Pub Date : 2024-09-27DOI: 10.1186/s12987-024-00577-x
Chris Greene, Nicolas Rebergue, Gwen Fewell, Damir Janigro, Yann Godfrin, Matthew Campbell, Sighild Lemarchant
Background: Alterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.
Methods: In vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBB models containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 µM), or its vehicle, for 4 h and up to 5 days. Tight junction (TJ) protein levels, permeability to dextrans and transendothelial electrical resistance (TEER) were evaluated. In vivo, young and old mice (3- and 21-month-old, respectively) were treated daily intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days and their brains collected at day 6 to measure TJ protein levels by immunohistochemistry.
Results: NX210c induced an increase in claudin-5 protein expression after 24-h and 72-h treatments in mouse EC. Occludin level was also increased after a 24-h treatment. Accordingly, NX210c decreased by half the permeability of EC to a 40-kDa FITC-dextran and increased TEER. In the human static BBB model, NX210c increased by ∼ 25% the TEER from 3 to 5 days. NX210c also increased TEER in the human 3D dynamic BBB model after 4 h, which was associated with a reduced permeability to a 4-kDa FITC-dextran. In line with in vitro results, after only 5 days of daily treatments in mice, NX210c restored aging-induced reduction of claudin-5 and occludin levels in the hippocampus, and also in the cortex for occludin.
Conclusions: In summary, we have gathered preclinical data showing the capacity of NX210c to strengthen BBB integrity. Through this property, NX210c holds great promises of being a disease-modifying treatment for several neurological disorders with high unmet medical needs.
{"title":"NX210c drug candidate peptide strengthens mouse and human blood-brain barriers.","authors":"Chris Greene, Nicolas Rebergue, Gwen Fewell, Damir Janigro, Yann Godfrin, Matthew Campbell, Sighild Lemarchant","doi":"10.1186/s12987-024-00577-x","DOIUrl":"https://doi.org/10.1186/s12987-024-00577-x","url":null,"abstract":"<p><strong>Background: </strong>Alterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.</p><p><strong>Methods: </strong>In vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBB models containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 µM), or its vehicle, for 4 h and up to 5 days. Tight junction (TJ) protein levels, permeability to dextrans and transendothelial electrical resistance (TEER) were evaluated. In vivo, young and old mice (3- and 21-month-old, respectively) were treated daily intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days and their brains collected at day 6 to measure TJ protein levels by immunohistochemistry.</p><p><strong>Results: </strong>NX210c induced an increase in claudin-5 protein expression after 24-h and 72-h treatments in mouse EC. Occludin level was also increased after a 24-h treatment. Accordingly, NX210c decreased by half the permeability of EC to a 40-kDa FITC-dextran and increased TEER. In the human static BBB model, NX210c increased by ∼ 25% the TEER from 3 to 5 days. NX210c also increased TEER in the human 3D dynamic BBB model after 4 h, which was associated with a reduced permeability to a 4-kDa FITC-dextran. In line with in vitro results, after only 5 days of daily treatments in mice, NX210c restored aging-induced reduction of claudin-5 and occludin levels in the hippocampus, and also in the cortex for occludin.</p><p><strong>Conclusions: </strong>In summary, we have gathered preclinical data showing the capacity of NX210c to strengthen BBB integrity. Through this property, NX210c holds great promises of being a disease-modifying treatment for several neurological disorders with high unmet medical needs.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"76"},"PeriodicalIF":5.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1186/s12987-024-00573-1
Laura Fritzen, Katharina Wienken, Lelia Wagner, Magdalena Kurtyka, Katharina Vogel, Jakob Körbelin, Sascha Weggen, Gert Fricker, Claus U. Pietrzik
The most crucial area to focus on when thinking of novel pathways for drug delivery into the CNS is the blood brain barrier (BBB). A number of nanoparticulate formulations have been shown in earlier research to target receptors at the BBB and transport therapeutics into the CNS. However, no mechanism for CNS entrance and movement throughout the CNS parenchyma has been proposed yet. Here, the truncated mini low-density lipoprotein receptor-related protein 1 mLRP1_DIV* was presented as blood to brain transport carrier, exemplified by antibodies and immunoliposomes using a systematic approach to screen the receptor and its ligands’ route across endothelial cells in vitro. The use of mLRP1_DIV* as liposomal carrier into the CNS was validated based on internalization and transport assays across an in vitro model of the BBB using hcMEC/D3 and bEnd.3 cells. Trafficking routes of mLRP1_DIV* and corresponding cargo across endothelial cells were analyzed using immunofluorescence. Modulation of γ-secretase activity by immunoliposomes loaded with the γ-secretase modulator BB25 was investigated in co-cultures of bEnd.3 mLRP1_DIV* cells and CHO cells overexpressing human amyloid precursor protein (APP) and presenilin 1 (PSEN1). We showed that while expressed in vitro, mLRP1_DIV* transports both, antibodies and functionalized immunoliposomes from luminal to basolateral side across an in vitro model of the BBB, followed by their mLRP1_DIV* dependent release of the cargo. Importantly, functionalized liposomes loaded with the γ-secretase modulator BB25 were demonstrated to effectively reduce toxic Aß42 peptide levels after mLRP1_DIV* mediated transport across a co-cultured endothelial monolayer. Together, the data strongly suggest mLRP1_DIV* as a promising tool for drug delivery into the CNS, as it allows a straight transport of cargo from luminal to abluminal side across an endothelial monolayer and it’s release into brain parenchyma in vitro, where it exhibits its intended therapeutic effect.
