Skip to main content

This was the year that was: brain barriers and brain fluid research in 2019

Abstract

This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

Editorial

Brain barrier and brain fluid research is thriving. For example, an Ovid MEDLINE search of the terms, “blood–brain barrier”, “brain + endothelium”, “neurovascular unit”, “cerebrospinal fluid”, “choroid plexus”, “arachnoid membrane”, “hydrocephalus”, “brain edema”, or “glymphatic system” lists ~ 9300 papers for 2019. This editorial highlights some of those papers and underlying themes for the Fluids and Barriers of the CNS readership.

The papers cited reflect the interests of the Editors-in-Chief and the list is not intended to be exhaustive. We touch on topics to, hopefully, inspire readers to a greater exploration of particular areas. As always, we welcome submission of more in-depth reviews. In 2019, we had a thematic series on, CNS Fluid and Solute Movement: Physiology, Modelling and Imaging. In 2020, we will have a thematic series on, Advances in In Vitro Modeling of the BloodBrain Barrier and Neurovascular Unit.

Tools

In the past few years, one major advance has been the introduction of human induced pluripotent stem cells (iPSCs) to produce different cell types composing the neurovascular unit (NVU). Methods have now been extended to produce not only iPSC-derived endothelial cells, astrocytes and neurons, but also pericyte-like cells [1]. Improved methods for producing NVU cells are continuously being developed (e.g. [2]) and all four cell types can be produced and co-cultured from the same iPSC donor [3]. Currently, studies are examining the effects of individual patient mutations using iPSC-derived endothelial cells [4]. The ability to derive multiple cell types from a single donor enables examination of not only the effects of mutations on a single cell type but also on the complete NVU (e.g. on cell to cell communication). One use of human iPSCs has been to produce cerebral organoids that have allowed studies of human brain development and the complex interactions between different cell types. Importantly, such organoids can now incorporate a vasculature that is perfused and has BBB characteristics [5]. There continue to be advances in the use of iPSCs in engineering a BBB-on-a-chip [6,7,8].

Many recent advances in brain barrier and brain fluid research have been driven by improvements in imaging. Now, super-resolution microscopy techniques [9] have opened the possibility of using light microscopy to examine cells, including live cells, at much greater resolution and these methods can be applied to the cerebral endothelium. Examples are structured illumination microscopy (SIM) to examine the actin cytoskeleton [10], and stochastic optical reconstruction microscopy (STORM) for changes in endothelial junction organization [11] and glycocalyx molecular structure [12]. Imaging using magnetic resonance (MR) to quantify brain metabolites and to measure dynamic changes is expanding. This technology has been applied to the blood–brain transport of lactate in brain and may also be applicable to other metabolites [13].

One issue in NVU research is how to evaluate the role of different cell types. For example, Dieguez-Hurtado et al. [14] found that inactivating a transcription factor, RBPJ, post-natally alters pericyte function, causing vascular instability and lesions with some similarities to cerebral cavernous malformations, and greater injury after ischemic stroke. Another advance for manipulating the NVU and brain (experimentally and therapeutically) is the finding by Alterman et al. [15] that a single CSF injection of divalent small interfering RNAs is effective in reducing huntingtin expression (mRNA and protein) throughout the mouse brain, with effects lasting for at least 6 months. They had similar results in cynomolgus macaques.

Other tools of relevance to brain barriers and brain fluids research have been developed. Tang et al. [16] found that peptides containing a conserved motif (phenylalanine-arginine-tryptophan) bind to the cerebrovasculature but not to other vascular beds. The binding appears to be at the endothelial junctions but, interestingly, the peptides do not bind to the retinal vasculature. Understanding this phenomenon further may aid in the development of brain-targeting therapeutics. Another technique impacting biological and medical research is the use of machine learning. For example, in brain, machine learning can be used for image analysis [17, 18]. Machine learning is poised to impact brain barriers and brain fluids research in, for example, analysis of brain edema on radiographic images [19, 20] or potentially to predict brain drug penetration [21, 22].

The cerebral endothelium and the neurovascular unit

Crosstalk and cellular signaling within the NVU

We are gaining greater insight into endothelial-neuronal signaling. For example, Tan et al. [23] found that semaphorin 3G release from brain endothelial cells regulates synaptic structure and plasticity in the hippocampus. Similarly, Wu et al. [24] found that engrafting endothelial cells into brain promoted synaptogenesis and improved neurological deficits in neonatal hypoxia–ischemia in mice.

The past few years have demonstrated the importance of Wnt/β-catenin signaling in promoting a BBB phenotype. A recent example of the importance of oligodendroglial-vascular communication is in multiple sclerosis where abnormal perivascular clustering of oligodendrocyte precursor cells affects barrier function and inflammation by impacting Wnt signaling (Niu et al. [25]). Interestingly, two recent studies have indicated that low endothelial Wnt/β-catenin signaling underlies blood vessel leakiness in the circumventricular organs that lack a BBB [26, 27].

The critical role of another type of glial cell, the astrocyte, at the NVU including BBB regulation has long been known (reviewed in [28]). Recently, Bonsack et al. [29] demonstrated the importance of astrocyte-derived pentraxin-3 in regulating BBB permeability. Tan et al. [30] have also shown that leukocytes can cause BBB disruption in stroke via effects on astrocytes. Leukocytes release interleukin-9 that causes astrocytes to release vascular endothelial growth factor-A which, in turn, causes BBB hyperpermeability. S100B is also released from astrocytes during brain injury and it is now becoming clear that S100B is a Damage-Associated Molecular Pattern (DAMP) molecule that affects multiple cell types [31].

The importance of the pericyte at the NVU has become evident in recent years [32]. For example, Nikolakopoulou et al. [33] have now shown that pericyte ablation results in vascular dysfunction, including BBB breakdown and reduced blood flow, and neuronal loss. The latter is linked to loss of a pericyte-derived growth factor, pleiotrophin, that makes neurons vulnerable to ischemic injury. Another example is from Coucha et al. [34] who found that specifically targeting pericyte Ephrin-B2 can inhibit neovascularization in the brain of diabetic rats.

One question arising in multiple neurological conditions is how a sporadic mutation in just a few cells can result in a change in overall phenotype. Malinverno et al. [35], studying cerebral cavernous malformation-3 (CCM3), have found that CCM3 null brain endothelial cells clonally expand and then recruit other normal endothelial cells and induce them to express a mesenchymal/stem cell phenotype (endothelial cell: endothelial cell communication). One family of molecules involved in cell: cell communication is the connexins that form gap junctions. Recent evidence suggests gap junction activity may also regulate tight junction function at the BBB. Thus, in a mouse CCM3 model, Johnson et al. [11] found that brain endothelial cells overexpress connexin 43 enhancing not only gap junction communication, but also inducing tight junction disruption and BBB hyperpermeability.

While most studies have focused on proteins/peptides as mediators of signaling between cells of the NVU, there is considerable evidence on the importance of microRNAs in BBB regulation (reviewed in [36, 37]). There is also new evidence on the importance of another type of non-coding RNA, the long non-coding RNAs, at the BBB [37,38,39]. For example, some long non-coding RNAs play an important role in stroke by modulating mRNA and microRNA function [40].

Non-coding RNAs and mRNAs may be released from cells encapsulated (along with other components) in exosomes/extracellular vesicles. Such encapsulation increases microRNA stability and exosomal microRNAs have multiple effects in the CNS including at the cerebral endothelium [41, 42]. Exosome encapsulation is also proposed as one mechanism that might enable microRNAs to cross the BBB for therapy [41]. One element that has hampered exosome research at the cerebral endothelium is uncertainty over what receptors are responsible for their uptake. Now, Kuroda et al. [43] suggest that CD46 is an important receptor for exosomes derived from a brain-metastatic cell line.

The role of epigenetics in affecting brain function and neurological diseases has been the subject of much research. At the BBB, histone deacetylases (HDACs) have a role in regulating p-glycoprotein expression and activity [44]. Similarly, HDAC3 inhibition can reduce the endothelial disruption induced by oxygen and glucose deprivation (an in vitro ‘stroke’ model) [45] adding to data on the importance of epigenetic mechanisms at the NVU during stroke [37]. Other signaling molecules that have deacetylase activity are the sirtuins that are important in aging. An endothelial-specific mouse knockout of sirtuin-6 exacerbates BBB damage after cerebral ischemia [46] and Stamatovic et al. [47] found a decline in brain endothelial sirtuin-1 with normal aging in mouse and human that leads to BBB dysfunction. Recently, Senatorov et al. [48] reported the importance of BBB dysfunction with aging and how it can induce neural dysfunction through transforming growth factor-β signaling. In an interesting study, Yousef et al. [49] found an age-related factor(s) in blood that impacts neuroinflammation and cognitive deficits via effects on vascular cell adhesion molecule-1. Cognitive impairment was also linked to barrier dysfunction through activation of endothelial adenosine receptors (Adora2a) in a model of obesity and insulin-resistance [50].

The importance of understanding the mechanisms regulating BBB/NVU function is highlighted in a recent study on folate transport by Alam et al. [51]. Folate transport at the choroid plexus involves proton-coupled folate transport and folate receptor alpha and interference with such transport causes low CSF folate levels and neurodegeneration. Alam et al. [51] found that upregulating the reduced folate transporter at the BBB, by activating the vitamin D nuclear receptor with calcitriol, could compensate for the loss of choroid plexus transport.

Transporters at the cerebral endothelium play a critical role in BBB function. Two studies in 2019 highlighted how the plasma membrane distribution of transporters may be regulated. Zhang et al. [52] describes how contactin-associated protein 1 (CASPR1/CNTNAP1) binds to a subunit of Na+/K+-ATPase regulating trafficking to the plasma membrane. Similarly, Hoshi et al. [53] have identified the effects of ERM proteins (ezrin/radixin/moesin) on the location and activity of different transporters. ERM proteins may act as linkers between transporters and the cytoskeleton.

Although this section has focused on signaling and crosstalk within the NVU and cerebral endothelium, it should be noted that the BBB is also an endocrine tissue. It is a both a target for blood-borne hormones and a secretor of hormones into either the brain interstitial space or blood. These multiple roles of the BBB, as well as the effects of endocrine disease have been recently reviewed by Banks [54].

Extracellular matrix

There is a growing awareness of the importance of the endothelial glycocalyx and basement membrane, and the brain extracellular matrix in BBB and NVU function in health and disease [55]. For example, there is recent evidence on the importance of the marked loss of the endothelial glycocalyx in cerebral malaria [56] where it was found that treating mice with cerebral malaria with either dexamethasone or antithrombin-3 could reduce glycocalyx loss, BBB disruption and mortality. Delsing et al. [57] also provided evidence of the importance of an extracellular matrix component, laminin, on astrocyte function, with iPSC-derived astrocytes having different gene expression profiles depending upon the type of laminin used. Yao and others have been dissecting the role of different basement membrane components on normal BBB physiology and how those components are affected by ischemic and hemorrhagic stroke or may contribute to stroke occurrence [58].

