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In response to Mutti et al. 2024 commentary on "Transient intracranial pressure elevations (B waves) associated with sleep apnea: the neglected role of cyclic alternating pattern". 回应Mutti等人2024年对“与睡眠呼吸暂停相关的短暂性颅内压升高(B波):循环交替模式被忽视的作用”的评论。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-19 DOI: 10.1186/s12987-024-00610-z
Casper Schwartz Riedel

The physiology of transient intracranial pressure (ICP) elevations (B waves), remains incompletely understood and appears to involve multiple mechanisms, including obstructive sleep apnea (OSA). Transient ICP elevations are associated with OSA and cyclic alternating pattern (CAP) metrics, suggesting a complex interplay between sleep fragmentation and ICP dynamics. Additionally, CAP metrics could complement standard OSA assessments, providing deeper insights into transient ICP fluctuations, particularly in conditions like normal-pressure hydrocephalus and idiopathic intracranial hypertension. Future studies should explore CAP-ICP interactions to elucidate their physiological and clinical implications.

短暂性颅内压(ICP)升高(B波)的生理机制尚不完全清楚,似乎涉及多种机制,包括阻塞性睡眠呼吸暂停(OSA)。短暂的ICP升高与OSA和循环交替模式(CAP)指标相关,表明睡眠碎片化和ICP动态之间存在复杂的相互作用。此外,CAP指标可以补充标准的OSA评估,为瞬态ICP波动提供更深入的见解,特别是在常压脑积水和特发性颅内高压等情况下。未来的研究应探讨CAP-ICP相互作用,以阐明其生理和临床意义。
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引用次数: 0
Recapitulation of physiologic and pathophysiologic pulsatile CSF flow in purpose-built high-throughput hydrocephalus bioreactors. 在特制的高通量脑积水生物反应器中再现生理和病理生理脉动脑脊液的流动。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-19 DOI: 10.1186/s12987-024-00600-1
Ahmad Faryami, Adam Menkara, Shaheer Ajaz, Christopher Roberts, Ryan Jaroudi, Blake Gura, Tala Hussini, Carolyn A Harris
<p><strong>Background: </strong>Hydrocephalus, an accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain, is often treated via a shunt system to divert the excess CSF to a different compartment; if left untreated, it can lead to serious complications and permanent brain damage. It is estimated that one in every 500 people are born with hydrocephalus. Despite more than 60 years of concerted efforts, shunts still have the highest failure rate of any neurological device requiring follow-up shunt revision surgeries and contributing to the $2 billion cost of hydrocephalus care in the US alone. The absence of a tested and validated long-term in-vitro model that can incorporate clinically relevant parameters has limited hypothesis-driven studies and, in turn, limited our progress in understanding the mechanisms of shunt obstruction in hydrocephalus. Testing clinical parameters of flow, pressure, shear, catheter material, surface modifications, and others while optimizing for minimal protein, cellular, and blood interactions has yet to be done systematically for ventricular catheters. Several studies point to the need to not only understand how cells and tissues have occluded these shunt catheters but also how to stop the likely multi-faceted failure. For instance, studies show us that tissue occluding the ventricular catheter is primarily composed of proliferating astrocytes and cells of the macrophage lineage. Cell reactivity has been observed to follow flow gradients, with elevated levels of typically pro-inflammatory interleukin-6 produced under shear stress conditions greater than 0.5 dyne/[Formula: see text]. But also, that shear can shift cellular attachment. The Automated, In vitro Model for hydrocephalus research (AIMS), presented here, improves upon our previous long-term in vitro systems with specific goals of recapitulating bulk pulsatile cerebrospinal fluid (CSF) waveforms and steady-state flow directionality relevant to ventricular catheters used in hydrocephalus.</p><p><strong>Methods: </strong>The AIMS setup was developed to recapitulate a wide range of physiologic and pathophysiologic CSF flow patterns with varying pulse amplitude, pulsation rate, and bulk flow rate with high throughput capabilities. These variables were specified in a custom-built user interface to match clinical CSF flow measurements. In addition to flow simulation capabilities, AIMS was developed as a modular setup for chamber testing and quality control. In this study, the capacity and consistency of single inlet resin chambers (N = 40), multidirectional resin chambers (N = 5), silicone chambers (N = 40), and PETG chambers (N = 50) were investigated. The impact of the internal geometry of the chamber types on flow vectors during pulsatile physiologic and pathophysiologic flow was visualized using Computational Fluid Dynamics (CFD). Dynamic changes in ventricular volume were investigated by combining AIMS with MRI-driven silicone model of a pediatric
在今后的工作中,将该系统与之前报道的三维水凝胶支架结合使用,将加深我们对分流相关并发症的了解,并通过降低阻塞率来改进治疗策略。
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引用次数: 0
Isolation method of brain microvessels from small frozen human brain tissue for blood-brain barrier protein expression analysis. 冷冻人小脑组织中分离脑微血管的血脑屏障蛋白表达分析方法。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-19 DOI: 10.1186/s12987-024-00609-6
Seiryo Ogata, Shingo Ito, Takeshi Masuda, Sumio Ohtsuki

