| 1. |
- Battistella, Roberta, et al.
(författare)
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Not All Lectins Are Equally Suitable for Labeling Rodent Vasculature
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 22:21
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Tidskriftsartikel (refereegranskat)abstract
- The vascular system is vital for all tissues and the interest in its visualization spans many fields. A number of different plant-derived lectins are used for detection of vasculature; however, studies performing direct comparison of the labeling efficacy of different lectins and techniques are lacking. In this study, we compared the labeling efficacy of three lectins: Griffonia simplicifolia isolectin B4 (IB4); wheat germ agglutinin (WGA), and Lycopersicon esculentum agglutinin (LEA). The LEA lectin was identified as being far superior to the IB4 and WGA lectins in histological labeling of blood vessels in brain sections. A similar signal-to-noise ratio was achieved with high concentrations of the WGA lectin injected during intracardial perfusion. Lectins were also suitable for labeling vasculature in other tissues, including spinal cord, dura mater, heart, skeletal muscle, kidney, and liver tissues. In uninjured tissues, the LEA lectin was as accurate as the Tie2-eGFP reporter mice and GLUT-1 immunohistochemistry for labeling the cerebral vasculature, validating its specificity and sensitivity. However, in pathological situations, e.g., in stroke, the sensitivity of the LEA lectin decreases dramatically, limiting its applicability in such studies. This work can be used for selecting the type of lectin and labeling method for various tissues.
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| 2. |
- Bohr, Tomas, et al.
(författare)
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The glymphatic system : Current understanding and modeling
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:9
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Forskningsöversikt (refereegranskat)abstract
- We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer's disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field.
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| 3. |
- Du, Ting, et al.
(författare)
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Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:2, s. 787-797
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral oedema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that oedema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of CSF. Oedema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of oedema. Oedema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of oedema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral oedema formation after cardiac arrest.
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| 4. |
- Martikainen, Maria-Viola, et al.
(författare)
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TUBE project: Transport-derived ultrafines and the brain effects
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- The adverse effects of air pollutants on the respiratory and cardiovascular systems are unquestionable. However, in recent years, indications of effects beyond these organ systems have become more evident. Traffic-related air pollution has been linked with neurological diseases, exacerbated cognitive dysfunction, and Alzheimer’s disease. However, the exact air pollutant compositions and exposure scenarios leading to these adverse health effects are not known. Although several components of air pollution may be at play, recent experimental studies point to a key role of ultrafine particles (UFPs). While the importance of UFPs has been recognized, almost nothing is known about the smallest fraction of UFPs, and only >23 nm emissions are regulated in the EU. Moreover, the role of the semivolatile fraction of the emissions has been neglected. The Transport-Derived Ultrafines and the Brain Effects (TUBE) project will increase knowledge on harmful ultrafine air pollutants, as well as semivolatile compounds related to adverse health effects. By including all the major current combustion and emission control technologies, the TUBE project aims to provide new information on the adverse health effects of current traffic, as well as information for decision makers to develop more effective emission legislation. Most importantly, the TUBE project will include adverse health effects beyond the respiratory system; TUBE will assess how air pollution affects the brain and how air pollution particles might be removed from the brain. The purpose of this report is to describe the TUBE project, its background, and its goals.
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| 5. |
- Mestre, Humberto, et al.
(författare)
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Aquaporin-4-dependent glymphatic solute transport in the rodent brain
- 2018
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Ingår i: eLife. - 2050-084X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.
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| 6. |
- Munk, Anne Sofie, et al.
(författare)
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PDGF-B Is Required for Development of the Glymphatic System
- 2019
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; , s. 3-2969
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Tidskriftsartikel (refereegranskat)abstract
- The glymphatic system is a highly polarized cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age. Formation of astrocytic endfeet and polarized expression of aquaporin 4 (AQP4) consistently coincided with the appearance of perivascular CSF transport. Deficiency of platelet-derived growth factor B (PDGF-B) function in the PDGF retention motif knockout mouse line Pdgfb ret/ret suppressed the development of the glymphatic system, whose functions remained suppressed in adulthood compared with wild-type mice. These experiments map the natural development of the glymphatic system in mice and define a critical role of PDGF-B in the development of perivascular CSF transport.