{"title":"Truncated mini LRP1 transports cargo from luminal to basolateral side across the blood brain barrier","authors":"Laura Fritzen, Katharina Wienken, Lelia Wagner, Magdalena Kurtyka, Katharina Vogel, Jakob Körbelin, Sascha Weggen, Gert Fricker, Claus U. Pietrzik","doi":"10.1186/s12987-024-00573-1","DOIUrl":"https://doi.org/10.1186/s12987-024-00573-1","url":null,"abstract":"The most crucial area to focus on when thinking of novel pathways for drug delivery into the CNS is the blood brain barrier (BBB). A number of nanoparticulate formulations have been shown in earlier research to target receptors at the BBB and transport therapeutics into the CNS. However, no mechanism for CNS entrance and movement throughout the CNS parenchyma has been proposed yet. Here, the truncated mini low-density lipoprotein receptor-related protein 1 mLRP1_DIV* was presented as blood to brain transport carrier, exemplified by antibodies and immunoliposomes using a systematic approach to screen the receptor and its ligands’ route across endothelial cells in vitro. The use of mLRP1_DIV* as liposomal carrier into the CNS was validated based on internalization and transport assays across an in vitro model of the BBB using hcMEC/D3 and bEnd.3 cells. Trafficking routes of mLRP1_DIV* and corresponding cargo across endothelial cells were analyzed using immunofluorescence. Modulation of γ-secretase activity by immunoliposomes loaded with the γ-secretase modulator BB25 was investigated in co-cultures of bEnd.3 mLRP1_DIV* cells and CHO cells overexpressing human amyloid precursor protein (APP) and presenilin 1 (PSEN1). We showed that while expressed in vitro, mLRP1_DIV* transports both, antibodies and functionalized immunoliposomes from luminal to basolateral side across an in vitro model of the BBB, followed by their mLRP1_DIV* dependent release of the cargo. Importantly, functionalized liposomes loaded with the γ-secretase modulator BB25 were demonstrated to effectively reduce toxic Aß42 peptide levels after mLRP1_DIV* mediated transport across a co-cultured endothelial monolayer. Together, the data strongly suggest mLRP1_DIV* as a promising tool for drug delivery into the CNS, as it allows a straight transport of cargo from luminal to abluminal side across an endothelial monolayer and it’s release into brain parenchyma in vitro, where it exhibits its intended therapeutic effect.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1186/s12987-024-00569-x
Carlotta Mutti, Clara Rapina, Francesco Rausa, Giulia Balella, Dario Bottignole, Marcello Giuseppe Maggio, Liborio Parrino
<p>Riedel et al. recently published an interesting paper on the association between intracranial pressure (ICP) elevation, measured through the Lundberg B waves, and sleep apnea in a group of patients with idiopathic intracranial hypertension (IIH) and hydrocephalus [1].</p><p>ICP B waves are defined as short, repetitive elevation of intracranial pressure of up to 50 mmHg with a frequency of 0.5-2 waves/min, which are typically observed in patients with IIH, but can also be measured in subjects with normal intracranial pressure [2].</p><p>Obstructive sleep apnea (OSA) is a multi-systemic syndrome characterized by phasic interruptions of airflow during sleep, leading to severe sleep fragmentation and cardiovascular consequences, presenting a typical 20-40 s periodicity (Panel A, Fig. 1).