Background: Protein expression analysis of isolated brain microvessels provides valuable insights into the function of the blood-brain barrier (BBB). However, isolation of brain microvessels from human brain tissue, particularly in small quantities, poses significant challenges. This study presents a method for isolating brain microvessels from a small amount of frozen human brain tissue, adapting techniques from an established mouse brain capillary isolation method.

Methods: Brain microvessel fractions were obtained from approximately 0.3 g of frozen human brain tissue (frontal cortex) using a bead homogenizer for homogenization, followed by purification with a combination of cell strainers and glass beads. Protein expression in the isolated human microvessel fractions and whole-brain lysates was analyzed by western blot and proteomic analysis.

Results: Microscopic imaging confirmed the successful isolation of brain microvessels from frozen human brain tissue. Protein quantification assays demonstrated that the microvessel fraction yielded sufficient protein for detailed expression analysis. Western blot analysis revealed an enrichment of BBB-selective proteins including multidrug resistance 1 (MDR1)/ATP-binding cassette sub-family B member 1 (ABCB1), glucose transporter protein type 1 (GLUT1)/solute carrier family 2 member 1 (SLC2A1), and claudin 5 (CLDN5), in the brain microvessel fraction compared to whole-brain lysates. Multiple reaction monitoring quantification of six BBB-selective proteins-MDR1, breast cancer resistance protein (BCRP)/ATP binding cassette subfamily G member 2 (ABCG2), GLUT1, monocarboxylate transporter 1 (MCT1)/solute carrier family 16 member 1 (SLC16A1), transferrin receptor, and CLDN5-revealed expression levels consistent with those observed in larger human brain samples. Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS)-based quantitative proteomics further demonstrated significant enrichment of human microvascular endothelial cells in the isolated fraction, corroborating the findings from mouse models.

Conclusions: We successfully developed a method for isolation of brain microvessels from a small amount of frozen human brain tissue, facilitating detailed study of BBB proteome in aging or pathological conditions. This technique provides valuable insights into BBB dysfunction in central nervous system disorders and holds potential for improving brain-targeted drug delivery strategies.

背景:分离脑微血管的蛋白表达分析为了解血脑屏障(BBB)的功能提供了有价值的见解。然而,从人脑组织中分离脑微血管,特别是少量分离,带来了重大挑战。本研究提出了一种从少量冷冻人脑组织中分离脑微血管的方法,该方法采用了已建立的小鼠脑毛细血管分离方法的技术。方法:从大约0.3 g的冷冻人脑组织(额叶皮质)中获得脑微血管部分,使用珠粒均质机进行均质,然后使用细胞过滤器和玻璃珠组合进行纯化。western blot和蛋白质组学分析分离的人微血管和全脑裂解物中的蛋白表达。结果:显微镜成像证实了从冷冻人脑组织中成功分离出脑微血管。蛋白质定量分析表明,微血管部分产生足够的蛋白质进行详细的表达分析。Western blot分析显示,与全脑裂解物相比,脑微血管部分富集了bbb选择性蛋白,包括多药耐药1 (MDR1)/ atp结合盒亚家族B成员1 (ABCB1)、葡萄糖转运蛋白1 (GLUT1)/溶质载体家族2成员1 (SLC2A1)和claudin 5 (CLDN5)。6种bbb选择性蛋白mdr1、乳腺癌耐药蛋白(BCRP)/ATP结合盒亚家族G成员2 (ABCG2)、GLUT1、单羧酸转运蛋白1 (MCT1)/溶质载体家族16成员1 (SLC16A1)、转铁蛋白受体和cldn5的多重反应监测定量显示,其表达水平与在更大的人脑样本中观察到的表达水平一致。基于全理论质谱(SWATH-MS)的序列窗口获取定量蛋白质组学进一步证实了分离片段中人类微血管内皮细胞的显著富集,证实了小鼠模型的发现。结论:我们成功开发了一种从少量冷冻人脑组织中分离脑微血管的方法,便于对衰老或病理状态下血脑屏障蛋白质组的详细研究。这项技术为研究中枢神经系统疾病中的血脑屏障功能障碍提供了有价值的见解,并具有改善脑靶向药物递送策略的潜力。
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引用次数: 0
Lumped parameter simulations of cervical lymphatic vessels: dynamics of murine cerebrospinal fluid efflux from the skull. 颈部淋巴管的集总参数模拟:小鼠脑脊液从颅骨流出的动力学。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-19 DOI: 10.1186/s12987-024-00605-w
Daehyun Kim, Jeffrey Tithof