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| 7. |
- Pavan, Chiara, et al.
(författare)
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DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis
- 2021
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 90:4, s. 653-669
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021.
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| 8. |
- Raizen, David M., et al.
(författare)
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Beyond the symptom : the biology of fatigue
- 2023
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Ingår i: Sleep. - : Oxford University Press. - 0161-8105 .- 1550-9109. ; 46:9
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Tidskriftsartikel (refereegranskat)abstract
- A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27–28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue.The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.
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| 9. |
- Ramos, Marta, et al.
(författare)
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Cisterna Magna Injection in Rats to Study Glymphatic Function
- 2019
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1938, s. 97-104
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Tidskriftsartikel (refereegranskat)abstract
- The recently discovered glymphatic system, which supports brain-wide clearance of metabolic waste, has become the subject of intense research within the past few years. Its nomenclature arose due to its functionally analogous nature to the lymphatic system in combination with glial cells that are part of its anatomical boundaries. The influx of cerebrospinal fluid (CSF) from perivascular spaces into the brain interstitium acts to clear intraparenchymal solutes. CSF is produced by the choroid plexus and flows from the ventricles to the subarachnoid space via the cisterna magna, and as such the injection of tracer molecules into any one of these spaces could be used for studying CSF movement through the glymphatic system. Of these options, the cisterna magna is most favorable as it offers a route of entry that does not involve craniotomy. Herein we describe the cisterna magna (CM) injection procedure carried out in rats, essential for studying glymphatic influx and efflux dynamics.
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| 10. |
- Reeves, Benjamin C., et al.
(författare)
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Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus
- 2020
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Ingår i: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914. ; 26:3, s. 285-295
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Forskningsöversikt (refereegranskat)abstract
- Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia–lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.
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| 11. |
- Shalgunov, Vladimir, et al.
(författare)
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Pretargeted imaging beyond the blood-brain barrier
- 2023
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Ingår i: RSC Medicinal Chemistry. - : Royal Society of Chemistry. - 2632-8682. ; 14:3, s. 444-453
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Tidskriftsartikel (refereegranskat)abstract
- Pretargeting is a powerful nuclear imaging strategy to achieve enhanced imaging contrast for nanomedicines and reduce the radiation burden to healthy tissue. Pretargeting is based on bioorthogonal chemistry. The most attractive reaction for this purpose is currently the tetrazine ligation, which occurs between trans-cyclooctene (TCO) tags and tetrazines (Tzs). Pretargeted imaging beyond the blood-brain barrier (BBB) is challenging and has not been reported thus far. In this study, we developed Tz imaging agents that are capable of ligating in vivo to targets beyond the BBB. We chose to develop F-18-labeled Tzs as they can be applied to positron emission tomography (PET) - the most powerful molecular imaging technology. Fluorine-18 is an ideal radionuclide for PET due to its almost ideal decay properties. As a non-metal radionuclide, fluorine-18 also allows for development of Tzs with physicochemical properties enabling passive brain diffusion. To develop these imaging agents, we applied a rational drug design approach. This approach was based on estimated and experimentally determined parameters such as the BBB score, pretargeted autoradiography contrast, in vivo brain influx and washout as well as on peripheral metabolism profiles. From 18 initially developed structures, five Tzs were selected to be tested for their in vivo click performance. Whereas all selected structures clicked in vivo to TCO-polymer deposited into the brain, [F-18]18 displayed the most favorable characteristics with respect to brain pretargeting. [F-18]18 is our lead compound for future pretargeted neuroimaging studies based on BBB-penetrant monoclonal antibodies. Pretargeting beyond the BBB will allow us to image targets in the brain that are currently not imageable, such as soluble oligomers of neurodegeneration biomarker proteins. Imaging of such currently non-imageable targets will allow early diagnosis and personalized treatment monitoring. This in turn will accelerate drug development and greatly benefit patient care.
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| 12. |
- van den Broek, Sara Lopes, et al.
(författare)
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Pretargeted Imaging beyond the Blood-Brain Barrier-Utopia or Feasible?