Claudins at the cerebral endothelium

While the importance of claudin-5 as a tight junction protein at the cerebral endothelium is widely recognized [59], the potential role of other claudins [60] is more contentious. Uchida et al. [61] recently provided evidence in multiple sclerosis that claudin-11 is decreased at the BBB (and the blood-spinal cord and the blood-arachnoid barriers) contributing to barrier leakiness. In contrast, Castro Dias et al. [62, 63] found that loss of claudin-12 and claudin-3 had no effect on BBB permeability in mice and that claudin-3 was absent from the cerebral endothelium. Even the permeability at the choroid plexus, where claudin-3 is expressed, was unaffected by its deletion, although there may be a compensatory change in claudin-2 [63]. In a twist, Sladojevic et al. [64] found that in chronic stroke there is an upregulation of claudin-1 that destabilizes (rather than stabilizes) the BBB leading to long-term low-level barrier leakiness that affects functional recovery.

There is interest in the potential role of claudin-5 changes in psychiatric diseases [59]. For example, schizophrenia risk is greatly enhanced in patients with 22q11.2 deletion syndrome and the claudin-5 gene is within the deleted region. Previously, Greene et al. [65] found a claudin-5 variant, rs10314, is associated with reduced endothelial claudin-5 expression and the occurrence of that variant in the remaining 22q11.2 region increased the risk of schizophrenia. Recently, Guo et al. [66] reported this increased risk occurred in female, but not male patients.

Choroid plexus and arachnoid membrane

Choroid plexus

During the past few years, there has been emphasis on the importance of the choroid plexus as a site of leukocyte entry into brain in a variety of neurological conditions. Mottahedin et al. [67] have recently delineated the mechanisms induced by toll-like receptor-2 activation at the choroid plexus that result in leukocyte migration. Yin et al. [68] examined how apolipoprotein-E affects neuroinflammation and found it avidly binds a component of the classical complement cascade, C1q, at the choroid plexus inhibiting that cascade during inflammation. Apart from being a site of leukocyte migration between blood and CSF, the choroid plexus also has resident leukocytes (e.g. the epiplexus cells on the apical surface and cells in the stroma). There has been increased interest in the role of macrophages at all blood-CNS interfaces (perivascular, leptomeningeal, dural and choroid plexus) [69]. At the choroid plexus, epiplexus cell activation occurs in different hydrocephalus models [70, 71].

The choroid plexus epithelium displays a polarized distribution of transporters and channels involved in directional movement across the epithelium. For example, the polarity of the water channel, aquaporin-1, at the choroid plexus is reversed in obstructive hydrocephalus from the apical to the basolateral membrane [72] that might be a compensatory response. It will be important to know if there are similar changes in ion transport involved in CSF production.

Evidence suggests that inflammatory pathways at the choroid plexus regulate CSF secretion. Interestingly, Simpson et al. [73] showed that cytokines and other inflammatory mediators regulate a non-selective cation channel, transient receptor potential vanilloid-4 (TRPV4), at the epithelium. There is some controversy about the role of the apically located Na+/K+/Cl-cotransporter (NKCC1) at the choroid plexus epithelium. NKCC1 can act as an influx or an efflux transporter dependent upon ion gradients. It has been proposed that it acts as an efflux transporter at the choroid plexus and is involved in CSF secretion but this has been questioned by Gregoriades et al. [74] who have provided evidence for influx activity. This is a difficult issue to resolve because different experimental preparations may alter cellular ion concentrations [75]. This is an important issue as NKCC1 is one potential target for altering CSF secretion and brain intracranial pressure [76]. It may be that NKCC1 may act as a sensitive regulator of CSF production with the ability to move ions into or out of CSF.

Arachnoid membrane and dura mater

The description of lymphatic vessels within the dura mater (see below) has led to an upswing in interest in the meninges. There has also been specific interest in the arachnoid membrane, one site of the blood-CSF barrier, where the absolute protein amount of a variety of transporters (e.g. p-glycoprotein and organic anion transporters) is greater than at the choroid plexus in pig and transporter distribution is polarized (e.g. CSF- or blood-facing) [77]. There are also continued efforts to describe the anatomy and immunology of the cerebrovasculature [78] and to understand the meninges as an immune-blood–brain interface [79].

Cerebrospinal fluid and the glymphatic hypothesis

CSF and glymphatic dynamics

There continues to be a lively debate about the proposed glymphatic system (e.g. [80, 81] and review [82]) and about CSF dynamics (e.g. [83, 84]). 2019 has seen many studies addressing aspects of the glymphatic system, para-arterial entry from CSF to brain, fluid flow within brain, where aquaporin 4 is proposed to play a critical role, and paravenous efflux from brain to CSF. MRI is now being used to study different elements of this system [85,86,87,88,89,90,91]. Paravenous clearance of solutes from brain has been less well studied than entry. Van Veluw et al. [92] have recently provided evidence on the importance of vasomotion in the clearance of solutes from brain in awake mice. New tools for studying the glymphatic system are welcome and Munk et al. [93] have recently identified platelet-derived growth factor-B as being essential for glymphatic development.

There continues to be great interest in the role of meningeal lymph vessels in CSF drainage. Ahn et al. [94] have now described meningeal lymph vessels at the base of the brain that have lymphatic valves (in contrast to the dorsal meningeal lymph vessels) and are involved in clearing macromolecules from CSF. Aging impacts those vessels potentially contributing to age-related neurological conditions. However, here are other routes for CSF egress to the lymphatic system. It has long been known that the cribriform plate is a major exit route, as further delineated by Norwood et al. [95], while Hsu et al. [96] have described how neuroinflammation impacts that route, changes that differ from meningeal lymph vessels.

A potential implication of a rapid paravascular entry of CSF from the subarachnoid space into brain relates to drug delivery, i.e. CSF delivered agents may rapidly reach targets within brain parenchyma. However, Ma et al. [97] found in conscious animals a rapid clearance of CSF-infused tracers to the lymph system significantly limits potential brain penetration.

There has been debate over the relative importance of choroid plexus and extrachoroidal sources of CSF. The choroid plexus expresses the water channel aquaporin-1, while ependyma and the glia limitans (as well as astrocyte endfeet) express aquaporin-4. Trillo-Contreras et al. [98] examined CSF outflow, intraventricular pressure and ventricular volume in aquaporin-1 and -4 knockout mice and the double knockout and concluded both are important in CSF production.

There has been much interest in the effects of the sleep/wake cycle on the clearance of metabolic waste products from the brain, particularly potentially toxic metabolites including β-amyloid (Aβ) and tau and this was reviewed in-depth by Hladky and Barrand [99]. Recently, Holth et al. [100] have examined the effects of the sleep/wake cycle on brain interstitial fluid and CSF tau and found high levels during wakefulness and sleep deprivation. Hablitz et al. [101] found that glymphatic influx (movement of tracers from CSF to brain) correlates with cortical delta power of electroencephalograms (EEG) and negatively with beta power and heart rate. The complexity of the changes in the fluid compartments during sleep/wakefulness in humans is highlighted by a study by Demiral et al. [87] using measurements of the apparent diffusion coefficient (ADC) for water with MRI. They found different effects of sleep within the brain depending on brain region and changes in CSF volume.

In another twist, there is also evidence of circadian rhythms in gene expression at the BBB and barrier function (reviewed in [102]). At the inner blood-retina barrier, Hudson et al. [103] have found that claudin-5 gene expression is regulated by BMAL-1, a clock gene. In 2018, there was also work on the importance of the choroid plexus in the circadian clock [104]. It is likely that the effects of the sleep cycle and circadian rhythms on barrier function and brain fluid movement will involve multiple sites. There has now been a study of the impact of long-duration space flight on ventricular CSF volume [105]. There was a ~ 12% increase in volume in each of the ventricles post-flight compared to pre-flight, perhaps due to reduced CSF resorption. While the magnitude of the increase was reduced 7-months post-flight, there was still a significant increase over pre-flight status (e.g. 7.7% increase in lateral ventricle volume).

Communication via CSF

Kaiser et al. [106] have provided important evidence for the role of choroid plexus-produced WNT5a in regulating hindbrain development. The hydrophobic WNT5a is transported through the CSF system bound to lipoprotein particles rather than in exosomes. There is also new evidence that choroid plexus-produced microRNA-204 regulates neural stem cells in the subependymal zone of the adult brain [107] and that OTX2, a homeoprotein transcription factor secreted by choroid plexus, regulates adult neurogenesis [108]. Esposito et al. [109] recently examined the role of brain to cervical lymph node communication in inflammation after stroke and showed that blocking such signaling reduces the peripheral inflammatory response and brain injury.

CSF biomarkers

CSF biomarkers continue to be investigated for potential diagnosis of various neurological conditions including different forms of neurodegeneration [110,111,112,113]. In Alzheimer’s disease (AD), many studies have focused on increases in CSF Aβ or tau species, proteins that are harmful, or injury markers such as neurofilament light chain. However, Ewers et al. [114] examined whether increases in CSF soluble TREM2 in patients might be associated with protection against AD. They found soluble TREM2 was associated with less cognitive and clinical decline in AD patients. Differences in protective molecules may contribute to interpatient variations in outcome as well as potentially identifying new therapeutic targets. Other important examples of the use of CSF biomarkers in 2019 include Blennow et al. [115], who found that a specific tau fragment in CSF correlates well with tau imaging on positron emission tomography (PET). Also, Kuiperij et al. [116] found that CSF apolipoprotein D levels can distinguish AD patients with and without cerebral amyloid angiopathy as well as from control patients. Similarly, Jeppsson et al. [117] found that idiopathic normal pressure hydrocephalus (iNPH) patients could be distinguished from patients with cognitive and movement disorders by having a lower combination of CSF markers: total-tau, Aβ40 and monocyte chemoattractant protein-1. A concern with CSF biomarker studies is potential effects of blood contamination during sampling and Batllori et al. [118], examining CSF metabolic biomarkers, found that CSF centrifugation prior to freezing for bio-banking minimized the effects of blood contamination for many biomarkers.

While most attention has focused on CSF proteins or metabolic markers [118], another recent approach is CSF DNA analysis. Thus, tumor DNA in CSF may help identify tumor mutations without the need for biopsies. Miller et al. [119] found that ~ 50% of glioma patients had tumor DNA in lumbar CSF samples with a variety of mutations. This approach shows great promise for enabling changes in tumor genetic makeup to be tracked with time or treatment.

