Permeability of the windows of the brain: feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

Abstract Background Circumventricular organs (CVOs) are small structures without a blood–brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood–brain barrier absence. Methods Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter. Results In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter. Conclusions Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures. Trial registration: Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

Download Full-text

Permeability of the windows of the brain: Feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

10.21203/rs.3.rs-46100/v3 ◽

2020 ◽

Author(s):

Inge C.M. Verheggen ◽

Joost J.A. de Jong ◽

Martin P.J. van Boxtel ◽

Alida A. Postma ◽

Frans R.J. Verhey ◽

...

Keyword(s):

Blood Brain Barrier ◽

Gray Matter ◽

Circumventricular Organs ◽

Brain Barrier ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Blood Brain ◽

Contrast Enhanced ◽

The Brain

Abstract Background: Circumventricular organs (CVOs) are small structures without a blood-brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood-brain barrier absence.Methods: Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter.Results: In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter.Conclusions: Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures.Trial registration: Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

Download Full-text

Permeability of the windows of the brain: Feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

10.21203/rs.3.rs-46100/v2 ◽

2020 ◽

Author(s):

Inge C.M. Verheggen ◽

Joost J.A. de Jong ◽

Martin P.J. van Boxtel ◽

Alida A. Postma ◽

Frans R.J. Verhey ◽

...

Keyword(s):

Blood Brain Barrier ◽

Gray Matter ◽

Circumventricular Organs ◽

Brain Barrier ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Blood Brain ◽

Contrast Enhanced ◽

The Brain

Abstract Background Circumventricular organs (CVOs) are small structures without a blood-brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood-brain barrier absence.Methods Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter.Results In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter.Conclusions Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures.Trial registration Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

Download Full-text

Permeability of the Windows of the Brain: Feasibility of Dynamic Contrast-enhanced MRI of the Circumventricular Organs

10.21203/rs.3.rs-46100/v1 ◽

2020 ◽

Author(s):

Inge C.M. Verheggen ◽

Joost J.A. de Jong ◽

Martin P.J. van Boxtel ◽

Alida A. Postma ◽

Frans R.J. Verhey ◽

...

Keyword(s):

Blood Brain Barrier ◽

Gray Matter ◽

Circumventricular Organs ◽

Brain Barrier ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Blood Brain ◽

Contrast Enhanced ◽

The Brain

Abstract BackgroundCircumventricular organs (CVOs) are small structures without a blood-brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood-brain barrier absence.MethodsTwenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter.ResultsIn both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer rates than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter.ConclusionsCurrent measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures.Trial registrationNetherlands Trial Register number: NL6358, date of registration: 2017-03-24

Download Full-text

Accurate Determination of Blood–Brain Barrier Permeability Using Dynamic Contrast-Enhanced T1-Weighted MRI: A Simulation and in vivo Study on Healthy Subjects and Multiple Sclerosis Patients

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.126 ◽

2014 ◽

Vol 34 (10) ◽

pp. 1655-1665 ◽

Cited By ~ 57

Author(s):

Stig P Cramer ◽

Henrik BW Larsson

Keyword(s):

Blood Brain Barrier ◽

Temporal Resolution ◽

Brain Barrier ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Blood Brain ◽

Accuracy And Precision ◽

Contrast Enhanced ◽

Measurement Duration

Dynamic contrast-enhanced magnetic resonance imaging (DCE–MRI) is increasingly used to estimate permeability in situations with subtle blood–brain barrier (BBB) leakage. However, the method's ability to differentiate such low values from zero is unknown, and no consensus exists on optimal selection of total measurement duration, temporal resolution, and modeling approach under varying physiologic circumstances. To estimate accuracy and precision of the DCE–MRI method we generated simulated data using a two-compartment model and progressively down-sampled and truncated the data to mimic low temporal resolution and short total measurement duration. Model fit was performed with the Patlak, the extended Tofts, and the Tikhonov two-compartment (Tik-2CM) models. Overall, 17 healthy controls were scanned to obtain in vivo data. Long total measurement duration (15 minutes) and high temporal resolution (1.25 seconds) greatly improved accuracy and precision for all three models, enabling us to differentiate values of permeability as low as 0.1 ml/100 g/min from zero. The Patlak model yielded highest accuracy and precision for permeability values <0.3 ml/100 g/min, but for higher values the Tik-2CM performed best. Our results emphasize the importance of optimal parameter setup and model selection when characterizing low BBB permeability.