Background: Growing evidence suggests that for rodents, a substantial fraction of cerebrospinal fluid (CSF) drains by crossing the cribriform plate into the nasopharyngeal lymphatics, eventually reaching the cervical lymphatic vessels (CLVs). Disruption of this drainage pathway is associated with various neurological disorders.

Methods: We employ a lumped parameter method to numerically model CSF drainage across the cribriform plate to CLVs. Our model uses intracranial pressure as an inlet pressure and central venous blood pressure as an outlet pressure. The model incorporates initial lymphatic vessels (modeling those in the nasal region) that absorb the CSF and collecting lymphatic vessels (modeling CLVs) to transport the CSF against an adverse pressure gradient. To determine unknown parameters such as wall stiffness and valve properties, we utilize a Monte Carlo approach and validate our simulation against recent in vivo experimental measurements.

Results: Our parameter analysis reveals the physical characteristics of CLVs. Our results suggest that the stiffness of the vessel wall and the closing state of the valve are crucial for maintaining the vessel size and volume flow rate observed in vivo. We find that a decreased contraction amplitude and frequency leads to a reduction in volume flow rate, and we test the effects of varying the different pressures acting on the CLVs. Finally, we provide evidence that branching of initial lymphatic vessels may deviate from Murray's law to reduce sensitivity to elevated intracranial pressure.

Conclusions: This is the first numerical study of CSF drainage through CLVs. Our comprehensive parameter analysis offers guidance for future numerical modeling of CLVs. This study also provides a foundation for understanding physiology of CSF drainage, helping guide future experimental studies aimed at identifying causal mechanisms of reduction in CLV transport and potential therapeutic approaches to enhance flow.

背景:越来越多的证据表明,在啮齿类动物中,相当一部分脑脊液(CSF)通过筛状板进入鼻咽淋巴管,最终到达颈淋巴管(CLVs)。这种排水通路的破坏与各种神经系统疾病有关。方法:采用集总参数法对经筛板至clv的脑脊液引流进行数值模拟。我们的模型使用颅内压作为入口压力,中心静脉压作为出口压力。该模型包括吸收脑脊液的初始淋巴管(模拟鼻腔区域的淋巴管)和收集淋巴管(模拟clv),以对抗不利的压力梯度运输脑脊液。为了确定壁刚度和阀门性能等未知参数,我们利用蒙特卡罗方法并根据最近的体内实验测量验证我们的模拟。结果:我们的参数分析揭示了clv的物理特征。我们的研究结果表明,血管壁的刚度和阀门的关闭状态对于维持体内观察到的血管大小和体积流量至关重要。我们发现收缩幅度和频率的降低导致体积流量的降低,我们测试了不同压力作用于clv的影响。最后,我们提供的证据表明,初始淋巴管分支可能偏离默里定律,以降低对颅内压升高的敏感性。结论:这是首次通过CLVs进行脑脊液引流的数值研究。我们的综合参数分析为clv的数值模拟提供了指导。该研究还为理解脑脊液引流的生理学奠定了基础,有助于指导未来旨在确定CLV转运减少的因果机制和潜在的增强血流的治疗方法的实验研究。
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引用次数: 0
Association between choroid plexus volume and cognitive function in community-dwelling older adults without dementia: a population-based cross-sectional analysis. 社区居住无痴呆老年人脉络膜丛体积与认知功能的关系:基于人群的横断面分析。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-18 DOI: 10.1186/s12987-024-00601-0
Yosuke Hidaka, Mamoru Hashimoto, Takashi Suehiro, Ryuji Fukuhara, Tomohisa Ishikawa, Naoko Tsunoda, Asuka Koyama, Kazuki Honda, Yusuke Miyagawa, Kazuhiro Yoshiura, Seiji Yuuki, Naoto Kajitani, Shuken Boku, Kazunari Ishii, Manabu Ikeda, Minoru Takebayashi

