中，模拟相同的临床情况，减少CBF，我们将使用手术植入和可调节的颅球囊装置和振荡泵系统，专门设计用于随着心脏周期充气/放气来控制血管- csf顺应性，作为“减震器”来抑制传入的动脉搏动，最终改善CBF。如果证明有效，该方法可用于治疗数百万CBF减少的患者，包括阿尔茨海默氏症和血管型痴呆，血管疾病如静脉高压和脑脊液疾病如脑积水。此外，该方法也可以有效地用于其他临床疾病，如中风、闭合性颅脑损伤、充血性心力衰竭等可能有进一步脑损伤风险的疾病中观察到的异常脑脊液脉冲的正常化。

DESCRIPTION (provided by applicant): Many neurological disorders, including hydrocephalus, result in brain injury and dysfunction in part through decreased cerebral blood flow (CBF). Evidence from clinical and experimental studies indicates that reduced CBF may be, in part, caused by impaired vascular and cerebrospinal fluid (CSF) compliance and resultant abnormal intracranial pressure (ICP) pulsatility. Therefore, vascular-CSF compliance coupling and importantly CSF space may play a significant role in regulating CBF. It has been hypothesized that the CSF may be important in the transfer of pulsatile, non-continuous flow to non-pulsatile, continuous flow in capillaries, a term referred to as the brain's Windkessel mechanism. We hypothesize that changes in CSF space compliance and pulsatility result in changes in vascular compliance, pulsatility and CBF. Furthermore, we hypothesize that through direct CSF volume changes synchronous to the cardiac cycle, we can alter CBF without changing mean systemic or intracranial pressure. The goal of the proposed study is to improve CBF through direct, controlled CSF space manipulation. The current investigation employs an experimental animal model of chronic hydrocephalus that mimics the same clinical condition having decreased CBF and CSF compliance. A surgically implantable and adjustable cranial balloon device and oscillating pump system designed specifically to synchronize with the cardiac cycle with the ability to change amplitude, frequency, phase and inflation/deflation rate has been developed to directly control (increase or decreased) CBF. Balloon inflation/deflation will coincide with the body's own physiological properties (i.e., systole/diastole), therefore matching closely the underlying Windkessel mechanism. The purpose of this oscillating balloon device is to: (1) increase CBF by improving CSF compliance, and (2) protect the brain from the trauma of unabsorbed arterial pulsations entering the closed cranial cavity. In this study, we will use the cranial balloon device to augment or reduce CSF pulsations under normal physiologic conditions, during acute (hyper/hypoventilation, CSF removal/infusion) changes, and after chronic hydrocephalus. Primary endpoint is CBF as measured quantitatively by tissue and flow probes and SPECT imaging, with changes in CSF pulsatility. Secondary endpoints will include brain oxygen delivery, and the assessment of parenchymal and blood vessel injury using immunohistochemistry, ELISA, and Western blot methods for neuron specific enolase (NSE), astrocytic protein S100B, and ischemia marker vascular endothelial growth factor (VEGF) receptor 2. The significance of this study will be to improve CBF through cardiac-synchronized CSF volume manipulation. If this approach works, then our understanding of the pathophysiology of hydrocephalus is changed from the traditional view of CSF accumulation to that of dynamic pulsation abnormality. New treatments based on this understanding may be applied to various neurological disease with diminished CBF including Alzheimer's and vascular type dementia, vascular diseases such as vasospasm, amyloidosis, atherosclerosis, venous hypertension, and CSF hydrodynamic disorders such as hydrocephalus and pseurdotumor cerebri. In addition, this method may also be used effectively to control abberant CSF pulsations observed in other clinical diseases including stroke, closed head injury, and congestive heart failure which may be at risk for further neurological damage related to decreased CBF and abnormal CSF pulsatility. PUBLIC HEALTH RELEVANCE: The goal of the current research study is to improve cerebral blood flow (CBF) through direct, controlled cerebrospinal fluid (CSF) manipulation. In an animal model of chronic hydrocephalus that mimics the same clinical condition with decreased CBF, we will use a surgically implantable and adjustable cranial balloon device and oscillating pump system designed specifically to inflate/deflate with the cardiac cycle to control vascular-CSF compliance, act as a "shock absorber" to dampen incoming arterial pulsations, and ultimately improve CBF. If proven effective, this approach may be used to treat millions of patients with diminished CBF including Alzheimer's and vascular type dementia, vascular diseases such as venous hypertension, and CSF disorders such as hydrocephalus. In addition, this method may also be used effectively to normalize abnormal CSF pulsations observed in other clinical diseases including stroke, closed head injury, and congestive heart failure which may be at risk for further brain injury.