</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png?as=webp" type="image/webp"/><img alt="figure 1" aria-describedby="Fig1" height="383" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png" width="685"/></picture><p><b>A</b> Vertical integration between CAP fluctuations during NREM sleep, respiratory events, oxygen desaturation and pulse rate dynamic in a patient affected by OSA. <b>B</b> figure published in Riedel et al., 2023 showing the vertical integration between ICP oscillations, obstructive apnea events and sleep fragmentation. <b>C</b> example of physiological CAP fluctuations during NREM sleep in a healthy subject. <b>D</b> example of stable NREM with no CAP intrusion</p><span>Full size image</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><p>According to Riedel et al. [1], there is an interesting association between ICP B waves and sleep apnea. The overlap of B waves with repetitive respiratory events induces a further increase in the ICP elevation (See Panel B in Fig. 1). The synusoidal pattern becomes particularly relevant during obstructive respiratory events (compared to central-type events), whereas the introduction of CPAP leads to overall reduction of phasic ICP elevations.</p><p>Riedel et al. [1] show the temporal coupling between ICP fluctuations, nasal airflow flattening, thorax and abdomen activity changes, SatO2% oscillations and sleep stage dynamics.</p><p>In Panel B (Fig. 1) severe sleep fragmentation characterized by numerous brief awakening lasting < 2 min is recognizable in a patient with idiopathic normal pressure hydrocephalus and OSA during stage N2 of NREM sleep.</p><p>It is known that OSA is closely associated cyclic alternating pattern (CAP) oscillations, including not only fast but also slow-wave arous
Riedel 等人最近发表了一篇有趣的论文，研究了一组特发性颅内高压（IIH）和脑积水患者的颅内压（ICP）升高（通过伦德伯格 B 波测量）与睡眠呼吸暂停之间的关系[1]。ICP B 波是指颅内压短时、重复性升高，最高可达 50 mmHg，频率为 0.5-2 波/分钟，通常在 IIH 患者中观察到，但也可在颅内压正常的受试者中测量到[2]。阻塞性睡眠呼吸暂停（OSA）是一种多系统综合征，其特点是睡眠期间气流的阶段性中断，导致严重的睡眠破碎和心血管后果，呈现典型的 20-40 秒周期性（图 1，A 组）。B 图发表于 Riedel 等人，2023 年，显示了 ICP 振荡、阻塞性呼吸暂停事件和睡眠片段之间的垂直整合。C 健康人 NREM 睡眠期间 CAP 生理波动示例。根据 Riedel 等人的研究[1]，ICP B 波与睡眠呼吸暂停之间存在有趣的联系。B 波与重复呼吸事件重叠会导致 ICP 进一步升高（见图 1 中的 B 小组）。Riedel 等人[1] 显示了 ICP 波动、鼻气流平缓、胸腹活动变化、SatO2% 振荡和睡眠阶段动态之间的时间耦合。众所周知，OSA 与周期性交替模式（CAP）振荡密切相关，不仅包括快波唤醒，还包括慢波唤醒[3]，与正在发生的睡眠呼吸紊乱的严重程度密切相关[4]。CAP 是睡眠不稳定性的电生理生物标记，在 NREM 睡眠期间周期性地干扰脑电图背景（C 小组）。值得注意的是，CAP 与伦德伯格 B 波的时域完全相同，从 2 秒到 60 秒不等，突破了睡眠评分 30 秒的硬性界限。NREM 睡眠期间剩余的静止脑电图活动被描述为非 CAP 睡眠（图 1，D 小组）。我们认为，CAP 指标更能反映 Lundberg B 波与 OSA 依赖性睡眠支离破碎之间的关联，而不是简短的觉醒或唤醒。Riedel 等人[1]的研究表明，在研究的 OSA 患者群中，CPAP 会显著改变 Lundberg B 波。这些发现可能解释了为什么在快速眼动睡眠中 ICP 波动会部分丧失清晰的振荡模式，因为众所周知，CAP 生理上只发生在快速眼动睡眠中[7].无论处于哪个睡眠阶段，快速眼动睡眠都可以被描述为稳定（非 CAP）和不稳定（CAP）交替的双峰大脑状态（分别见图 1 中的面板 C 和面板 D）。垂直整合 "方法包括脑电图以外的特征（如心肺耦合、行为变化，或许还包括颅内 B 波），可能是研究 NREM 睡眠期间所有振荡的最适当方法[8]。据我们所知，探索 ICP 升高与 CAP 之间联系的研究从未进行过。Riedel CS, Martinez-Tejada I, Andresen M, Wilhjelm JE, Jennum P, Juhler M. Transient intracranial pressure elevations (B waves) are associated with sleep apnea.Fluids Barriers CNS.2023;20(1):69. https://doi.org/10.1186/s12987-023-00469-6.Article PubMed PubMed Central Google Scholar Riedel CS, Martinez-Tejada I, Norager NH, Kempfner L, Jennum P, Juhler M. B波存在于无颅内压紊乱的患者中。J Sleep Res. 2021;30(4): e13214. https://doi.org/10.1111/jsr.13214.Article PubMed Google Scholar Milioli G, Bosi M, Grassi A, et al. Can sleep microstructure improve diagnosis of OSAS? integrative information from CAP parameters.2015;153(2-3):194-203. https://doi.org/10.12871/0003982920152344.