Background: An increase in choroid plexus (CP) volume may be associated with cognitive decline in older individuals without dementia. In this study, we aimed to clarify whether CP volume can serve as an imaging marker of cognitive decline, determine how strongly CP volume is associated with cognitive decline, and explore factors associated with CP volume in older adults.

Methods: We measured CP volume, brain parenchyma, and cerebrospinal fluid (CSF) spaces associated with disproportionately enlarged subarachnoid space hydrocephalus (DESH), an imaging feature of normal-pressure hydrocephalus, in community-dwelling older adults aged ≥ 65 years without dementia.

Results: In 1,370 participants, lower Mini-Mental State Examination (MMSE) scores were significantly associated with higher CP volume, even after adjusting for DESH-related CSF space and brain parenchymal volume. CP volume was more strongly associated with MMSE scores than DESH-related CSF space and brain parenchymal volume. History of smoking, white matter hyperintensity, enlarged perivascular spaces, age, body mass index, and diabetes mellitus were also associated with increased CP volume.

Conclusions: CP volume may be a highly sensitive imaging marker of cognitive decline in community-dwelling older adults without dementia, as it is linked to cognitive decline independently of brain parenchyma and CSF volumes. Our findings emphasize the importance of investigating CP volume increase to maintain cognitive function in older individuals. Accordingly, further longitudinal studies are required.

背景:无痴呆的老年人脉络丛(CP)体积增加可能与认知能力下降有关。在本研究中,我们旨在阐明脑cp体积是否可以作为认知能力下降的影像学标志物,确定脑cp体积与认知能力下降的相关性有多强,并探讨老年人脑cp体积的相关因素。方法:我们测量了与不成比例增大的蛛网膜下腔脑积水(DESH)相关的CP体积、脑实质和脑脊液(CSF)间隙,DESH是常压脑积水的影像学特征,在≥65岁无痴呆的社区居住老年人中。结果:在1370名参与者中,即使在调整了与desh相关的CSF空间和脑实质体积后,较低的迷你精神状态检查(MMSE)得分与较高的CP体积显著相关。脑脊液体积与MMSE评分的相关性强于与desh相关的脑脊液空间和脑实质体积。吸烟史、白质高、血管周围间隙增大、年龄、体重指数和糖尿病也与CP容积增加有关。结论:脑脊液体积可能是社区居住的无痴呆老年人认知能力下降的一个高度敏感的影像学标志物,因为它与认知能力下降独立于脑组织和脑脊液体积。我们的研究结果强调了研究脑脊液容量增加对维持老年人认知功能的重要性。因此,需要进一步的纵向研究。
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引用次数: 0
Numerical study of the effects of minor structures and mean velocity fields in the cerebrospinal fluid flow. 小结构和平均速度场对脑脊液流动影响的数值研究。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-18 DOI: 10.1186/s12987-024-00604-x
Ziyu Wang, Mohammad Majidi, Chenji Li, Arezoo Ardekani