Download Full-text

EXTH-02. THE BLOOD BRAIN BARRIER (BBB) PERMEABILITY IS ALTERED BY TUMOR TREATING FIELDS (TTFIELDS) IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/noz175.336 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi82-vi82 ◽

Cited By ~ 2

Author(s):

Ellina Schulz ◽

Almuth F Kessler ◽

Ellaine Salvador ◽

Dominik Domröse ◽

Malgorzata Burek ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Dce Mri ◽

Tumor Treating Fields ◽

Blood Brain ◽

Vessel Structure ◽

Bbb Permeability ◽

The Brain

Abstract OBJECTIVE For glioblastoma patients Tumor Treating Fields (TTFields) have been established as adjuvant therapy. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Therefore, the BBB may block delivery of drugs for treatment of brain tumors. Here, the influence of TTFields on BBB permeability was assessed in vivo. METHODS Rats were treated with 100 kHz TTFields for 72 h and thereupon i.v. injected with Evan’s Blue (EB) which directly binds to Albumin. To evaluate effects on BBB, EB was extracted after brain homogenization and quantified. In addition, cryosections of rat brains were prepared following TTFields application. The sections were stained for tight junction proteins Claudin-5 and Occludin and for immunoglobulin G (IgG) to assess vessel structure. Furthermore, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent was performed before and after TTFields application. RESULTS TTFields application significantly increased the EB accumulation in the rat brain. In TTFields-treated rats, the vessel structure became diffuse compared to control cryosections of rat brains; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue. Serial DCE-MRI demonstrated significantly increased accumulation of Gadolinium in the brain, observed directly after 72 h of TTFields application. The effect of TTFields on the BBB disappeared 96 h after end of treatment and no difference in contrast enhancement between controls and TTFields treated animals was detectable. CONCLUSION By altering BBB integrity and permeability, application of TTFields at 100 kHz may have the potential to deliver drugs to the brain, which are unable to cross the BBB. Utilizing TTFields to open the BBB and its subsequent recovery could be a clinical approach of drug delivery for treatment of brain tumors and other diseases of the central nervous system. These results will be further validated in clinical Trials.

Download Full-text

P11.28 Alteration of blood brain barrier (BBB) permeability by Tumor Treating Fields (TTFields) in vivo

Neuro-Oncology ◽

10.1093/neuonc/noz126.174 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii49-iii49

Author(s):

A F Keßler ◽

E Salvador ◽

D Domröse ◽

M Burek ◽

C Tempel Brami ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Dce Mri ◽

Tumor Treating Fields ◽

Blood Brain ◽

Vessel Structure ◽

Bbb Permeability ◽

The Brain

Abstract BACKGROUND Alternating electric fields with intermediate frequency (100 - 300 kHz) and low intensity (1 - 3 V/cm), known as Tumor Treating Fields (TTFields), have been established as a novel adjuvant therapy for glioblastoma (GBM) patients. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Due to this regulation, the BBB may block delivery of drugs for treatment of brain tumors, in particular GBM. In this study, we investigated the influence of TTFields on BBB permeability in vivo. MATERIAL AND METHODS For determination of BBB permeability, rats were treated with 100 kHz TTFields for 72 h. At the end of treatment, rats were i.v. injected with Evan′s Blue (EB), which binds Albumin (~70 kDa) upon injection to the blood. EB was extracted after brain homogenization and quantified at 610 nm. In addition, cryosections of rat brains were prepared following TTFields application at 100 kHz for 72 h, and sections were stained for Claudin 5, Occludin and immunoglobulin G (IgG) to assess vessel structure. Moreover, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent (Gd) was performed before and after TTFields application. RESULTS In vivo, the EB accumulation in the brain was significantly increased by application of TTFields to the rat head. Claudin 5 and Occludin staining was visible in vessel endothelial cells and localized at the cells’ edges in control cryosections of rat brains. In TTFields-treated rats, the vessel structure became diffuse; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue and not solely inside the vessels, as it is normally the case. Serial DCE-MRI demonstrated significantly increased accumulation of Gd in the brain, detected directly after 72 h of TTFields application. 96 h after end of TTFields treatment the effect on the BBB disappeared and no difference in contrast enhancement between controls and TTFields treated animals was observable. CONCLUSION Application of TTFields at 100 kHz could have the potential to deliver drugs to the brain, which normally are unable to cross the BBB by altering BBB integrity and permeability. Utilizing TTFields to open the BBB and its subsequent recovery, as demonstrated by the data presented herein, could lead to a clinical approach of drug delivery for treatment of malignant brain tumors and other diseases of the central nervous system. These results will be further validated in clinical trials.