- 2022
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Ingår i: Pharmaceuticals. - : MDPI. - 1424-8247. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Pretargeting is a promising nuclear imaging technique that allows for the usage of antibodies (Abs) with enhanced imaging contrast and reduced patient radiation burden. It is based on bioorthogonal chemistry with the tetrazine ligation-a reaction between trans-cyclooctenes (TCOs) and tetrazines (Tzs)-currently being the most popular reaction due to its high selectivity and reactivity. As Abs can be designed to bind specifically to currently 'undruggable' targets such as protein isoforms or oligomers, which play a crucial role in neurodegenerative diseases, pretargeted imaging beyond the BBB is highly sought after, but has not been achieved yet. A challenge in this respect is that large molecules such as Abs show poor brain uptake. Uptake can be increased by receptor mediated transcytosis; however, it is largely unknown if the achieved brain concentrations are sufficient for pretargeted imaging. In this study, we investigated whether the required concentrations are feasible to reach. As a model Ab, we used the bispecific anti-amyloid beta (A beta) anti-transferrin receptor (TfR) Ab 3D6scFv8D3 and conjugated it to a different amount of TCOs per Ab and tested different concentrations in vitro. With this model in hand, we estimated the minimum required TCO concentration to achieve a suitable contrast between the high and low binding regions. The estimation was carried out using pretargeted autoradiography on brain sections of an Alzheimer's disease mouse model. Biodistribution studies in wild-type (WT) mice were used to correlate how different TCO/Ab ratios alter the brain uptake. Pretargeted autoradiography showed that increasing the number of TCOs as well as increasing the TCO-Ab concentration increased the imaging contrast. A minimum brain concentration of TCOs for pretargeting purposes was determined to be 10.7 pmol/g in vitro. Biodistribution studies in WT mice showed a brain uptake of 1.1% ID/g using TCO-3D6scFv8D3 with 6.8 TCO/Ab. According to our estimations using the optimal parameters, pretargeted imaging beyond the BBB is not a utopia. Necessary brain TCO concentrations can be reached and are in the same order of magnitude as required to achieve sufficient contrast. This work gives a first estimate that pretargeted imaging is indeed possible with antibodies. This could allow the imaging of currently 'undruggable' targets and therefore be crucial to monitor (e.g., therapies for intractable neurodegenerative diseases).
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| 13. |
- van Osch, Matthias J. P., et al.
(författare)
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Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood
- 2024
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Ingår i: NMR in Biomedicine. - : John Wiley & Sons. - 0952-3480 .- 1099-1492.
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Forskningsöversikt (refereegranskat)abstract
- Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the “EU Joint Programme – Neurodegenerative Disease Research (JPND)” consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration–time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.
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| 14. |
- Xavier, Anna L.R., et al.
(författare)
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Cannula Implantation into the Cisterna Magna of Rodents
- 2018
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Ingår i: Journal of visualized experiments : JoVE. - : MyJove Corporation. - 1940-087X. ; :135
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Tidskriftsartikel (refereegranskat)abstract
- Cisterna magna cannulation (CMc) is a straightforward procedure that enables direct access to the cerebrospinal fluid (CSF) without operative damage to the skull or the brain parenchyma. In anesthetized rodents, the exposure of the dura mater by blunt dissection of the neck muscles allows the insertion of a cannula into the cisterna magna (CM). The cannula, composed either by a fine beveled needle or borosilicate capillary, is attached via a polyethylene (PE) tube to a syringe. Using a syringe pump, molecules can then be injected at controlled rates directly into the CM, which is continuous with the subarachnoid space. From the subarachnoid space, we can trace CSF fluxes by convective flow into the perivascular space around penetrating arterioles, where solute exchange with the interstitial fluid (ISF) occurs. CMc can be performed for acute injections immediately following the surgery, or for chronic implantation, with later injection in anesthetized or awake, freely moving rodents. Quantitation of tracer distribution in the brain parenchyma can be performed by epifluorescence, 2-photon microscopy, and magnetic resonance imaging (MRI), depending on the physico-chemical properties of the injected molecules. Thus, CMc in conjunction with various imaging techniques offers a powerful tool for assessment of the glymphatic system and CSF dynamics and function. Furthermore, CMc can be utilized as a conduit for fast, brain-wide delivery of signaling molecules and metabolic substrates that could not otherwise cross the blood brain barrier (BBB).
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