The importance of optimizing intrathecal drug delivery is highlighted by its potential to improve patient health outcomes. Findings from previous computational studies, based on an individual or a small group, may not be applicable to the wider population due to substantial geometric variability. Our study aims to circumvent this problem by evaluating an individual's cycle-averaged Lagrangian velocity field based on the geometry of their spinal subarachnoid space. It has been shown by Lawrence et al. (J Fluid Mech 861:679-720, 2019) that dominant physical mechanisms, such as steady streaming and Stokes drift, are key to facilitating mass transport within the spinal canal. In this study, we computationally modeled pulsatile cerebrospinal fluid flow fields and Lagrangian velocity field within the spinal subarachnoid space. Our findings highlight the essential role of minor structures, such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane, in modulating flow and transport dynamics within the spinal subarachnoid space. We found that these structures can enhance fluid transport. We also emphasized the need for particle tracking in computational studies of mass transport within the spinal subarachnoid space. Our research illuminates the relationship between the geometry of the spinal canal and transport dynamics, characterized by a large upward cycle-averaged Lagrangian velocity zone in the wider region of the geometry, as opposed to a downward zone in the narrower region and areas close to the wall. This highlights the potential for optimizing intrathecal injection protocols by harnessing natural flow dynamics within the spinal canal.

优化鞘内给药的重要性强调了其改善患者健康结果的潜力。先前基于个体或小群体的计算研究的结果可能不适用于更广泛的人群,因为存在大量的几何变异性。我们的研究旨在通过评估个体的周期平均拉格朗日速度场来规避这个问题,该速度场是基于他们的脊髓蛛网膜下腔空间的几何形状。Lawrence等人(J Fluid Mech 861:679-720, 2019)表明,稳定流和Stokes漂移等主要物理机制是促进椎管内物质运输的关键。在本研究中,我们计算模拟了脊髓蛛网膜下腔内脉动脑脊液流场和拉格朗日速度场。我们的研究结果强调了次要结构,如神经根、齿状韧带和波浪形蛛网膜,在调节脊髓蛛网膜下腔内的流动和运输动力学中的重要作用。我们发现这些结构可以增强流体的输送。我们还强调了在脊髓蛛网膜下腔内质量传输的计算研究中粒子跟踪的必要性。我们的研究阐明了椎管的几何形状和传输动力学之间的关系,其特点是在较宽的几何形状区域有一个较大的向上周期平均拉格朗日速度区,而在较窄的区域和靠近壁的区域则有一个向下的区域。这突出了通过利用椎管内的自然流动动力学来优化鞘内注射方案的潜力。
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引用次数: 0
Brain endothelial permeability, transport, and flow assessed over 10 orders of magnitude using the in situ brain perfusion technique. 采用原位脑灌注技术对脑内皮通透性、运输和血流进行了超过10个数量级的评估。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1186/s12987-024-00584-y
Quentin R Smith, Haritha Mandula, Jagan Mohan R Parepally, Jun Oki, Fancy Thomas, Helen R Thorsheim, Abraham J Al-Ahmad, Thomas J Abbruscato, Per Ask, David S Hage, Peter J Robinson

Background: Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDA-approved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.

Methods: Rat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum albumin or alpha-acid glycoprotein. Plasma protein was added to the saline perfusion fluid to lower extraction into the measurable range using the Crone Renkin "diffusion-flow" equation to calculate brain PoS.

Results: Cerebrovascular Po was determined for 125 solutes, of which 78 showed little or no evidence of active efflux transport. Fifty of the solutes were in the lipophilicity zone (Log Poct 1-5) of most FDA-approved CNS drugs. Care was taken to ensure the integrity of the brain vasculature during perfusion and to measure flow accurately using markers that had been verified for the flow rates. The results showed a linear relationship between Log Po and Log Poct over ~10 orders of magnitude with values for diazepam, estradiol, testosterone, and other agents that exceed prior published values by fivefold to 200-fold.

Conclusions: The results show that brain vascular permeability can be measured directly in vivo for highly lipophilic solutes and the PS values obtained match reasonably with that predicted by the Crone-Renkin flow diffusion equation with care taken to validate the accuracy for the component measurements and with no need to invoke "enhanced" or "induced" dissociation.