{"title":"Commentary on “Transient intracranial pressure elevations (B waves) associated with sleep apnea”: the neglected role of cyclic alternating pattern","authors":"Carlotta Mutti, Clara Rapina, Francesco Rausa, Giulia Balella, Dario Bottignole, Marcello Giuseppe Maggio, Liborio Parrino","doi":"10.1186/s12987-024-00569-x","DOIUrl":"https://doi.org/10.1186/s12987-024-00569-x","url":null,"abstract":"<p>Riedel et al. recently published an interesting paper on the association between intracranial pressure (ICP) elevation, measured through the Lundberg B waves, and sleep apnea in a group of patients with idiopathic intracranial hypertension (IIH) and hydrocephalus [1].</p><p>ICP B waves are defined as short, repetitive elevation of intracranial pressure of up to 50 mmHg with a frequency of 0.5-2 waves/min, which are typically observed in patients with IIH, but can also be measured in subjects with normal intracranial pressure [2].</p><p>Obstructive sleep apnea (OSA) is a multi-systemic syndrome characterized by phasic interruptions of airflow during sleep, leading to severe sleep fragmentation and cardiovascular consequences, presenting a typical 20-40 s periodicity (Panel A, Fig. 1).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"383\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png\" width=\"685\"/></picture><p><b>A</b> Vertical integration between CAP fluctuations during NREM sleep, respiratory events, oxygen desaturation and pulse rate dynamic in a patient affected by OSA. <b>B</b> figure published in Riedel et al., 2023 showing the vertical integration between ICP oscillations, obstructive apnea events and sleep fragmentation. <b>C</b> example of physiological CAP fluctuations during NREM sleep in a healthy subject. <b>D</b> example of stable NREM with no CAP intrusion</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>According to Riedel et al. [1], there is an interesting association between ICP B waves and sleep apnea. The overlap of B waves with repetitive respiratory events induces a further increase in the ICP elevation (See Panel B in Fig. 1). The synusoidal pattern becomes particularly relevant during obstructive respiratory events (compared to central-type events), whereas the introduction of CPAP leads to overall reduction of phasic ICP elevations.</p><p>Riedel et al. [1] show the temporal coupling between ICP fluctuations, nasal airflow flattening, thorax and abdomen activity changes, SatO2% oscillations and sleep stage dynamics.</p><p>In Panel B (Fig. 1) severe sleep fragmentation characterized by numerous brief awakening lasting < 2 min is recognizable in a patient with idiopathic normal pressure hydrocephalus and OSA during stage N2 of NREM sleep.</p><p>It is known that OSA is closely associated cyclic alternating pattern (CAP) oscillations, including not only fast but also slow-wave arous","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blood–brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer’s disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (Ktrans) were calculated within regions of interest. Spearman’s correlation and multivariate linear regression were applied to analyze associations between Ktrans and specific clinical characteristics. In members of the DLB (vs HC) group, Ktrans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and Ktrans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased Ktrans values of parietal ( $$upbeta$$ = 0.391; p = 0.001) and occipital ( $$upbeta$$ = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased Ktrans values of cerebral cortex ( $$upbeta$$ = 0.285; p = 0.015), frontal lobe ( $$upbeta$$ = 0.237; p = 0.043), and parietal lobe ( $$upbeta$$ = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments. BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity.
血脑屏障（BBB）功能障碍一直被视为神经退行性疾病的潜在潜在机制，可能与阿尔茨海默病（AD）的发病机制和进展有关。然而，血脑屏障功能障碍与路易体痴呆（DLB）之间的关系还有待系统研究。鉴于AD和DLB的临床特征和神经病理学有重叠之处，我们试图评估DLB的BBB通透性，并使用动态对比增强磁共振成像（DCE-MRI）确定其与血浆淀粉样蛋白-β（Aβ）的关系。在这项前瞻性研究中，我们对2020年12月至2022年4月期间的健康对照组（24人，HC组）和确诊为AD（29人）或DLB（20人）的患者进行了检查。基于 DCE-MRI 研究，我们计算了相关区域内造影剂从血管内向血管外转移的平均速率（Ktrans）。斯皮尔曼相关性和多变量线性回归用于分析 Ktrans 与特定临床特征之间的关联。在DLB（vs HC）组中，大脑皮层（p = 0.024）、顶叶（p = 0.007）和枕叶（p = 0.014）的Ktrans值显著高于AD组；而在DLB组中，大脑皮层（p = 0.041）和枕叶（p = 0.018）的Ktrans值显著高于AD组。所有参与者的顶叶（$$upbeta$$ = 0.391; p = 0.001）和枕叶（$$upbeta$$ = 0.357; p = 0.002）的Ktrans值也显示出增加，在对年龄和性别进行调整后，这与临床痴呆评级的较高分数显著相关。同样，经上述调整后，大脑皮层（$$upbeta$$ = 0.285; p = 0.015）、额叶（$$upbeta$$ = 0.237; p = 0.043）和顶叶（$$upbeta$$ = 0.265; p = 0.024）的Ktrans值增加与血浆Aβ1-42/Aβ1-40比率升高有显著联系。BBB 渗漏是 DLB 的常见特征，在大脑的某些区域可能比 AD 更为严重。BBB 渗漏似乎与血浆 Aβ1-42/Aβ1-40 比率和痴呆症严重程度相关。
{"title":"Blood–brain barrier breakdown in dementia with Lewy bodies","authors":"Jinghuan Gan, Ziming Xu, Zhichao Chen, Shuai Liu, Hao Lu, Yajie Wang, Hao Wu, Zhihong Shi, Huijun Chen, Yong Ji","doi":"10.1186/s12987-024-00575-z","DOIUrl":"https://doi.org/10.1186/s12987-024-00575-z","url":null,"abstract":"Blood–brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer’s disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (Ktrans) were calculated within regions of interest. Spearman’s correlation and multivariate linear regression were applied to analyze associations between Ktrans and specific clinical characteristics. In members of the DLB (vs HC) group, Ktrans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and Ktrans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased Ktrans values of parietal ( $$upbeta$$ = 0.391; p = 0.001) and occipital ( $$upbeta$$ = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased Ktrans values of cerebral cortex ( $$upbeta$$ = 0.285; p = 0.015), frontal lobe ( $$upbeta$$ = 0.237; p = 0.043), and parietal lobe ( $$upbeta$$ = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments. BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1186/s12987-024-00571-3