The brain barriers and brain fluids in disease

Hydrocephalus

To date, inheritable congenital hydrocephalus has been linked to eight genes. One gene is MPDZ that encodes a scaffolding protein and Yang et al. [120] investigated the underlying cause of the hydrocephalus in Mpdz knockout mice finding that the loss of the gene caused choroid plexus hyperpermeability. This may be due to increased transcytosis but they also reported a loss of tight junction proteins, ZO-1 and JAM-C, and an increased Na+/K+/Cl cotransporter (NKCC1) expression at the choroid plexus. Recently, Diets et al. [121] identified a pathogenic variant of SMARCB1, which encodes a protein involved in chromatin remodeling. Four patients with this mutation had choroid plexus hyperplasia and resultant hydrocephalus and severe intellectual disability. Another recently identified human mutation associated with hydrocephalus is in the K+/Cl-cotransporter KCC3 (SLC12A) [122]. How the mutation leads to hydrocephalus is still unclear (e.g. which cell type(s) is involved).

Intraventricular post-hemorrhagic hydrocephalus (IVH)

Intraventricular hemorrhage commonly results in hydrocephalus in low birth weight infants and results in serious neurological problems [123]. Research has been directed at mitigating these effects: for example, Romantsik et al. [124] found that α1-microglobin, a heme and free radical scavenger, protects against periventricular damage in a preterm rabbit model of intraventricular hemorrhage. Ding et al. [125] have found evidence of an impaired glymphatic system in a model of germinal matrix hemorrhage and that olomoucine, an inhibitor of astrogliosis, ameliorated that impairment, reduced hydrocephalus and improved neurological outcome. Fast diffusion MR imaging is helping to identify abnormal periventricular tissue in premature infants with post hemorrhagic hydrocephalus [126].

Idiopathic normal pressure hydrocephalus (iNPH)

Diagnosing idiopathic normal pressure hydrocephalus (iNPH), a condition that affects the elderly, poses many challenges and identifying patients for surgery is difficult. However, neuroimaging techniques are becoming more sophisticated for non-invasive diagnosis and the development of guidelines (reviewed in [127]). Co-morbidities may impact the condition: for example, Hudson et al. [128] recently reviewed the occurrence of diabetes mellitus in patients with iNPH. They found much higher incidence (~ 2-4 fold) in age- and cohort-matched patients with iNPH. This may further impact these patients and an elucidation of underlying mechanisms is needed. A transcranial magnetic stimulation study [129] in iNPH patients has shown impaired cholinergic transmission in NPH patients, which could contribute to gait disturbance and neurological defects. As noted above, there has been increased interest in the impact of long non-coding RNAs in neurological conditions and Shi et al. [130] identified 1575 changes in the expression of such RNAs in a kaolin model of hydrocephalus in mice. They particularly regulate inflammatory pathways.

There is a suggestion that the glymphatic system may be involved in hydrocephalus pathogenesis since a defective system might impair fluid flow, reduce removal of toxic products and contribute to neurological deficits. Impairments in glymphatic circulation have been reported in iNPH patients [88], and also in spontaneously hypertensive rats that begin to develop hydrocephalus several weeks after birth [91]. MR diffusion imaging studying paravascular fluid flow in patients and controls, supports the concept of an impaired flow system and such imaging could be used to aid diagnosis for patients with iNPH [131]. Aquaporin 4 is thought to play a key role in the glymphatic system and Hasan-Olive et al. [89] found a reduced density of aquaporin 4 in astrocytic endfeet along cortical microvessels in iNPH patients. That group also found evidence of pathological mitochondria in the perivascular astrocytic endfeet in those patients [132].

Cilia defects have been implicated in hydrocephalus pathology for some time and primary ciliopathies affect various aspects of brain development, including hydrocephalus [133]. For example, Morimoto et al. [134] identified a loss of function mutation in CFAP3, a cilia-associated protein, in a Japanese family where some members have NPH. In addition, they found that Cfap3-deficient mice also develop hydrocephalus. Similarly, Chiani et al. [135] found that loss of Ccdc151, which causes a primary ciliary dyskinesia, is associated with hydrocephalus in mice. The paucity of known mechanisms for iNPH highlights a desperate need for new therapeutic targets and approaches for hydrocephalus and associated neural injury.

Idiopathic intracranial hypertension (IIH)

The underlying cause of idiopathic intracranial hypertension (IIH) is uncertain: it primarily affects obese women of reproductive age, is of increasing incidence and can lead to vision loss [136]. A diagnostic feature is the presence of increased peri-optic CSF determined by neuroimaging [137]. O’Reilly et al. [138] examined the systemic and CSF androgen metabolome in patients with IIH and found a unique signature of androgen excess and provide evidence that this may affect CSF secretion. There is also evidence that these patients may have defects in CSF drainage due to increased sagittal sinus venous pressure [139] and that there may be BBB dysfunction as measured by extravasated fibrinogen in the brain [136].

Meningitis

There have been several interesting papers on meningitis this past year. Ma et al. [140] found that streptococcus expresses a protein containing a Fic domain that disrupts the BBB by activating moesin allowing bacterial entry into the brain. In another study, Kim et al. [141] found that streptococcus exposure inhibited p-glycoprotein in brain endothelial cells and this effect was replicated in an in vivo meningitis model. This may impact drug regimen design. Mohanty et al. [142] identified a novel potential target for pneumococcal meningitis. In infections, neutrophils release neutrophil extracellular traps (NETs) that snare and kill bacteria. However, while NETs are produced in CSF during pneumococcal meningitis, it appears that they have a detrimental effect preventing bacterial clearance.

The contribution of brain vascular dysfunction to different disease states

A vast array of neurological events and conditions (if not all) impact the BBB and the NVU. For example, different degrees of traumatic brain injury cause BBB dysfunction. Thus, there is evidence of BBB dysfunction in adolescent rugby players to professional mixed martial arts fighters [143] and Yoo et al. [144] found that BBB dysfunction after mild traumatic brain injury was associated with post-concussion syndrome (events such as headaches and dizziness lasting for weeks). In more severe traumatic brain injury, there is evidence that cerebral microvascular injury is a therapeutic target by contributing to neurodegeneration [145]. The recent CRASH-3 clinical trial [146], using tranexamic acid to limit cerebral bleeding after traumatic brain injury, significantly improved mortality.

There is a growing understanding of the importance of BBB dysfunction in multiple forms of acute brain injury and chronic neurodegeneration [147]. Sweeney et al. [148] have recently reviewed the importance of vascular dysfunction in AD. Interestingly, Nation et al. [149] also found that patients developing early cognitive dysfunction have evidence of BBB dysfunction even without increased Aβ or Tau. Milikovsky et al. [150] found evidence that BBB dysfunction underlies electroencephalogram changes in AD in patients and animal models. One marker of cerebrovascular dysfunction in the elderly is the presence of cerebral microbleeds and in a meta-analysis, Debette et al. [151] reported that patients with such microbleeds on MRI had 1.9- and 3.8-fold increased risk of ischemic and hemorrhagic stroke.

Much focus on BBB changes in disease states has centered on inflammatory changes and increased permeability, either due to endothelial tight junction disruption, increased transcytosis or even endothelial cell death (for a recent review of the latter see [152]). However, disease states affect the BBB and the NVU at many levels. For example, there are changes in BBB transport in stroke, AD and psychiatric disorders [153,154,155]. Krueger et al. [156] recently highlighted the importance of endothelial edema after stroke. Because of the prevalence of vascular changes across neurological disorders, there have been studies looking for commonalities (and differences). Two recent studies examining the transcriptome are by Munji et al. [157] on the brain endothelial response and Guo et al. [158] on the vasculome in brain and heart.

Drug delivery

Entry of drugs across the BBB remains a major hurdle for developing therapies for neurological disorders. In addition, the distribution of therapeutics entering the brain may be inhomogeneous, raising difficulties in ensuring proper target engagement. Vendel et al. [159] reviewed the complexity of modelling brain distribution for therapeutics and concluded that more work is still needed. Another example of complexity of drug delivery to brain is the intranasal route. Lochhead and Davis [160] have recently reviewed how the perineural and perivascular pathways are important in such delivery. Enhanced drug delivery across the BBB can be achieved by conjugating drugs to antibodies targeting receptors involved in transcytosis. Much of such work has focused on targeting the BBB transferrin receptor and Johnsen et al. [161] provide a review of that work. There has also been a thrust for using antibody fragments rather than full-length antibodies and Belanger et al. [162] reviewed current work on the use of small single-domain antibodies. Alternatively, Thom et al. [163] used a peptide from melanotransferrin to enhance delivery of an interleukin-1 receptor antagonist to reduce neuropathic pain in mice. Similarly, Wu et al. [164] used a bacteriophage-derived peptide to target the transferrin receptor and the receptor for advanced glycation-end products (RAGE). They complexed the peptide with a siRNA to down-regulate β-secretase within the brain.

There has been great interest in using variants of adeno-associated virus (AAV) serotypes that can cross the BBB for gene therapy delivery. An example of this approach has been the neurotropic AAV-PHP.B variant. Hordeaux et al. [165] have identified that this variant enters the mouse brain by binding to a protein, LY6A but they also note that primates have no homolog of LY6A which may explain why AAV-PHP.B does not increase CNS transduction in non-human primates. There is a need for more information on differences in BBB protein expression across species. In addition to gene delivery, the AAV technology can be applied to mechanistic studies. For example, the role of ferroportin in iron import to the brain and retina was demonstrated by deletion of this protein from endothelial cells of the brain and retina [166].

Some drugs may be substrates for solute transporters at the BBB. For example, Albekairi et al. [153] have found that the potent opioid receptor agonist, biphalin, is a substrate of the organic anion transporting polypeptide OATP1. The expression of BBB solute transporters can vary in neurological conditions giving potential opportunities for drug delivery: for example, OATP1 is increased in stroke [153].

Focused ultrasound has been used to transiently open the BBB to enhance drug delivery in vivo in animal models [167, 168] and, as discussed below, in the clinic [169, 170]. An interesting further use of ultrasound-induced barrier disruption has been to allow entry of a contrast agent into the brain of patients which can then be tracked non-invasively by MRI to examine clearance routes (e.g. the glymphatic system) [171]. Another approach to modulate the BBB has been to target brain endothelial junction proteins and a series of peptides have been developed that bind to claudins [172]. In 2019, one of those peptides was used to down-regulate claudin-1 at the BBB long-term after stroke as that particular claudin causes barrier instability [64]. Similarly, Yang et al. [173] have used a peptide targeting E-cadherin to enhance brain uptake of eflornithine, a drug used to treat trypanosomiasis.

There has been a wealth of studies in 2019 on potential therapeutics for neurological disorders where changes at the BBB have been an endpoint. It is usually unclear whether the therapeutic is having a direct effect on the brain endothelium or a secondary effect via neuroprotection. This is an important point as dosing regimens will differ greatly for an endothelial target versus a target beyond the BBB. There continues to be a need for more studies that address the specific role of endothelial dysfunction in neurological disorders.