背景:通常情况下,脑血流会限制体内可测量的脑血管通透性(P)的大小。在正常的脑血流中,对于大多数fda批准的中枢神经系统药物,这个极限落在亲脂性的低端。在这项研究中,我们报告了两种方法,可用于克服这一限制,并使用原位脑灌注技术测量高达1000倍的脑血管通透性值。方法:在不同浓度血浆蛋白、血清白蛋白或α -酸性糖蛋白存在的情况下,以增加流速的生理盐水灌注大鼠脑。在生理盐水灌注液中加入血浆蛋白,使其提取率降至可测范围,采用Crone Renkin“扩散流”方程计算脑pos。结果:测定了125个溶质的脑血管Po,其中78个溶质很少或没有主动外排转运的证据。50个溶质位于大多数fda批准的CNS药物的亲脂区(Log Poct 1-5)。在灌注过程中注意确保脑血管系统的完整性,并使用已验证的流速标记物准确测量流量。结果显示,logpo和logpoct与安定、雌二醇、睾酮和其他药物的值之间的线性关系超过10个数量级,这些药物的值超过先前公布的值的5倍至200倍。结论:结果表明,高亲脂性溶质可以直接在体内测量脑血管渗透性,得到的PS值与Crone-Renkin流动扩散方程预测的PS值吻合较好,并注意验证了组分测量的准确性,无需调用“增强”或“诱导”解离。
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引用次数: 0
Abstracts from Hydrocephalus 2024: The 16th Meeting of the Hydrocephalus Society. 摘要脑积水2024:脑积水学会第16届会议。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-11 DOI: 10.1186/s12987-024-00596-8
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引用次数: 0
Choroid plexus aging: structural and vascular insights from the HCP-aging dataset. 脉络膜丛老化:结构和血管的见解从hcp老化数据集。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-05 DOI: 10.1186/s12987-024-00603-y
Zhe Sun, Chenyang Li, Jiangyang Zhang, Thomas Wisniewski, Yulin Ge

Background: The choroid plexus (ChP), a highly vascularized structure within the ventricles, is essential for cerebrospinal fluid (CSF) production and metabolic waste clearance, crucial for neurofluid homeostasis and cognitive function. ChP enlargement is seen in normal aging and neurodegenerative diseases like Alzheimer's disease (AD). Despite its key role of in the blood-CSF barrier (BCSFB), detailed studies on age-related changes in its perfusion and microstructure remain limited.

Methods: We analyzed data from 641 healthy individuals aged between 36 and 90, using the Human Connectome Project Aging (HCP-A) dataset. Volumetric, perfusion, and diffusion metrics of the ChP were derived from structural MRI, arterial spin labeling (ASL), and diffusion-weighted imaging (DWI), respectively. Partial correlations were used to explore age-related ChP changes, and independent t-tests to examine sex differences across age decades. One-way ANOVA was employed to compare perfusion characteristics among ChP, gray matter (GM), and white matter (WM). Relationships between volume, perfusion, and diffusion were investigated, adjusting for age and sex. Additionally, the distribution of cyst-like structures within the ChP and their diffusion/perfusion MRI characteristics were analyzed across different age groups.

Results: The ChP undergoes notable changes with age, including an increase in volume (r2 = 0.2, P < 0.001), a decrease in blood flow (r2 = 0.17, P < 0.001), and elevated mean diffusivity (MD) values (r2 = 0.16, P < 0.001). Perfusion characteristics showed significant differences between the ChP, GM, and WM (P < 0.001). Both the ChP and GM exhibited age-related declines in CBF, with a more pronounced decline in the ChP. A negative correlation was observed between the age-related increase in ChP volume and the decrease in CBF, suggesting compensatory dystrophic hyperplasia in response to perfusion decline. Cyst-like structures in ChP, characterized by lower MD and reduced CBF, were found to be more prevalent in older individuals.

Conclusions: Our findings provide a detailed quantitative assessment of age-related changes in ChP perfusion and diffusion, which may affect CSF production and circulation, potentially leading to waste solute accumulation and cognitive impairment.

Grant support: This work was supported in part by the NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568.

