Immunohistochemical and Ultrastructural Findings Related to the Blood–Brain Barrier in the Blood Vessels of the Cerebral White Matter in Aged Dogs

Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH.

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PATH-04. THE BLOOD-BRAIN BARRIER IN DIFFUSE MIDLINE GLIOMA AND ITS IMPLICATIONS FOR DRUG DELIVERY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.686 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii164-ii164

Author(s):

Rianne Haumann ◽

Fatma El-Khouly ◽

Marjolein Breur ◽

Sophie Veldhuijzen van Zanten ◽

Gertjan Kaspers ◽

...

Keyword(s):

Drug Delivery ◽

Blood Vessels ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Vascular Density ◽

Zonula Occludens ◽

Blood Brain ◽

Zonula Occludens 1 ◽

End Stage ◽

Diffuse Midline Glioma

Abstract INTRODUCTION Chemotherapy has been unsuccessful for pediatric diffuse midline glioma (DMG) most likely due to an intact blood-brain barrier (BBB). However, the BBB has not been characterized in DMG and therefore its implications for drug delivery are unknown. In this study we characterized the BBB in DMG patients and compared this to healthy controls. METHODS End-stage DMG pontine samples (n=5) were obtained from the VUmc diffuse intrinsic pontine glioma (DIPG) autopsy study and age-matched healthy pontine samples (n=22) were obtained from the NIH NeuroBioBank. Tissues were stained for BBB markers claudin-5, zonula occludens-1, laminin, and PDGFRβ. Claudin-5 stains were used to determine vascular density and diameter. RESULTS In DMG, expression of claudin-5 was reduced and dislocated to the abluminal side of endothelial cells. In addition, the expression of zonula occludens-1 was reduced. The basement membrane protein laminin expression was reduced at the glia limitans in both pre-existent vessels and neovascular proliferation. PDGFRβ expression was not observed in DMG but was present in healthy pons. Furthermore, the number of blood vessels in DMG was significantly (P< 0.01) reduced (13.9 ± 11.8/mm2) compared to healthy pons (26.3 ± 14.2/mm2). Markedly, the number of small blood vessels (< 10µm) was significantly lower (P< 0.01) while larger blood vessels (> 10µm) were not significantly different (P= 0.223). The mean vascular diameter was larger for DMG 9.3 ± 9.9µm compared to 7.7 ± 9.0µm for healthy pons (P= 0.016). CONCLUSION Both the BBB and the vasculature are altered at end-stage DMG. The reduced vascular density might have implications for several drug delivery methods such as focused ultrasound and convection enhanced delivery that are being explored for the treatment of DMG. The functional effects of the structurally altered BBB remain unknown and further research is needed to evaluate the BBB integrity at end-stage DMG

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Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

NeuroImage Clinical ◽

10.1016/j.nicl.2013.12.001 ◽

2014 ◽

Vol 4 ◽

pp. 182-189 ◽

Cited By ~ 99

Author(s):

S.P. Cramer ◽

H. Simonsen ◽

J.L. Frederiksen ◽

E. Rostrup ◽

H.B.W. Larsson

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Normal Appearing White Matter ◽

Blood Brain ◽

Brain Barrier Permeability

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Blood-brain barrier breakdown in non-enhancing multiple sclerosis lesions detected by 7-Tesla MP2RAGE ΔT1 mapping

PLoS ONE ◽

10.1371/journal.pone.0249973 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249973

Author(s):

Seongjin Choi ◽

Margaret Spini ◽

Jun Hua ◽

Daniel M. Harrison

Keyword(s):

Multiple Sclerosis ◽

Relaxation Time ◽

White Matter ◽

Blood Brain Barrier ◽

White Matter Lesions ◽

Brain Barrier ◽

7 Tesla ◽

T1 Relaxation Time ◽

T1 Relaxation ◽

Blood Brain

Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a biomarker for disease severity and treatment effect in MS.