Translation to the clinic

An ultimate goal of preclinical research is to translate data to the clinic and 2019 has provided several examples of progress on that front. Reperfusion (induced by tissue plasminogen activator or thrombectomy) is the only current therapy for ischemic stroke, but reperfusion can lead to cerebral hemorrhage. There has, therefore, been great interest in targeting the cerebral endothelium to prevent such hemorrhage; i.e. combining neuro- and endothelial protectants [174]. Preclinically, a recombinant variant of activated protein C is endothelial protective and a Phase II clinical trial (RHAPSODY) using that drug in combination with reperfusion has just been completed with promising results [175].

Brain drug delivery remains a major challenge for a wide range of neurological disorders. Ultrasound can be used to induce transient BBB disruption to enhance drug delivery. For example, Idbaih et al. [170] have just reported results on an ultrasound device implanted in the skull of patients with recurrent glioblastoma. They used the low-intensity pulsed ultrasound to disrupt the BBB repeatedly during sequential carboplatin treatments. That preliminary study on a limited number of patients showed the safety of the device and procedure and had a tendency towards improving survival. Similarly, Abrahao et al. [169] recently showed the safety of MR guided focused ultrasound in patients with amyotrophic lateral sclerosis (ALS).

The choroid plexus is a source of neurotrophins and a formulation consisting of encapsulated pig choroid plexus cells has been developed that can be implanted into patients. This underwent a phase IIb clinical trial in patients with Parkinson’s disease (at least 5 years after onset). While the formulation was safe, it did not improve outcomes in those patients [176]. One drug formulation that is being pursued to treat brain edema in multiple neurological conditions is an intravenous preparation of glibenclamide (BIIB093). That includes clinical trials in brain ischemia and traumatic brain injury [177]. Glibenclamide targets SUR1-TRPM4 channels that are upregulated in several NVU cell types after injury. Brain edema treatments have not changed for decades and a new drug would be very welcome.

In memoriam

Brain barriers and brain fluid research sadly lost two major figures in 2019: Malcolm Segal and Ed Stopa.

Malcolm B. Segal (August 1st, 1937–July 29th, 2019)

Malcolm Segal spent many years in the Division of Physiology at United Medical and Dental School of Guy’s and St. Thomas’ Hospitals, where he rose to Chairman. After the merger with King’s College, he continued in the Department of Physiology until his retirement. During his career, Malcolm made many seminal findings on choroid plexus and CSF and helped develop the ventriculo-cisternal perfusion technique, as well as methods for determining the resistance to CSF drainage and establishing the isolated perfused sheep choroid plexus preparation. His studies covered a wide range from CSF secretion and drainage [178, 179], choroid plexus transport of many compounds [180,181,182,183] and the impact of development and aging on the blood–brain barriers [184, 185]. Malcolm also co-authored with Hugh Davson and Keasley Welch the essential tome on all things CSF, The Physiology and Pathology of the Cerebrospinal Fluid [186] and subsequently Physiology of the CSF and Bloodbrain Barriers with Hugh Davson [187]. A reflection on the important role of Malcolm had in our understanding of choroid plexus/CSF physiology and in the training of many current scientists has recently been published in Fluids and Barriers of the CNS [188]. He will be greatly missed.

Edward G. Stopa (July 6th, 1954–September 18th, 2019)

Ed Stopa was Professor of Pathology and Neurosurgery at Brown University as well as Director of Neuropathology at Rhode Island Hospital. While Ed was best known for his work on AD and other forms of dementia [189,190,191,192], he also worked on hydrocephalus [193, 194] and contributed to our understanding of the roles of CSF [195, 196] and the BBB [192, 197]. He served as an Editorial Board member of Fluids and Barriers of the CNS. The field can ill-afford to lose a trained neuropathologist with his range of interests and expertise. An obituary can be found in Journal of Alzheimer’s Disease [198].

Conclusions

We would like to thank the readers, authors, reviewers and editorial board members of Fluids and Barriers of the CNS for their support in 2019. As shown by these ‘highlights of 2019’, the field is vibrant with new ideas and important findings. May that continue in 2020!

Availability of data and materials

Not applicable.

References

  1. Stebbins MJ, Gastfriend BD, Canfield SG, Lee MS, Richards D, Faubion MG, Li WJ, Daneman R, Palecek SP, Shusta EV. Human pluripotent stem cell-derived brain pericyte-like cells induce blood–brain barrier properties. Sci Adv. 2019;5(3):eaau7375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Neal EH, Marinelli NA, Shi Y, McClatchey PM, Balotin KM, Gullett DR, Hagerla KA, Bowman AB, Ess KC, Wikswo JP, et al. A simplified, fully defined differentiation scheme for producing blood–brain barrier endothelial cells from human iPSCs. Stem Cell Rep. 2019;12(6):1380–8.

    Article  CAS  Google Scholar 

  3. Canfield SG, Stebbins MJ, Faubion MG, Gastfriend BD, Palecek SP, Shusta EV. An isogenic neurovascular unit model comprised of human induced pluripotent stem cell-derived brain microvascular endothelial cells, pericytes, astrocytes, and neurons. Fluids Barriers CNS. 2019;16(1):25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Katt ME, Mayo LN, Ellis SE, Mahairaki V, Rothstein JD, Cheng L, Searson PC. The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model. Fluids Barriers CNS. 2019;16(1):20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Cakir B, Xiang Y, Tanaka Y, Kural MH, Parent M, Kang YJ, Chapeton K, Patterson B, Yuan Y, He CS, et al. Engineering of human brain organoids with a functional vascular-like system. Nat Methods. 2019;16(11):1169–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Motallebnejad P, Thomas A, Swisher SL, Azarin SM. An isogenic hiPSC-derived BBB-on-a-chip. Biomicrofluidics. 2019;13(6):064119.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Park TE, Mustafaoglu N, Herland A, Hasselkus R, Mannix R, FitzGerald EA, Prantil-Baun R, Watters A, Henry O, Benz M, et al. Hypoxia-enhanced blood–brain barrier chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun. 2019;10(1):2621.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, et al. Human iPSC-derived blood–brain barrier chips enable disease modeling and personalized medicine applications. Cell Stem Cell. 2019;24(6):995–1005.e1006.

    Article  CAS  PubMed  Google Scholar 

  9. Schermelleh L, Ferrand A, Huser T, Eggeling C, Sauer M, Biehlmaier O, Drummen GPC. Super-resolution microscopy demystified. Nat Cell Biol. 2019;21(1):72–84.

    Article  CAS  PubMed  Google Scholar 

  10. Neglia L, Fumagalli S, Orsini F, Zanetti A, Perego C, De Simoni MG. Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells. J Cerebral Blood Flow Metab. 2019;7:271678x19874509.

    Google Scholar 

  11. Johnson AM, Roach JP, Hu A, Stamatovic SM, Zochowski MR, Keep RF, Andjelkovic AV. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure. FASEB J. 2018;32(5):2615–29.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fan J, Sun Y, Xia Y, Tarbell JM, Fu BM. Endothelial surface glycocalyx (ESG) components and ultra-structure revealed by stochastic optical reconstruction microscopy (STORM). Biorheology. 2019;56(2–3):77–88.

    Article  CAS  PubMed  Google Scholar 

  13. Takado Y, Cheng T, Bastiaansen JAM, Yoshihara HAI, Lanz B, Mishkovsky M, Lengacher S, Comment A. Hyperpolarized (13)C magnetic resonance spectroscopy reveals the rate-limiting role of the blood–brain barrier in the cerebral uptake and metabolism of l-lactate in vivo. ACS Chem Neurosci. 2018;9(11):2554–62.

    Article  CAS  PubMed  Google Scholar 

  14. Dieguez-Hurtado R, Kato K, Giaimo BD, Nieminen-Kelha M, Arf H, Ferrante F, Bartkuhn M, Zimmermann T, Bixel MG, Eilken HM, et al. Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes. Nat Commun. 2019;10(1):2817.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Alterman JF, Godinho B, Hassler MR, Ferguson CM, Echeverria D, Sapp E, Haraszti RA, Coles AH, Conroy F, Miller R, et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat Biotechnol. 2019;37(8):884–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tang FHF, Staquicini FI, Teixeira AAR, Michaloski JS, Namiyama GM, Taniwaki NN, Setubal JC, da Silva AM, Sidman RL, Pasqualini R, et al. A ligand motif enables differential vascular targeting of endothelial junctions between brain and retina. Proc Natl Acad Sci USA. 2019;116(6):2300–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Elshafeey N, Kotrotsou A, Hassan A, Elshafei N, Hassan I, Ahmed S, Abrol S, Agarwal A, El Salek K, Bergamaschi S, et al. Multicenter study demonstrates radiomic features derived from magnetic resonance perfusion images identify pseudoprogression in glioblastoma. Nat Commun. 2019;10(1):3170.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Sakai K, Yamada K. Machine learning studies on major brain diseases: 5-year trends of 2014-2018. Jpn J Radiol. 2019;37(1):34–72.

    Article  PubMed  Google Scholar 

  19. Dhar R, Chen Y, An H, Lee JM. Application of machine learning to automated analysis of cerebral edema in large cohorts of ischemic stroke patients. Front Neurol. 2018;9:687.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dhar R, Falcone GJ, Chen Y, Hamzehloo A, Kirsch EP, Noche RB, Roth K, Acosta J, Ruiz A, Phuah CL, et al. Deep learning for automated measurement of hemorrhage and perihematomal edema in supratentorial intracerebral hemorrhage. Stroke. 2020;51:648–651.

    Article  PubMed  Google Scholar 

  21. Miao R, Xia LY, Chen HH, Huang HH, Liang Y. Improved classification of blood–brain-barrier drugs using deep learning. Sci Rep. 2019;9(1):8802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Saxena D, Sharma A, Siddiqui MH, Kumar R. Blood brain barrier permeability prediction using machine learning techniques: an update. Curr Pharm Biotechnol. 2019;20(14):1163–71.

    Article  CAS  PubMed  Google Scholar 

  23. Tan C, Lu NN, Wang CK, Chen DY, Sun NH, Lyu H, Korbelin J, Shi WX, Fukunaga K, Lu YM, et al. Endothelium-derived semaphorin 3g regulates hippocampal synaptic structure and plasticity via neuropilin-2/PlexinA4. Neuron. 2019;101(5):920–937.e913.

    Article  CAS  PubMed  Google Scholar 

  24. Wu KW, Lv LL, Lei Y, Qian C, Sun FY. Endothelial cells promote excitatory synaptogenesis and improve ischemia-induced motor deficits in neonatal mice. Neurobiol Dis. 2019;121:230–9.