Yuanqi Sun, Di Cao, Jay J. Pillai, Adrian Paez, Yinghao Li, Chunming Gu, Jacob M. Pogson, Linda Knutsson, Peter B. Barker, Peter C. M. van Zijl, Arnold Bakker, Bryan K. Ward, Jun Hua
Pathways for intravenously administered gadolinium-based-contrast-agents (GBCAs) entering cerebrospinal-fluid (CSF) circulation in the human brain are not well-understood. The blood-CSF-barrier (BCSFB) in choroid-plexus (CP) has long been hypothesized to be a main entry-point for intravenous-GBCAs into CSF. Most existing studies on this topic were performed in animals and human patients with various diseases. Results in healthy human subjects are limited. Besides, most studies were performed using MRI methods with limited temporal resolution and significant partial-volume effects from blood and CSF. This study employs the recently developed dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI approach to measure GBCA-distribution in the CSF immediately and 4 h after intravenous-GBCA administration in healthy subjects. With a temporal resolution of 10 s, cDSC MRI can track GBCA-induced CSF signal changes during the bolus phase, which has not been investigated previously. It employs a long echo-time (TE = 1347 ms) to suppress tissue and blood signals so that pure CSF signal is detected with minimal partial-volume effects. GBCA concentration in the CSF can be estimated from cDSC MRI. In this study, cDSC and FLAIR MRI were performed immediately and 4 h after intravenous GBCA administration in 25 healthy volunteers (age 48.9 ± 19.5 years; 14 females). Paired t-tests were used to compare pre-GBCA and post-GBCA signal changes, and their correlations with age were evaluated using Pearson-correlation-coefficients. At ~ 20 s post-GBCA, GBCA-induced cDSC signal changes were detected in the CSF around CP (ΔS/S = − 2.40 ± 0.30%; P < .001) but not in the rest of lateral ventricle (LV). At 4 h, significant GBCA-induced cDSC signal changes were observed in the entire LV (ΔS/S = − 7.58 ± 3.90%; P = .002). FLAIR MRI showed a similar trend. GBCA-induced CSF signal changes did not correlate with age. These results provided direct imaging evidence that GBCAs can pass the BCSFB in the CP and enter ventricular CSF immediately after intravenous administration in healthy human brains. Besides, our results in healthy subjects established a basis for clinical studies in brain diseases exploiting GBCA-enhanced MRI to detect BCSFB dysfunction.
{"title":"Rapid imaging of intravenous gadolinium-based contrast agent (GBCA) entering ventricular cerebrospinal fluid (CSF) through the choroid plexus in healthy human subjects","authors":"Yuanqi Sun, Di Cao, Jay J. Pillai, Adrian Paez, Yinghao Li, Chunming Gu, Jacob M. Pogson, Linda Knutsson, Peter B. Barker, Peter C. M. van Zijl, Arnold Bakker, Bryan K. Ward, Jun Hua","doi":"10.1186/s12987-024-00571-3","DOIUrl":"https://doi.org/10.1186/s12987-024-00571-3","url":null,"abstract":"Pathways for intravenously administered gadolinium-based-contrast-agents (GBCAs) entering cerebrospinal-fluid (CSF) circulation in the human brain are not well-understood. The blood-CSF-barrier (BCSFB) in choroid-plexus (CP) has long been hypothesized to be a main entry-point for intravenous-GBCAs into CSF. Most existing studies on this topic were performed in animals and human patients with various diseases. Results in healthy human subjects are limited. Besides, most studies were performed using MRI methods with limited temporal resolution and significant partial-volume effects from blood and CSF. This study employs the recently developed dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI approach to measure GBCA-distribution in the CSF immediately and 4 h after intravenous-GBCA administration in healthy subjects. With a temporal resolution of 10 s, cDSC MRI can track GBCA-induced CSF signal changes during the bolus phase, which has not been investigated previously. It employs a long echo-time (TE = 1347 ms) to suppress tissue and blood signals so that pure CSF signal is detected with minimal partial-volume effects. GBCA concentration in the CSF can be estimated from cDSC MRI. In this study, cDSC and FLAIR MRI were performed immediately and 4 h after intravenous GBCA administration in 25 healthy volunteers (age 48.9 ± 19.5 years; 14 females). Paired t-tests were used to compare pre-GBCA and post-GBCA signal changes, and their correlations with age were evaluated using Pearson-correlation-coefficients. At ~ 20 s post-GBCA, GBCA-induced cDSC signal changes were detected in the CSF around CP (ΔS/S = − 2.40 ± 0.30%; P < .001) but not in the rest of lateral ventricle (LV). At 4 h, significant GBCA-induced cDSC signal changes were observed in the entire LV (ΔS/S = − 7.58 ± 3.90%; P = .002). FLAIR MRI showed a similar trend. GBCA-induced CSF signal changes did not correlate with age. These results provided direct imaging evidence that GBCAs can pass the BCSFB in the CP and enter ventricular CSF immediately after intravenous administration in healthy human brains. Besides, our results in healthy subjects established a basis for clinical studies in brain diseases exploiting GBCA-enhanced MRI to detect BCSFB dysfunction.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"78 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1186/s12987-024-00572-2
Adam M. Wright, Yu-Chien Wu, Ho-Ching Yang, Shannon L. Risacher, Andrew J. Saykin, Yunjie Tong, Qiuting Wen
Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in $$frac{d}{dphi }fMRI$$ and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (−0.015 vs. −0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: −0.15 vs. −0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89). This study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.