Download Full-text

SURG-41. BLOOD-BRAIN BARRIER DISRUPTION WITH HIGH-FREQUENCY ELECTROPORATION IN VIVO: A PRELIMINARY INVESTIGATION DEMONSTRATING THE EFFECTS OF VARIED PULSE WIDTHS AND INTRA-PHASE DELAYS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.887 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii212-ii212

Author(s):

Melvin Lorenzo ◽

Sean Thomas ◽

Scott Verbridge ◽

John Robertson ◽

John Rossmeisl ◽

...

Keyword(s):

Blood Brain Barrier ◽

Electric Fields ◽

High Frequency ◽

Pulse Width ◽

Phase Delay ◽

Brain Barrier ◽

Blood Brain ◽

Contrast Enhanced ◽

The Brain

Abstract OBJECTIVE Treatment of CNS disorders suffer from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). High-frequency electroporation (HFE) employs a series of high voltage pulsed electric fields to disrupt the BBB and/or ablate tumor tissue while sparring proteinaceous structures. Pulsing parameters pulse width and intra-phase delay can be modulated to reduce excitation of muscle and nervous tissues, though this is inherently accompanied by an increase in thresholds for ablation in non-CNS tissues. Here, we investigate the effects of pulse width and intra-phase delay on intracranial tissue for BBB disruption (BBBD) in an in vivo healthy rodent model. METHODS 18 male Fisher rats underwent craniectomy procedure and two blunt tipped monopolar electrodes were advanced into the brain for HFE therapy. 200 bursts of HFE were delivered at a voltage-to-distance ratio 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye). RESULTS Gross pathological sections and contrast enhanced T1W scans demonstrated BBBD for 2-2-2 µs (n = 4, 36.6 ± 9.4 mm3, 36.7 ± 13.0 mm3), 2-5-2 µs (n = 4, 74.1 ± 7.7 mm3, 74.7 ± 9.8 mm3), 5-2-5 µs (n = 4, 53.9 ± 8.1 mm3, 59.2 ± 10.8 mm3), 5-5-5 µs (n = 4, 81.2 ± 7.9 mm3, 84.1 ± 8.7 mm3), and 10-1-10 µs (n = 2, 61.0 ± 2.8 mm3, 60.0 ± 4.2 mm3) HFE. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated the threshold for HFE-mediated BBBD as low magnitude electric fields (< 201 V/cm). These data suggest HFE-mediated BBBD is only modestly affected by changes in pulse width and intra-phase delay.

Download Full-text

WED 168 Blood-brain barrier imaging with dynamic contrast-enhanced mri

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-abn.76 ◽

2018 ◽

Vol 89 (10) ◽

pp. A21.2-A21

Author(s):

Varatharaj Aravinthan ◽

Liljeroth Maria ◽

Darekar Angela ◽

BW Larsson Henrik ◽

Galea Ian ◽

...

Keyword(s):

White Matter ◽

Blood Brain Barrier ◽

Cerebral Blood Volume ◽

Brain Barrier ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Normal Appearing White Matter ◽

Blood Brain ◽

Contrast Enhanced ◽

Bbb Permeability

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can detect subtle blood-brain barrier (BBB) permeability. We developed a protocol and conducted experiments to validate the technique.Methods12 subjects with relapsing-remitting multiple sclerosis (RRMS) and 13 controls were recruited. Whole-brain 3D DCE-MRI at 3 Tesla was used to calculate the influx constant Ki (Patlak method). Values were derived for manual regions of interest (ROI) as well as segmented tissue masks. In controls, cerebral blood volume (CBV) was measured in grey and white matter.ResultsIn RRMS, Ki in visibly-enhancing lesions was significantly higher than in normal-appearing white matter (NAWM) (p=0.002). Ki in NAWM was significantly higher in RRMS than controls, by both ROI (p=0.014) and segmentation (p=0.019) methods. In controls, Ki was significantly higher in grey than white matter (p=0.001). CBV (and therefore vascular surface area) was also significantly higher in grey matter (p=0.005), with a mean ratio of 1.9.ConclusionsOur method produces results in line with the expected behaviour of a BBB permeability marker, and the grey/white matter CBV ratio is in agreement with the histologically-established value.

Download Full-text