背景:脉络膜丛(ChP)是脑室内高度血管化的结构,对脑脊液(CSF)的产生和代谢废物的清除至关重要,对神经液稳态和认知功能至关重要。ChP增大见于正常衰老和阿尔茨海默病(AD)等神经退行性疾病。尽管它在血- csf屏障(BCSFB)中起着关键作用,但关于其灌注和微观结构与年龄相关变化的详细研究仍然有限。方法:我们使用人类连接组计划衰老(HCP-A)数据集分析了641名年龄在36至90岁之间的健康个体的数据。ChP的体积、灌注和扩散指标分别来自结构MRI、动脉自旋标记(ASL)和扩散加权成像(DWI)。偏相关用于探索与年龄相关的ChP变化,独立t检验用于检查不同年龄的性别差异。采用单因素方差分析比较ChP、灰质(GM)和白质(WM)的灌注特征。研究了体积、灌注和扩散之间的关系,并根据年龄和性别进行了调整。此外,我们还分析了不同年龄组ChP内囊肿样结构的分布及其扩散/灌注MRI特征。结果:ChP随着年龄的增长而发生显著变化,包括体积的增加(r2 = 0.2, p2 = 0.17, p2 = 0.16, P)。结论:我们的研究结果为ChP灌注和扩散的年龄相关变化提供了详细的定量评估,这些变化可能影响脑脊液的产生和循环,可能导致废物溶质积累和认知障碍。经费支持:本工作由NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568部分支持。
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引用次数: 0
Non-invasive MRI of blood-cerebrospinal fluid-barrier function in a mouse model of Alzheimer's disease: a potential biomarker of early pathology. 阿尔茨海默病小鼠模型血-脑脊液屏障功能的无创MRI:早期病理的潜在生物标志物。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-04 DOI: 10.1186/s12987-024-00597-7
Charith Perera, Renata Cruz, Noam Shemesh, Tânia Carvalho, David L Thomas, Jack Wells, Andrada Ianuș

Background: Choroid plexus (CP) or blood-cerebrospinal fluid-barrier (BCSFB) is a unique functional tissue which lines the brain's fluid-filled ventricles, with a crucial role in CSF production and clearance. BCSFB dysfunction is thought to contribute to toxic protein build-up in neurodegenerative disorders, including Alzheimer's disease (AD). However, the dynamics of this process remain unknown, mainly due to the paucity of in-vivo methods for assessing CP function.

Methods: We harness recent developments in Arterial Spin Labelling MRI to measure water delivery across the BCSFB as a proxy for CP function, as well as cerebral blood flow (CBF), at different stages of AD in the widely used triple transgenic mouse model (3xTg), with ages between 8 and 32 weeks. We further compared the MRI results with Y-maze behaviour testing, and histologically validated the expected pathological changes, which recapitulate both amyloid and tau deposition.

Results: Total BCSFB-mediated water delivery is significantly higher in 3xTg mice (> 50%) from 8 weeks (preclinical stage), an increase which is not explained by differences in ventricular volumes, while tissue parameters such as CBF and T1 are not different between groups at all ages. Behaviour differences between the groups were observed starting at 20 weeks, especially in terms of locomotion, with 3xTg animals showing a significantly smaller number of arm entries in the Y-maze.

Conclusions: Our work strongly suggests the involvement of CP in the early stages of AD, before the onset of symptoms and behavioural changes, providing a potential biomarker of pathology.

背景:脉络膜丛(CP)或血-脑脊液屏障(BCSFB)是排列在充满液体的脑室的一种独特的功能组织,在脑脊液的产生和清除中起着至关重要的作用。BCSFB功能障碍被认为有助于神经退行性疾病(包括阿尔茨海默病(AD))中毒性蛋白的积累。然而,这一过程的动力学仍然未知,主要是由于缺乏评估CP功能的体内方法。方法:我们利用动脉自旋标记MRI的最新发展来测量BCSFB的水输送,作为CP功能的代理,以及脑血流量(CBF),在AD的不同阶段,广泛使用的三联转基因小鼠模型(3xTg),年龄在8至32周之间。我们进一步将MRI结果与y迷宫行为测试进行了比较,并从组织学上验证了预期的病理变化,这些变化概括了淀粉样蛋白和tau沉积。结果:3xTg小鼠从8周(临床前阶段)开始,bcsfb介导的总水输送量显著增加(> 50%),这种增加不是由心室容积的差异来解释的,而CBF和T1等组织参数在各年龄组之间没有差异。从20周开始观察各组之间的行为差异,特别是在运动方面,3xTg的动物在y形迷宫中表现出明显较少的手臂进入次数。结论:我们的研究强烈表明,在阿尔茨海默病症状和行为改变出现之前,CP参与了阿尔茨海默病的早期阶段,提供了一种潜在的病理生物标志物。
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Fluids and Barriers of the CNS
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