{"title":"Coupled pulsatile vascular and paravascular fluid dynamics in the human brain","authors":"Adam M. Wright, Yu-Chien Wu, Ho-Ching Yang, Shannon L. Risacher, Andrew J. Saykin, Yunjie Tong, Qiuting Wen","doi":"10.1186/s12987-024-00572-2","DOIUrl":"https://doi.org/10.1186/s12987-024-00572-2","url":null,"abstract":"Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in $$frac{d}{dphi }fMRI$$ and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (−0.015 vs. −0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: −0.15 vs. −0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89). This study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s12987-024-00567-z
Virginia Plá, Styliani Bitsika, Michael J. Giannetto, Antonio Ladrón-de-Guevara, Daniel Gahn-Martinez, Yuki Mori, Maiken Nedergaard, Kjeld Møllgård
Histological studies have for decades documented that each of the classical meningeal membranes contains multiple fibroblast layers with distinct cellular morphology. Particularly, the sublayers of the arachnoid membranes have received attention due to their anatomical complexity. Early studies found that tracers injected into the cerebrospinal fluid (CSF) do not distribute freely but are restricted by the innermost sublayer of the arachnoid membrane. The existence of restrictions on CSF movement and the subdivision of the subarachnoid space into several distinct compartments have recently been confirmed by in vivo 2-photon studies of rodents, as well as macroscopic imaging of pigs and magnetic resonance imaging of human brain. Based on in vivo imaging and immunophenotyping characterization, we identified the structural basis for this compartmentalization of the subarachnoid space, which we term ‘Subarachnoid lymphatic-like membrane’, SLYM. The SLYM layer engages the subarachnoid vasculature as it approaches the brain parenchyma, demarcating a roof over pial perivascular spaces. Functionally, the separation of pial periarterial and perivenous spaces in the larger subarachnoid space is critical for the maintenance of unidirectional glymphatic clearance. In light of its close apposition to the pial surface and to the brain perivascular fluid exit points, the SLYM also provides a primary locus for immune surveillance of the brain. Yet, the introduction of SLYM, in terms of its anatomic distinction and hence functional specialization, has met resistance. Its critics assert that SLYM has been described in the literature by other terms, including the inner arachnoid membrane, the interlaminate membrane, the outer pial layer, the intermediate lamella, the pial membrane, the reticular layer of the arachnoid membrane or, more recently, BFB2-3. We argue that our conception of SLYM as an anatomically and functionally distinct construct is both necessary and warranted since its functional roles are wholly distinct from those of the overlying arachnoid barrier layer. Our terminology also lends clarity to a complex anatomy that has hitherto been ill-described. In that regard, we also note the lack of specificity of DPP4, which has recently been introduced as a ‘selected defining marker’ of the arachnoid barrier layer. We note that DPP4 labels fibroblasts in all meningeal membranes as well as in the trabecula arachnoides and the vascular adventitial layers, thus obviating its utility in meningeal characterization. Instead, we report a set of glymphatic-associated proteins that serve to accurately specify SLYM and distinguish it from its adjacent yet functionally distinct membranes.
{"title":"Response to Commentary on “Structural characterization of SLYM – a 4th meningeal membrane” by Julie Siegenthaler and Christer Betsholtz","authors":"Virginia Plá, Styliani Bitsika, Michael J. Giannetto, Antonio Ladrón-de-Guevara, Daniel Gahn-Martinez, Yuki Mori, Maiken Nedergaard, Kjeld Møllgård","doi":"10.1186/s12987-024-00567-z","DOIUrl":"https://doi.org/10.1186/s12987-024-00567-z","url":null,"abstract":"Histological studies have for decades documented that each of the classical meningeal membranes contains multiple fibroblast layers with distinct cellular morphology. Particularly, the sublayers of the arachnoid membranes have received attention due to their anatomical complexity. Early studies found that tracers injected into the cerebrospinal fluid (CSF) do not distribute freely but are restricted by the innermost sublayer of the arachnoid membrane. The existence of restrictions on CSF movement and the subdivision of the subarachnoid space into several distinct compartments have recently been confirmed by in vivo 2-photon studies of rodents, as well as macroscopic imaging of pigs and magnetic resonance imaging of human brain. Based on in vivo imaging and immunophenotyping characterization, we identified the structural basis for this compartmentalization of the subarachnoid space, which we term ‘Subarachnoid lymphatic-like membrane’, SLYM. The SLYM layer engages the subarachnoid vasculature as it approaches the brain parenchyma, demarcating a roof over pial perivascular spaces. Functionally, the separation of pial periarterial and perivenous spaces in the larger subarachnoid space is critical for the maintenance of unidirectional glymphatic clearance. In light of its close apposition to the pial surface and to the brain perivascular fluid exit points, the SLYM also provides a primary locus for immune surveillance of the brain. Yet, the introduction of SLYM, in terms of its anatomic distinction and hence functional specialization, has met resistance. Its critics assert that SLYM has been described in the literature by other terms, including the inner arachnoid membrane, the interlaminate membrane, the outer pial layer, the intermediate lamella, the pial membrane, the reticular layer of the arachnoid membrane or, more recently, BFB2-3. We argue that our conception of SLYM as an anatomically and functionally distinct construct is both necessary and warranted since its functional roles are wholly distinct from those of the overlying arachnoid barrier layer. Our terminology also lends clarity to a complex anatomy that has hitherto been ill-described. In that regard, we also note the lack of specificity of DPP4, which has recently been introduced as a ‘selected defining marker’ of the arachnoid barrier layer. We note that DPP4 labels fibroblasts in all meningeal membranes as well as in the trabecula arachnoides and the vascular adventitial layers, thus obviating its utility in meningeal characterization. Instead, we report a set of glymphatic-associated proteins that serve to accurately specify SLYM and distinguish it from its adjacent yet functionally distinct membranes.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s12987-024-00568-y