    Article  CAS  PubMed  Google Scholar 

  25. Niu J, Tsai HH, Hoi KK, Huang N, Yu G, Kim K, Baranzini SE, Xiao L, Chan JR, Fancy SPJ. Aberrant oligodendroglial-vascular interactions disrupt the blood–brain barrier, triggering CNS inflammation. Nat Neurosci. 2019;22(5):709–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Benz F, Wichitnaowarat V, Lehmann M, Germano RF, Mihova D, Macas J, Adams RH, Taketo MM, Plate KH, Guerit S, et al. Low wnt/beta-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice. eLife. 2019;8(04):01.

    Google Scholar 

  27. Wang Y, Sabbagh MF, Gu X, Rattner A, Williams J, Nathans J. Beta-catenin signaling regulates barrier-specific gene expression in circumventricular organ and ocular vasculatures. eLife. 2019;8(04):01.

    Google Scholar 

  28. Spampinato SF, Bortolotto V, Canonico PL, Sortino MA, Grilli M. Astrocyte-derived paracrine signals: relevance for neurogenic niche regulation and blood–brain barrier integrity. Front Pharmacol. 2019;10:1346.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bonsack B, Borlongan MC, Lo EH, Arai K. Brief overview: protective roles of astrocyte-derived pentraxin-3 in blood–brain barrier integrity. Brain Circulation. 2019;5(3):145–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tan S, Shan Y, Lin Y, Liao S, Zhang B, Zeng Q, Wang Y, Deng Z, Chen C, Hu X, et al. Neutralization of interleukin-9 ameliorates experimental stroke by repairing the blood–brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A. FASEB J. 2019;33(3):4376–87.

    Article  CAS  PubMed  Google Scholar 

  31. Michetti F, D’Ambrosi N, Toesca A, Puglisi MA, Serrano A, Marchese E, Corvino V, Geloso MC. The S100B story: from biomarker to active factor in neural injury. J Neurochem. 2019;148(2):168–87.

    Article  CAS  PubMed  Google Scholar 

  32. Brown LS, Foster CG, Courtney JM, King NE, Howells DW, Sutherland BA. Pericytes and neurovascular function in the healthy and diseased brain. Front Cell Neurosci. 2019;13:282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazic D, Sweeney MD, Kong P, et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci. 2019;22(7):1089–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Coucha M, Barrett AC, Elgebaly M, Ergul A, Abdelsaid M. Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats. PLoS ONE. 2019;14(1):e0210523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Malinverno M, Maderna C, Abu Taha A, Corada M, Orsenigo F, Valentino M, Pisati F, Fusco C, Graziano P, Giannotta M, et al. Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nat Commun. 2019;10(1):2761.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Ma F, Zhang X, Yin KJ. MicroRNAs in central nervous system diseases: a prospective role in regulating blood–brain barrier integrity. Exp Neurol. 2019;323:113094.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Stamatovic SM, Phillips CM, Martinez-Revollar G, Keep RF, Andjelkovic AV. Involvement of epigenetic mechanisms and non-coding rnas in blood–brain barrier and neurovascular unit injury and recovery after stroke. Front Neurosci. 2019;13:864.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ruan W, Li J, Xu Y, Wang Y, Zhao F, Yang X, Jiang H, Zhang L, Saavedra JM, Shi L, et al. MALAT1 Up-regulator polydatin protects brain microvascular integrity and ameliorates stroke through C/EBPbeta/MALAT1/CREB/PGC-1alpha/PPARgamma pathway. Cell Mol Neurobiol. 2019;39(2):265–86.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang J, Dong B, Hao J, Yi S, Cai W, Luo Z. LncRNA Snhg3 contributes to dysfunction of cerebral microvascular cells in intracerebral hemorrhage rats by activating the TWEAK/Fn14/STAT3 pathway. Life Sci. 2019;237:116929.

    Article  PubMed  CAS  Google Scholar 

  40. Alishahi M, Ghaedrahmati F, Kolagar TA, Winlow W, Nikkar N, Farzaneh M, Khoshnam SE. Long non-coding RNAs and cell death following ischemic stroke. Metab Brain Dis. 2019;34(5):1243–51.

    Article  CAS  PubMed  Google Scholar 

  41. Xia X, Wang Y, Huang Y, Zhang H, Lu H, Zheng JC. Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents. Prog Neurobiol. 2019;183:101694.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Yuan X, Wu Q, Wang P, Jing Y, Yao H, Tang Y, Li Z, Zhang H, Xiu R. Exosomes derived from pericytes improve microcirculation and protect blood-spinal cord barrier after spinal cord injury in mice. Front Neurosci. 2019;13:319.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kuroda H, Tachikawa M, Yagi Y, Umetsu M, Nurdin A, Miyauchi E, Watanabe M, Uchida Y, Terasaki T. Cluster of differentiation 46 Is the major receptor in human blood–brain barrier endothelial cells for uptake of exosomes derived from brain-metastatic melanoma cells (SK-Mel-28). Mol Pharm. 2019;16(1):292–304.

    Article  CAS  PubMed  Google Scholar 

  44. You D, Wen X, Gorczyca L, Morris A, Richardson JR, Aleksunes LM. Increased MDR1 transporter expression in human brain endothelial cells through enhanced histone acetylation and activation of aryl hydrocarbon receptor signaling. Mol Neurobiol. 2019;56(10):6986–7002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao Q, Yu Z, Zhang F, Huang L, Xing C, Liu N, Xu Y, Wang X. HDAC3 inhibition prevents oxygen glucose deprivation/reoxygenation-induced transendothelial permeability by elevating PPARgamma activity in vitro. J Neurochem. 2019;149(2):298–310.

    Article  CAS  PubMed  Google Scholar 

  46. Liberale L, Gaul DS, Akhmedov A, Bonetti NR, Nageswaran V, Costantino S, Pahla J, Weber J, Fehr V, Vdovenko D, et al. Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study. Eur Heart J. 2019;11:11.

    Google Scholar 

  47. Stamatovic SM, Martinez-Revollar G, Hu A, Choi J, Keep RF, Andjelkovic AV. Decline in sirtuin-1 expression and activity plays a critical role in blood–brain barrier permeability in aging. Neurobiol Dis. 2019;126:105–16.

    Article  CAS  PubMed  Google Scholar 

  48. Senatorov VV Jr, Friedman AR, Milikovsky DZ, Ofer J, Saar-Ashkenazy R, Charbash A, Jahan N, Chin G, Mihaly E, Lin JM, et al. blood–brain barrier dysfunction in aging induces hyperactivation of TGFbeta signaling and chronic yet reversible neural dysfunction. Sci Translational Med. 2019;11(521):04.

    Article  CAS  Google Scholar 

  49. Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, Zandstra J, Berber E, Lehallier B, Mathur V, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25(6):988–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yamamoto M, Guo D-H, Hernandez CM, Stranahan AM. Endothelial Adora2a activation promotes blood–brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance. J Neurosci. 2019;39(21):4179–92.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Alam C, Aufreiter S, Georgiou CJ, Hoque MT, Finnell RH, O’Connor DL, Goldman ID, Bendayan R. Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha. Proc Natl Acad Sci USA. 2019;116(35):17531–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang SH, Liu DX, Wang L, Li YH, Wang YH, Zhang H, Su ZK, Fang WG, Qin XX, Shang DS, et al. A CASPR1-ATP1B3 protein interaction modulates plasma membrane localization of Na + K +-ATPase in brain microvascular endothelial cells. J Biol Chem. 2019;294(16):6375–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hoshi Y, Uchida Y, Kuroda T, Tachikawa M, Couraud PO, Suzuki T, Terasaki T. Distinct roles of ezrin, radixin and moesin in maintaining the plasma membrane localizations and functions of human blood–brain barrier transporters. J Cereb Blood Flow Metab. 2019;14:19868880.

    Google Scholar 

  54. Banks WA. The blood–brain barrier as an endocrine tissue. Nat Rev Endocrinol. 2019;15(8):444–55.

    Article  CAS  PubMed  Google Scholar 

  55. Reed MJ, Damodarasamy M, Banks WA. The extracellular matrix of the blood–brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease. Tissue Barriers. 2019;7(4):1651157.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Hempel C, Sporring J, Kurtzhals JAL. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx. FASEB J. 2019;33(2):2058–71.

    Article  CAS  PubMed  Google Scholar 

  57. Delsing L, Kallur T, Zetterberg H, Hicks R, Synnergren J. Enhanced xeno-free differentiation of hiPSC-derived astroglia applied in a blood–brain barrier model. Fluids Barriers CNS. 2019;16(1):27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Yao Y. Basement membrane and stroke. J Cereb Blood Flow Metab. 2019;39(1):3–19.

    Article  CAS  PubMed  Google Scholar 

  59. Greene C, Hanley N, Campbell M. Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS. 2019;16(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Berndt P, Winkler L, Cording J, Breitkreuz-Korff O, Rex A, Dithmer S, Rausch V, Blasig R, Richter M, Sporbert A, et al. Tight junction proteins at the blood–brain barrier: far more than claudin-5. Cell Mol Life Sci. 2019;76(10):1987–2002.

    Article  CAS  PubMed  Google Scholar 

  61. Uchida Y, Sumiya T, Tachikawa M, Yamakawa T, Murata S, Yagi Y, Sato K, Stephan A, Ito K, Ohtsuki S, et al. Involvement of claudin-11 in disruption of blood–brain, -spinal cord, and -arachnoid barriers in multiple sclerosis. Mol Neurobiol. 2019;56(3):2039–56.

    Article  CAS  PubMed  Google Scholar 

  62. Dias MC, Coisne C, Baden P, Enzmann G, Garrett L, Becker L, Hölter SM, de Angelis MH, Deutsch U, Engelhardt B, German Mouse Clinic Consortium. Claudin is not required for blood–brain barrier tight junction function. Fluids Barriers CNS. 2019;16(1):30.

    Article  CAS  Google Scholar 

  63. Castro Dias M, Coisne C, Lazarevic I, Baden P, Hata M, Iwamoto N, Francisco DMF, Vanlandewijck M, He L, Baier FA, et al. Claudin-3-deficient C57BL/6 J mice display intact brain barriers. Sci Rep. 2019;9(1):203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sladojevic N, Stamatovic SM, Johnson AM, Choi J, Hu A, Dithmer S, Blasig IE, Keep RF, Andjelkovic AV. Claudin-1-dependent destabilization of the blood–brain barrier in chronic stroke. J Neurosci. 2019;39(4):743–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Greene C, Kealy J, Humphries MM, Gong Y, Hou J, Hudson N, Cassidy LM, Martiniano R, Shashi V, Hooper SR, et al. Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Mol Psychiatry. 2018;23(11):2156–66.

    Article  CAS  PubMed  Google Scholar 

  66. Guo Y, Singh LN, Zhu Y, Gur RE, Resnick A, Anderson SA, Alvarez JI. Association of a functional Claudin-5 variant with schizophrenia in female patients with the 22q112 deletion syndrome. Schizophrenia Res. 2019;23:23.