Julie Siegenthaler, Christer Betsholtz
For centuries, the meninges have been described as three membranes: the inner pia, middle arachnoid and outer dura. It was therefore sensational when in early 2023 Science magazine published a report of a previously unrecognized — 4th — meningeal membrane located between the pia and arachnoid. Multiple features were claimed for this new membrane: a single cell layer marked by the transcription factor Prox1 that formed a barrier to low molecular weight substances and separated the subarachnoid space (SAS) into two fluid-filled compartments, not one as previously described. These features were further claimed to facilitate unidirectional glymphatic cerebrospinal fluid transport. These claims were immediately questioned by several researchers as misinterpretations of the authors’ own data. The critics argued that (i) the 4th meningeal membrane as claimed did not exist as a separate structure but was part of the arachnoid, (ii) the “outer SAS” compartment was likely an artifactual subdural space created by the experimental procedures, and (iii) the 4th membrane barrier property was confused with the arachnoid barrier. Subsequent publications in late 2023 indeed showed that Prox1 + cells are embedded within the arachnoid and located immediately inside of and firmly attached to the arachnoid barrier cells by adherens junctions and gap junctions. In a follow-up study, published in this journal, the lead authors of the Science paper Kjeld Møllgård and Maiken Nedergaard reported additional observations they claim support the existence of a 4th meningeal membrane and the compartmentalization of the SAS into two non-communicating spaces. Their minor modification to the original paper was the 4th meningeal membrane was better observable at the ventral side of the brain than at the dorsal side where it was originally reported. The authors also claimed support for the existence of a 4th meningeal membrane in classical literature. Here, we outline multiple concerns over the new data and interpretation and argue against the claim there is prior support in the literature for a 4th meningeal membrane.
{"title":"Commentary on “Structural characterization of SLYM – a 4th meningeal membrane”","authors":"Julie Siegenthaler, Christer Betsholtz","doi":"10.1186/s12987-024-00568-y","DOIUrl":"https://doi.org/10.1186/s12987-024-00568-y","url":null,"abstract":"For centuries, the meninges have been described as three membranes: the inner pia, middle arachnoid and outer dura. It was therefore sensational when in early 2023 Science magazine published a report of a previously unrecognized — 4th — meningeal membrane located between the pia and arachnoid. Multiple features were claimed for this new membrane: a single cell layer marked by the transcription factor Prox1 that formed a barrier to low molecular weight substances and separated the subarachnoid space (SAS) into two fluid-filled compartments, not one as previously described. These features were further claimed to facilitate unidirectional glymphatic cerebrospinal fluid transport. These claims were immediately questioned by several researchers as misinterpretations of the authors’ own data. The critics argued that (i) the 4th meningeal membrane as claimed did not exist as a separate structure but was part of the arachnoid, (ii) the “outer SAS” compartment was likely an artifactual subdural space created by the experimental procedures, and (iii) the 4th membrane barrier property was confused with the arachnoid barrier. Subsequent publications in late 2023 indeed showed that Prox1 + cells are embedded within the arachnoid and located immediately inside of and firmly attached to the arachnoid barrier cells by adherens junctions and gap junctions. In a follow-up study, published in this journal, the lead authors of the Science paper Kjeld Møllgård and Maiken Nedergaard reported additional observations they claim support the existence of a 4th meningeal membrane and the compartmentalization of the SAS into two non-communicating spaces. Their minor modification to the original paper was the 4th meningeal membrane was better observable at the ventral side of the brain than at the dorsal side where it was originally reported. The authors also claimed support for the existence of a 4th meningeal membrane in classical literature. Here, we outline multiple concerns over the new data and interpretation and argue against the claim there is prior support in the literature for a 4th meningeal membrane.","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"82 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1186/s12987-024-00570-4
Tomas Vikner, Kevin M Johnson, Robert V Cadman, Tobey J Betthauser, Rachael E Wilson, Nathaniel Chin, Laura B Eisenmenger, Sterling C Johnson, Leonardo A Rivera-Rivera
Background: Cerebrospinal fluid (CSF) dynamics are increasingly studied in aging and neurological disorders. Models of CSF-mediated waste clearance suggest that altered CSF dynamics could play a role in the accumulation of toxic waste in the CNS, with implications for Alzheimer's disease and other proteinopathies. Therefore, approaches that enable quantitative and volumetric assessment of CSF flow velocities could be of value. In this study we demonstrate the feasibility of 4D flow MRI for simultaneous assessment of CSF dynamics throughout the ventricular system, and evaluate associations to arterial pulsatility, ventricular volumes, and age.
Methods: In a cognitively unimpaired cohort (N = 43; age 41-83 years), cardiac-resolved 4D flow MRI CSF velocities were obtained in the lateral ventricles (LV), foramens of Monro, third and fourth ventricles (V3 and V4), the cerebral aqueduct (CA) and the spinal canal (SC), using a velocity encoding (venc) of 5 cm/s. Cerebral blood flow pulsatility was also assessed with 4D flow (venc = 80 cm/s), and CSF volumes were obtained from T1- and T2-weighted MRI. Multiple linear regression was used to assess effects of age, ventricular volumes, and arterial pulsatility on CSF velocities.
Results: Cardiac-driven CSF dynamics were observed in all CSF spaces, with region-averaged velocity range and root-mean-square (RMS) velocity encompassing from very low in the LVs (RMS 0.25 ± 0.08; range 0.85 ± 0.28 mm/s) to relatively high in the CA (RMS 6.29 ± 2.87; range 18.6 ± 15.2 mm/s). In the regression models, CSF velocity was significantly related to age in 5/6 regions, to CSF space volume in 2/3 regions, and to arterial pulsatility in 3/6 regions. Group-averaged waveforms indicated distinct CSF flow propagation delays throughout CSF spaces, particularly between the SC and LVs.
Conclusions: Our findings show that 4D flow MRI enables assessment of CSF dynamics throughout the ventricular system, and captures independent effects of age, CSF space morphology, and arterial pulsatility on CSF motion.
{"title":"CSF dynamics throughout the ventricular system using 4D flow MRI: associations to arterial pulsatility, ventricular volumes, and age.","authors":"Tomas Vikner, Kevin M Johnson, Robert V Cadman, Tobey J Betthauser, Rachael E Wilson, Nathaniel Chin, Laura B Eisenmenger, Sterling C Johnson, Leonardo A Rivera-Rivera","doi":"10.1186/s12987-024-00570-4","DOIUrl":"10.1186/s12987-024-00570-4","url":null,"abstract":"<p><strong>Background: </strong>Cerebrospinal fluid (CSF) dynamics are increasingly studied in aging and neurological disorders. Models of CSF-mediated waste clearance suggest that altered CSF dynamics could play a role in the accumulation of toxic waste in the CNS, with implications for Alzheimer's disease and other proteinopathies. Therefore, approaches that enable quantitative and volumetric assessment of CSF flow velocities could be of value. In this study we demonstrate the feasibility of 4D flow MRI for simultaneous assessment of CSF dynamics throughout the ventricular system, and evaluate associations to arterial pulsatility, ventricular volumes, and age.</p><p><strong>Methods: </strong>In a cognitively unimpaired cohort (N = 43; age 41-83 years), cardiac-resolved 4D flow MRI CSF velocities were obtained in the lateral ventricles (LV), foramens of Monro, third and fourth ventricles (V3 and V4), the cerebral aqueduct (CA) and the spinal canal (SC), using a velocity encoding (venc) of 5 cm/s. Cerebral blood flow pulsatility was also assessed with 4D flow (venc = 80 cm/s), and CSF volumes were obtained from T1- and T2-weighted MRI. Multiple linear regression was used to assess effects of age, ventricular volumes, and arterial pulsatility on CSF velocities.</p><p><strong>Results: </strong>Cardiac-driven CSF dynamics were observed in all CSF spaces, with region-averaged velocity range and root-mean-square (RMS) velocity encompassing from very low in the LVs (RMS 0.25 ± 0.08; range 0.85 ± 0.28 mm/s) to relatively high in the CA (RMS 6.29 ± 2.87; range 18.6 ± 15.2 mm/s). In the regression models, CSF velocity was significantly related to age in 5/6 regions, to CSF space volume in 2/3 regions, and to arterial pulsatility in 3/6 regions. Group-averaged waveforms indicated distinct CSF flow propagation delays throughout CSF spaces, particularly between the SC and LVs.</p><p><strong>Conclusions: </strong>Our findings show that 4D flow MRI enables assessment of CSF dynamics throughout the ventricular system, and captures independent effects of age, CSF space morphology, and arterial pulsatility on CSF motion.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"68"},"PeriodicalIF":5.9,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1186/s12987-024-00566-0
Vishal Sangha, Sara Aboulhassane, Reina Bendayan
Background: Folates are a family of B9 vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood-brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency.
Methods: In immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins.
Results: Immunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5.
Conclusion: These results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired.
{"title":"Regulation of folate transport at the mouse arachnoid barrier.","authors":"Vishal Sangha, Sara Aboulhassane, Reina Bendayan","doi":"10.1186/s12987-024-00566-0","DOIUrl":"10.1186/s12987-024-00566-0","url":null,"abstract":"<p><strong>Background: </strong>Folates are a family of B<sub>9</sub> vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood-brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency.</p><p><strong>Methods: </strong>In immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins.</p><p><strong>Results: </strong>Immunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5.</p><p><strong>Conclusion: </strong>These results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"67"},"PeriodicalIF":5.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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