    Google Scholar 

  67. Mottahedin A, Joakim Ek C, Truve K, Hagberg H, Mallard C. Choroid plexus transcriptome and ultrastructure analysis reveals a TLR2-specific chemotaxis signature and cytoskeleton remodeling in leukocyte trafficking. Brain Behav Immun. 2019;79:216–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, Nietzsche S, Westermann M, Peng L, Hu D, et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 2019;25(3):496–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kierdorf K, Masuda T, Jordao MJC, Prinz M. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat Rev Neurosci. 2019;20(9):547–62.

    Article  CAS  PubMed  Google Scholar 

  70. Gu C, Hao X, Li J, Hua Y, Keep RF, Xi G. Effects of minocycline on epiplexus macrophage activation, choroid plexus injury and hydrocephalus development in spontaneous hypertensive rats. J Cereb Blood Flow Metab. 2019;39(10):1936–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wan Y, Hua Y, Garton HJL, Novakovic N, Keep RF, Xi G. Activation of epiplexus macrophages in hydrocephalus caused by subarachnoid hemorrhage and thrombin. CNS Neurosci Ther. 2019;25(10):1134–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Castaneyra-Ruiz L, Hernandez-Abad LG, Carmona-Calero EM, Castaneyra-Perdomo A, Gonzalez-Marrero I. AQP1 overexpression in the CSF of obstructive hydrocephalus and inversion of its polarity in the choroid plexus of a chiari malformation type II case. J Neuropathol Exp Neurol. 2019;78(7):641–7.

    Article  PubMed  Google Scholar 

  73. Simpson S, Preston D, Schwerk C, Schroten H, Blazer-Yost B. Cytokine and inflammatory mediator effects on TRPV4 function in choroid plexus epithelial cells. Am J Physiol Cell Physiol. 2019;317(5):C881–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gregoriades JMC, Madaris A, Alvarez FJ, Alvarez-Leefmans FJ. Genetic and pharmacological inactivation of apical Na+-K+-2Cl- cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter. Am J Physiol Cell Physiol. 2019;316(4):C525–44.

    Article  PubMed  Google Scholar 

  75. Delpire E, Gagnon KB. Elusive role of the Na-K-2Cl cotransporter in the choroid plexus. Am J Physiol Cell Physiol. 2019;316(4):C522–4.

    Article  PubMed  Google Scholar 

  76. Bothwell SW, Janigro D, Patabendige A. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS. 2019;16(1):9.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Uchida Y, Goto R, Takeuchi H, Luczak M, Usui T, Tachikawa M, Terasaki T. Abundant expression of OCT2, MATE1, OAT1, OAT3, PEPT2, BCRP, MDR1 and xCT transporters in blood-arachnoid barrier of pig, and polarized localizations at CSF- and blood-facing plasma membranes. Drug Metab Dispos. 2019;26:26.

    Google Scholar 

  78. Mastorakos P, McGavern D. The anatomy and immunology of vasculature in the central nervous system. Sci Immunol. 2019;4(37):eaav0492. https://doi.org/10.1126/scimmunol.aav0492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rustenhoven J, Kipnis J. Bypassing the blood–brain barrier. Science. 2019;366(6472):1448–9.

    Article  CAS  PubMed  Google Scholar 

  80. Iliff J, Simon M. CrossTalk proposal: the glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J Physiol. 2019;597(17):4417–9.

    Article  CAS  PubMed  Google Scholar 

  81. Smith AJ, Verkman AS. Crosstalk opposing view: going against the flow: interstitial solute transport in brain is diffusive and aquaporin-4 independent. J Physiol. 2019;597(17):4421–4.

    Article  CAS  PubMed  Google Scholar 

  82. Bakker E, Naessens DMP, VanBavel E. Paravascular spaces: entry to or exit from the brain? Exp Physiol. 2019;104(7):1013–7.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Baledent O, Czosnyka Z, Czosnyka M. “Bucket” cerebrospinal fluid bulk flow-is it a fact or a fiction? Acta Neurochir. 2019;161(2):257–8.

    Article  PubMed  Google Scholar 

  84. Eide PK, Sorteberg A, Sorteberg W, Lindstrom EK, Mardal KA, Ringstad G. “Bucket” cerebrospinal fluid bulk flow: when the terrain disagrees with the map. Acta Neurochir. 2019;161(2):259–61.

    Article  PubMed  Google Scholar 

  85. Croci M, Vinje V, Rognes ME. Uncertainty quantification of parenchymal tracer distribution using random diffusion and convective velocity fields. Fluids Barriers CNS. 2019;16(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Davoodi-Bojd E, Ding G, Zhang L, Li Q, Li L, Chopp M, Zhang Z, Jiang Q. Modeling glymphatic system of the brain using MRI. Neuroimage. 2019;188:616–27.

    Article  PubMed  Google Scholar 

  87. Demiral SB, Tomasi D, Sarlls J, Lee H, Wiers CE, Zehra A, Srivastava T, Ke K, Shokri-Kojori E, Freeman CR, et al. Apparent diffusion coefficient changes in human brain during sleep—does it inform on the existence of a glymphatic system? Neuroimage. 2019;185:263–73.

    Article  PubMed  Google Scholar 

  88. Eide PK, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: a glymphatic magnetic resonance imaging study. J Cereb Blood Flow Metab. 2019;39(7):1355–68.

    Article  PubMed  Google Scholar 

  89. Hasan-Olive MM, Enger R, Hansson HA, Nagelhus EA, Eide PK. Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus. GLIA. 2019;67(1):91–100.

    Article  PubMed  Google Scholar 

  90. Magdoom KN, Brown A, Rey J, Mareci TH, King MA, Sarntinoranont M. MRI of whole rat brain perivascular network reveals role for ventricles in brain waste clearance. Sci Rep. 2019;9(1):11480.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Mortensen KN, Sanggaard S, Mestre H, Lee H, Kostrikov S, Xavier ALR, Gjedde A, Benveniste H, Nedergaard M. Impaired glymphatic transport in spontaneously hypertensive rats. J Neurosci. 2019;39(32):6365–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. van Veluw SJ, Hou SS, Calvo-Rodriguez M, Arbel-Ornath M, Snyder AC, Frosch MP, Greenberg SM, Bacskai BJ. Vasomotion as a driving force for paravascular clearance in the awake mouse brain. Neuron. 2019;09:09.

    Article  Google Scholar 

  93. Munk AS, Wang W, Bechet NB, Eltanahy AM, Cheng AX, Sigurdsson B, Benraiss A, Mae MA, Kress BT, Kelley DH, et al. PDGF-B is required for development of the glymphatic system. Cell Rep. 2019;26(11):2955–2969.e2953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, Suh SH, Hong SP, Song JH, Hong YK, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019;572(7767):62–6.

    Article  CAS  PubMed  Google Scholar 

  95. Norwood JN, Zhang Q, Card D, Craine A, Ryan TM, Drew PJ. Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate. Life. 2019;8(05):07.

    Google Scholar 

  96. Hsu M, Rayasam A, Kijak JA, Choi YH, Harding JS, Marcus SA, Karpus WJ, Sandor M, Fabry Z. Neuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells. Nat Commun. 2019;10(1):229.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Ma Q, Ries M, Decker Y, Muller A, Riner C, Bucker A, Fassbender K, Detmar M, Proulx ST. Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta Neuropathol. 2019;137(1):151–65.

    Article  PubMed  Google Scholar 

  98. Trillo-Contreras JL, Toledo-Aral JJ, Echevarria M, Villadiego J. AQP1 and AQP4 contribution to cerebrospinal fluid homeostasis. Cells. 2019;8(2):24.

    Article  CAS  Google Scholar 

  99. Hladky SB, Barrand MA. Metabolite clearance during wakefulness and sleep. Handbook Exp Pharmacol. 2019;253:385–423.

    Article  Google Scholar 

  100. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363(6429):880–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hablitz LM, Vinitsky HS, Sun Q, Staeger FF, Sigurdsson B, Mortensen KN, Lilius TO, Nedergaard M. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019;5(2):eaav5447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cuddapah VA, Zhang SL, Sehgal A. Regulation of the blood–brain barrier by circadian rhythms and sleep. Trends Neurosci. 2019;42(7):500–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hudson N, Celkova L, Hopkins A, Greene C, Storti F, Ozaki E, Fahey E, Theodoropoulou S, Kenna PF, Humphries MM, et al. Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. JCI Insight. 2019;4(15):130273. https://doi.org/10.1172/jci.insight.130273.

    Article  PubMed  Google Scholar 

  104. Myung J, Schmal C, Hong S, Tsukizawa Y, Rose P, Zhang Y, Holtzman MJ, De Schutter E, Herzel H, Bordyugov G, et al. The choroid plexus is an important circadian clock component. Nat Commun. 2018;9(1):1062.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Van Ombergen A, Jillings S, Jeurissen B, Tomilovskaya E, Rumshiskaya A, Litvinova L, Nosikova I, Pechenkova E, Rukavishnikov I, Manko O, et al. Brain ventricular volume changes induced by long-duration spaceflight. Proc Natl Acad Sci USA. 2019;116(21):10531–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  106. Kaiser K, Gyllborg D, Prochazka J, Salasova A, Kompanikova P, Molina FL, Laguna-Goya R, Radaszkiewicz T, Harnos J, Prochazkova M, et al. WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis. Nat Commun. 2019;10(1):1498.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Lepko T, Pusch M, Muller T, Schulte D, Ehses J, Kiebler M, Hasler J, Huttner HB, Vandenbroucke RE, Vandendriessche C, et al. Choroid plexus-derived miR-204 regulates the number of quiescent neural stem cells in the adult brain. EMBO J. 2019;38(17):e100481.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  108. Planques A, Oliveira Moreira V, Dubreuil C, Prochiantz A, Di Nardo AA. OTX2 signals from the choroid plexus to regulate adult neurogenesis. Eneuro. 2019. https://doi.org/10.1523/ENEURO.0262-18.2019.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Esposito E, Ahn BJ, Shi J, Nakamura Y, Park JH, Mandeville ET, Yu Z, Chan SJ, Desai R, Hayakawa A, et al. Brain-to-cervical lymph node signaling after stroke. Nat Commun. 2019;10(1):5306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Bridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, Alvarez-Cermeno JC, Andreasson U, Axelsson M, Backstrom DC, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. 2019;17:17.

    Google Scholar 

  111. Mohn N, Luo Y, Skripuletz T, Schwenkenbecher P, Zerr I, Lange P, Stangel M. Tau-protein concentrations are not elevated in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. Fluids Barriers CNS. 2019;16(1):28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Sandelius A, Portelius E, Kallen A, Zetterberg H, Rot U, Olsson B, Toledo JB, Shaw LM, Lee VMY, Irwin DJ, et al. Elevated CSF GAP-43 is Alzheimer’s disease specific and associated with tau and amyloid pathology. Alzheimer’s Dementia. 2019;15(1):55–64.

    Article  PubMed  Google Scholar 

  113. Simren J, Ashton NJ, Blennow K, Zetterberg H. An update on fluid biomarkers for neurodegenerative diseases: recent success and challenges ahead. Curr Opin Neurobiol. 2019;61:29–39.

    Article  PubMed  CAS  Google Scholar 

  114. Ewers M, Franzmeier N, Suarez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, et al. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci Translational Med. 2019;11(507):28.

    Article  CAS  Google Scholar 

  115. Blennow K, Chen C, Cicognola C, Wildsmith KR, Manser PT, Bohorquez SMS, Zhang Z, Xie B, Peng J, Hansson O, et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain J Neurol. 2019;13:13.

    Google Scholar 

  116. Kuiperij HB, Hondius DC, Kersten I, Versleijen AA, Rozemuller AJ, Greenberg SM, Schreuder FH, Klijn CJ, Verbeek MM. Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy. Neuropathol Appl Neurobiol. 2019;23:23.

    Google Scholar 

  117. Jeppsson A, Wikkelso C, Blennow K, Zetterberg H, Constantinescu R, Remes AM, Herukka SK, Rauramaa T, Nagga K, Leinonen V, et al. CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry. 2019;90(10):1117–23.

    Article  PubMed  Google Scholar 

  118. Batllori M, Casado M, Sierra C, Salgado MDC, Marti-Sanchez L, Maynou J, Fernandez G, Garcia-Cazorla A, Ormazabal A, Molero-Luis M, et al. Effect of blood contamination of cerebrospinal fluid on amino acids, biogenic amines, pterins and vitamins. Fluids Barriers CNS. 2019;16(1):34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, Distefano N, Zheng Y, Skakodub A, Mehta SA, Campos C, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature. 2019;565(7741):654–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yang J, Simonneau C, Kilker R, Oakley L, Byrne MD, Nichtova Z, Stefanescu I, Pardeep-Kumar F, Tripathi S, Londin E, et al. Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus. EMBO Mol Med. 2019;11(1):01.

    Article  CAS  Google Scholar 

  121. Diets IJ, Prescott T, Champaigne NL, Mancini GMS, Krossnes B, Fric R, Kocsis K, Jongmans MCJ, Kleefstra T. A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus. Genet Med. 2019;21(3):572–9.

    Article  CAS  PubMed  Google Scholar 

  122. Jin SC, Furey CG, Zeng X, Allocco A, Nelson-Williams C, Dong W, Karimy JK, Wang K, Ma S, Delpire E, et al. SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus. Mol Genet Genomic Med. 2019;7(9):e892.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Valdez Sandoval P, Hernandez Rosales P, Quinones Hernandez DG, Chavana Naranjo EA, Garcia Navarro V. Intraventricular hemorrhage and posthemorrhagic hydrocephalus in preterm infants: diagnosis, classification, and treatment options. Child’s Nerv Syst. 2019;35(6):917–27.

    Article  Google Scholar 

  124. Romantsik O, Agyemang AA, Sveinsdottir S, Rutardottir S, Holmqvist B, Cinthio M, Morgelin M, Gumus G, Karlsson H, Hansson SR, et al. The heme and radical scavenger alpha 1-microglobulin (A1M) confers early protection of the immature brain following preterm intraventricular hemorrhage. J Neuroinflam. 2019;16(1):122.

    Article  CAS  Google Scholar 

  125. Ding Y, Zhang T, Wu G, McBride DW, Xu N, Klebe DW, Zhang Y, Li Q, Tang J, Zhang JH. Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage. Exp Neurol. 2019;320:113003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Isaacs AM, Smyser CD, Lean RE, Alexopoulos D, Han RH, Neil JJ, Zimbalist SA, Rogers CE, Yan Y, Shimony JS, et al. MR diffusion changes in the perimeter of the lateral ventricles demonstrate periventricular injury in post-hemorrhagic hydrocephalus of prematurity. NeuroImage Clin. 2019;24:102031.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Capone PM, Bertelson JA, Ajtai B. Neuroimaging of normal pressure hydrocephalus and hydrocephalus. Neurol Clin. 2020;38(1):171–83.

    Article  PubMed  Google Scholar 

  128. Hudson M, Nowak C, Garling RJ, Harris C. Comorbidity of diabetes mellitus in idiopathic normal pressure hydrocephalus: a systematic literature review. Fluids Barriers CNS. 2019;16(1):5.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Nardone R, Golaszewski S, Schwenker K, Brigo F, Maccarrone M, Versace V, Sebastianelli L, Saltuari L, Holler Y. Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study. J Neural Transm (Vienna). 2019;126(8):1073–80.

    Article  Google Scholar 

  130. Shi YH, He XW, Liu FD, Liu YS, Hu Y, Shu L, Cui GH, Zhao R, Zhao L, Su JJ, et al. Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus. Gene. 2019;697:184–93.

    Article  CAS  PubMed  Google Scholar 

  131. Yokota H, Vijayasarathi A, Cekic M, Hirata Y, Linetsky M, Ho M, Kim W, Salamon N. diagnostic performance of glymphatic system evaluation using diffusion tensor imaging in idiopathic normal pressure hydrocephalus and mimickers. Curr Gerontol Geriatr Res. 2019;2019:5675014.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Hasan-Olive MM, Enger R, Hansson HA, Nagelhus EA, Eide PK. Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients. Fluids Barriers CNS. 2019;16(1):39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Thomas S, Boutaud L, Reilly ML, Benmerah A. Cilia in hereditary cerebral anomalies. Biol Cell. 2019;111(9):217–31.

    Article  PubMed  Google Scholar 

  134. Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N, Matsuda K, Sakaguchi M, Tanaka T, Komohara Y, et al. Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities. Neurology. 2019;92(20):e2364–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chiani F, Orsini T, Gambadoro A, Pasquini M, Putti S, Cirilli M, Ermakova O, Tocchini-Valentini GP. Functional loss of Ccdc1 51 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia. Dis Models Mech. 2019;12(8):02.

    Article  CAS  Google Scholar 

  136. Hasan-Olive MM, Hansson HA, Enger R, Nagelhus EA, Eide PK. Blood–brain barrier dysfunction in idiopathic intracranial hypertension. J Neuropathol Exp Neurol. 2019;78(9):808–18.

    Article  PubMed  Google Scholar 

  137. Onder H, Kisbet T. Neuroimaging findings in patients with idiopathic intracranial hypertension and cerebral venous thrombosis, and their association with clinical features. Neurol Res. 2020;42:141–7.

    Article  PubMed  Google Scholar 

  138. O’Reilly MW, Westgate CS, Hornby C, Botfield H, Taylor AE, Markey K, Mitchell JL, Scotton WJ, Mollan SP, Yiangou A, et al. A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. Jci Insight. 2019;4(6):21.

    Google Scholar 

  139. Lalou AD, Czosnyka M, Czosnyka ZH, Krishnakumar D, Pickard JD, Higgins NJ. Coupling of CSF and sagittal sinus pressure in adult patients with pseudotumour cerebri. Acta Neurochirurgica. 2019. https://doi.org/10.1007/s00701-019-04095-w.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Ma Z, Peng J, Yu D, Park JS, Lin H, Xu B, Lu C, Fan H, Waldor MK. A streptococcal Fic domain-containing protein disrupts blood–brain barrier integrity by activating moesin in endothelial cells. PLoS Pathog. 2019;15(5):e1007737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kim BJ, McDonagh MA, Deng L, Gastfriend BD, Schubert-Unkmeir A, Doran KS, Shusta EV. Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells. Fluids Barriers CNS. 2019;16(1):26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Mohanty T, Fisher J, Bakochi A, Neumann A, Cardoso JFP, Karlsson CAQ, Pavan C, Lundgaard I, Nilson B, Reinstrup P, et al. Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis. Nat Commun. 2019;10(1):1667.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. O’Keeffe E, Kelly E, Liu Y, Giordano C, Wallace E, Hynes M, Tiernan S, Meagher A, Greene C, Hughes S, et al. Dynamic blood–brain barrier regulation in mild traumatic brain injury. J Neurotrauma. 2019;08:08.

    Google Scholar 

  144. Yoo RE, Choi SH, Oh BM, Do Shin S, Lee EJ, Shin DJ, Jo SW, Kang KM, Yun TJ, Kim JH, et al. Quantitative dynamic contrast-enhanced MR imaging shows widespread blood–brain barrier disruption in mild traumatic brain injury patients with post-concussion syndrome. Eur Radiol. 2019;29(3):1308–17.

    Article  PubMed  Google Scholar 

  145. Sandsmark DK, Bashir A, Wellington CL, Diaz-Arrastia R. Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron. 2019;103(3):367–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Investigators CC. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713–23.

    Article  Google Scholar 

  147. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood–brain barrier: from physiology to disease and back. Physiol Rev. 2019;99(1):21–78.

    Article  CAS  PubMed  Google Scholar 

  148. Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, Harrington MG, Pa J, Law M, Wang DJJ, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimer’s Dementia. 2019;15(1):158–67.

    Article  PubMed  Google Scholar 

  149. Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Milikovsky DZ, Ofer J, Senatorov VV Jr, Friedman AR, Prager O, Sheintuch L, Elazari N, Veksler R, Zelig D, Weissberg I, et al. Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood–brain barrier dysfunction. Sci Transl Med. 2019;11(521):8954. https://doi.org/10.1126/scitranslmed.aaw8954.

    Article  Google Scholar 

  151. Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurology. 2019;76(1):81–94.

    Article  PubMed  Google Scholar 

  152. Zille M, Ikhsan M, Jiang Y, Lampe J, Wenzel J, Schwaninger M. The impact of endothelial cell death in the brain and its role after stroke: a systematic review. Cell Stress. 2019;3(11):330–47.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Albekairi TH, Vaidya B, Patel R, Nozohouri S, Villalba H, Zhang Y, Lee YS, Al-Ahmad A, Abbruscato TJ. Brain delivery of a potent opioid receptor agonist, biphalin during ischemic stroke: role of organic anion transporting polypeptide (OATP). Pharmaceutics. 2019;11(9):10.

    Article  Google Scholar 

  154. Medin T, Medin H, Hefte MB, Storm-Mathisen J, Bergersen LH. Upregulation of the lactate transporter monocarboxylate transporter 1 at the blood–brain barrier in a rat model of attention-deficit/hyperactivity disorder suggests hyperactivity could be a form of self-treatment. Behav Brain Res. 2019;360:279–85.

    Article  CAS  PubMed  Google Scholar 

  155. Sekhar GN, Fleckney AL, Boyanova ST, Rupawala H, Lo R, Wang H, Farag DB, Rahman KM, Broadstock M, Reeves S, et al. Region-specific blood–brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease. Fluids Barriers CNS. 2019;16(1):38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Krueger M, Mages B, Hobusch C, Michalski D. Endothelial edema precedes blood–brain barrier breakdown in early time points after experimental focal cerebral ischemia. Acta Neuropathol Commun. 2019;7(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Munji RN, Soung AL, Weiner GA, Sohet F, Semple BD, Trivedi A, Gimlin K, Kotoda M, Korai M, Aydin S, et al. Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood–brain barrier dysfunction module. Nat Neurosci. 2019;22(11):1892–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Guo S, Deng W, Xing C, Zhou Y, Ning M, Lo EH. Effects of aging, hypertension and diabetes on the mouse brain and heart vasculomes. Neurobiol Dis. 2019;126:117–23.

    Article  PubMed  Google Scholar 

  159. Vendel E, Rottschafer V, de Lange ECM. The need for mathematical modelling of spatial drug distribution within the brain. Fluids Barriers CNS. 2019;16(1):12.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Lochhead JJ, Davis TP. Perivascular and perineural pathways involved in brain delivery and distribution of drugs after intranasal administration. Pharmaceutics. 2019;11(11):12.

    Article  Google Scholar 

  161. Johnsen KB, Burkhart A, Thomsen LB, Andresen TL, Moos T. Targeting the transferrin receptor for brain drug delivery. Prog Neurobiol. 2019;181:101665.

    Article  PubMed  CAS  Google Scholar 

  162. Belanger K, Iqbal U, Tanha J, MacKenzie R, Moreno M, Stanimirovic D. Single-domain antibodies as therapeutic and imaging agents for the treatment of cns diseases. Antibodies. 2019;8(2):05.

    Article  CAS  Google Scholar 

  163. Thom G, Tian MM, Hatcher JP, Rodrigo N, Burrell M, Gurrell I, Vitalis TZ, Abraham T, Jefferies WA, Webster CI, et al. A peptide derived from melanotransferrin delivers a protein-based interleukin 1 receptor antagonist across the BBB and ameliorates neuropathic pain in a preclinical model. J Cereb Blood Flow Metab. 2019;39(10):2074–88.

    Article  CAS  PubMed  Google Scholar 

  164. Wu LP, Ahmadvand D, Su J, Hall A, Tan X, Farhangrazi ZS, Moghimi SM. Crossing the blood–brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide. Nat Commun. 2019;10(1):4635.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Hordeaux J, Yuan Y, Clark PM, Wang Q, Martino RA, Sims JJ, Bell P, Raymond A, Stanford WL, Wilson JM. The GPI-linked protein LY6A drives AAV-PHPB transport across the blood–brain barrier. Mol Ther. 2019;27(5):912–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Baumann BH, Shu W, Song Y, Simpson EM, Lakhal-Littleton S, Dunaief JL. Ferroportin-mediated iron export from vascular endothelial cells in retina and brain. Exp Eye Res. 2019;187:107728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Janowicz PW, Leinenga G, Gotz J, Nisbet RM. Ultrasound-mediated blood–brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody. Sci Rep. 2019;9(1):9255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A, Ironside S, Heyn C, Alkins R, Trudeau M, Sahgal A, et al. Blood–brain barrier opening in primary brain tumors with non-invasive mr-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep. 2019;9(1):321.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Abrahao A, Meng Y, Llinas M, Huang Y, Hamani C, Mainprize T, Aubert I, Heyn C, Black SE, Hynynen K, et al. First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat Commun. 2019;10(1):4373.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G, Asquier N, Law-Ye B, Leclercq D, Bissery A, et al. Safety and feasibility of repeated and transient blood–brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res. 2019;25(13):3793–801.

    Article  PubMed  Google Scholar 

  171. Meng Y, Abrahao A, Heyn CC, Bethune AJ, Huang Y, Pople CB, Aubert I, Hamani C, Zinman L, Hynynen K, et al. Glymphatics visualization after focused ultrasound-induced blood–brain barrier opening in humans. Ann Neurol. 2019;86(6):975–80.

    Article  CAS  PubMed  Google Scholar 

  172. Dithmer S, Staat C, Muller C, Ku MC, Pohlmann A, Niendorf T, Gehne N, Fallier-Becker P, Kittel A, Walter FR, et al. Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery. Ann N Y Acad Sci. 2017;1397(1):169–84.

    Article  CAS  PubMed  Google Scholar 

  173. Yang S, Chen Y, Feng M, Rodriguez L, Wu JQ, Wang MZ. Improving eflornithine oral bioavailability and brain uptake by modulating intercellular junctions with an E-cadherin peptide. J Pharm Sci. 2019;108(12):3870–8.

    Article  PubMed  CAS  Google Scholar 

  174. Andjelkovic AV, Xiang J, Stamatovic SM, Hua Y, Xi G, Wang MM, Keep RF. Endothelial targets in stroke: translating animal models to human. Arterioscler Thromb Vasc Biol. 2019;39(11):2240–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lyden P, Pryor KE, Coffey CS, Cudkowicz M, Conwit R, Jadhav A, Sawyer RN Jr, Claassen J, Adeoye O, Song S, et al. Final results of the RHAPSODY trial: a multi-center, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A-APC, A recombinant variant of human activated protein c, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. Ann Neurol. 2019;85(1):125–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Snow B, Mulroy E, Bok A, Simpson M, Smith A, Taylor K, Lockhart M, Lam BJ, Frampton C, Schweder P, et al. A phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL R [immunoprotected (alginate–encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2019;61:88–93.

    Article  PubMed  Google Scholar 

  177. Pergakis M, Badjatia N, Chaturvedi S, Cronin CA, Kimberly WT, Sheth KN, Simard JM. BIIB093 (IV glibenclamide): an investigational compound for the prevention and treatment of severe cerebral edema. Expert Opin Investig Drugs. 2019;28(12):1031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Davson H, Hollingsworth G, Segal MB. The mechanism of drainage of the cerebrospinal fluid. Brain J Neurol. 1970;93(4):665–78.

    Article  CAS  Google Scholar 

  179. Davson H, Segal MB. The effects of some inhibitors and accelerators of sodium transport on the turnover of 22Na in the cerebrospinal fluid and the brain. J Physiol. 1970;209(1):131–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Deane R, Segal MB. The transport of sugars across the perfused choroid plexus of the sheep. J Physiol. 1985;362:245–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Preston JE, Segal MB. The uptake of anionic and cationic amino acids by the isolated perfused sheep choroid plexus. Brain Res. 1992;581(2):351–5.

    Article  CAS  PubMed  Google Scholar 

  182. Schreiber G, Aldred AR, Jaworowski A, Nilsson C, Achen MG, Segal MB. Thyroxine transport from blood to brain via transthyretin synthesis in choroid plexus. Am J Physiol Regul Integr Comp Physiol. 1990;258(2 27-2):R338–45.

    Article  CAS  Google Scholar 

  183. Segal MB, Preston JE, Collis CS, Zlokovic BV. Kinetics and Na independence of amino acid uptake by blood side of perfused sheep choroid plexus. Am J Physiol. 1990;258(5 Pt 2):F1288–94.

    CAS  PubMed  Google Scholar 

  184. Chen RL, Kassem NA, Redzic ZB, Chen CP, Segal MB, Preston JE. Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol. 2009;44(4):289–96.

    Article  CAS  PubMed  Google Scholar 

  185. Evans CAN, Reynolds JM, Reynolds ML, Saunders NR, Segal MB. The development of a blood–brain barrier mechanism in foetal sheep. J Physiol. 1974;238(2):371–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Davson H, Welch K, Segal MB. The physiology and pathology of the cerebrospinal fluid. New York: Churchill Livingstone; 1987.

    Google Scholar 

  187. Davson H, Segal MB. Physiology of the CSF and blood–brain barriers. Boca Raton: CRC Press; 1996.

    Google Scholar 

  188. Chodobski A, Ghersi-Egea JF, Preston-Kennedy J, Redzic Z, Strazielle N, Szmydynger-Chodobska J, Thorne RG. The legacy of malcolm beverley segal (1937–2019) on the science and fields concerned with choroid plexus and cerebrospinal fluid physiology. Fluids Barriers CNS. 2019;16(1):41.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Donahue JE, Flaherty SL, Johanson CE, Duncan Iii JA, Silverberg GD, Miller MC, Tavares R, Yang W, Wu Q, Sabo E, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol. 2006;112(4):405–15.

    Article  CAS  PubMed  Google Scholar 

  190. Stopa EG, Tanis KQ, Miller MC, Nikonova EV, Podtelezhnikov AA, Finney EM, Stone DJ, Camargo LM, Parker L, Verma A, et al. Comparative transcriptomics of choroid plexus in Alzheimer’s disease, frontotemporal dementia and Huntington’s disease: implications for CSF homeostasis. Fluids Barriers CNS. 2018;15(1):18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA. 1994;91(11):4766–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood–brain barrier leakage in Alzheimer’s disease. Neurobiol Aging. 2007;28(7):977–86.

    Article  CAS  PubMed  Google Scholar 

  193. Johanson CE, Szmydynger-Chodobska J, Chodobski A, Baird A, McMillan P, Stopa EG. Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus. Am J Physiol. 1999;277(1):R263–71.

    CAS  PubMed  Google Scholar 

  194. Silverberg GD, Miller MC, Pascale CL, Caralopoulos IN, Agca Y, Agca C, Stopa EG. Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP. Fluids Barriers CNS. 2015;12(1):2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11(1):10. https://doi.org/10.1186/2045-8118-11-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Johanson CE, Duncan JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5(1):10. https://doi.org/10.1186/1743-8454-5-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Silverberg GD, Messier AA, Miller MC, Machan JT, Majmudar SS, Stopa EG, Donahue JE, Johanson CE. Amyloid efflux transporter expression at the blood–brain barrier declines in normal aging. J Neuropathol Exp Neurol. 2010;69(10):1034–43.

    Article  CAS  PubMed  Google Scholar 

  198. de la Monte SM, Donahue JE, Aswad BI. Edward G. Stopa, MD, July 6, 1954-September 18, 2019. J Neuropathol Exp Neurol. 2019. https://doi.org/10.1093/jnen/nlz10.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

RFK wrote the initial draft. HCJ and LRD added sections and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Richard F. Keep.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

RFK, HCJ and LRD are co-Editors-in-Chief of Fluids Barriers of the CNS.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keep, R.F., Jones, H.C. & Drewes, L.R. This was the year that was: brain barriers and brain fluid research in 2019. Fluids Barriers CNS 17, 20 (2020). https://doi.org/10.1186/s12987-020-00181-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/s12987-020-00181-9