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Astrocyte plasticity ensures continued endfoot coverage of cerebral blood vessels and integrity of the blood brain barrier, with plasticity declining with normal aging

10.1242/prelights.30126 ◽

2021 ◽

Author(s):

Ranabir Chakraborty

Keyword(s):

Blood Vessels ◽

Blood Brain Barrier ◽

Normal Aging ◽

Brain Barrier ◽

Cerebral Blood Vessels ◽

Blood Brain

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Adverse effects of erenumab on cerebral proliferative angiopathy: A case report

Cephalalgia ◽

10.1177/0333102420950484 ◽

2020 ◽

pp. 033310242095048

Author(s):

Laura L Lehman ◽

Rebecca Bruccoleri ◽

Amy Danehy ◽

Julie Swanson ◽

Christine Mrakotsky ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

White Matter ◽

Magnetic Resonance ◽

Blood Brain Barrier ◽

Vascular Malformations ◽

Hippocampal Sclerosis ◽

White Matter Injury ◽

Brain Barrier ◽

Resonance Imaging ◽

Blood Brain

Background Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky. Case We describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits. Conclusion The evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.

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A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib – A drug intended for treatment of brain metastases in non-small cell lung cancer

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19843776 ◽

2019 ◽

Vol 40 (4) ◽

pp. 799-807 ◽

Cited By ~ 4

Author(s):

Andrea Varrone ◽

Katarina Varnäs ◽

Aurelija Jucaite ◽

Zsolt Cselényi ◽

Peter Johnström ◽

...

Keyword(s):

White Matter ◽

Brain Metastases ◽

Blood Brain Barrier ◽

Healthy Subjects ◽

Standardized Uptake Value ◽

Brain Barrier ◽

Pharmacokinetic Parameters ◽

Blood Brain ◽

Brain Exposure ◽

The Brain

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood–brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax (brain) (standardized uptake value), Tmax (brain) and AUC0–90 min brain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume ( VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0–90 min brain/blood ratio were 1.5 (range 1–1.8), 13 min (range 5–30 min), and 3.8 (range 3.3–4.1). Whole brain and white matter VT were 14 mL×cm−3 (range 11–18) and 7 mL×cm−3 (range 5–12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood–brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.

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Immunolocalization of Heat Shock Protein after Fluid Percussive Brain Injury and Relationship to Breakdown of the Blood-Brain Barrier

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.14 ◽

1993 ◽

Vol 13 (1) ◽

pp. 116-124 ◽

Cited By ~ 68

Author(s):

Hirokazu Tanno ◽

Russ P. Nockels ◽

Lawrence H. Pitts ◽

Linda J. Noble

Keyword(s):

Brain Injury ◽

Head Injury ◽

Blood Vessels ◽

Blood Brain Barrier ◽

Time Course ◽

Cortical Layer ◽

Brain Barrier ◽

Impact Site ◽

Blood Brain ◽

The Impact

We have previously developed a model of mild, lateral fluid percussive head injury in the rat and demonstrated that although this injury produced minimal hemorrhage, breakdown of the blood–brain barrier was a prominent feature. The relationship between posttraumatic blood–brain barrier disruption and cellular injury is unclear. In the present study we examined the distribution and time course of expression of the stress protein HSP72 after brain injury and compared these findings with the known pattern of breakdown of the blood–brain barrier after a similar injury. Rats were subjected to a lateral fluid percussive brain injury (4.8–5.2 atm, 20 ms) and killed at 1, 3, and 6 h and 1,3, and 7 days after injury. HSP72-like immunoreactivity was evaluated in sections of brain at the light-microscopic level. The earliest expression of HSP72 occurred at 3 h postinjury and was restricted to neurons and glia in the cortex surrounding a necrotic area at the impact site. By 6 h, light immunostaining was also noted in the pia-arachnoid adjacent to the impact site and in certain blood vessels that coursed through the area of necrosis. Maximal immunostaining was observed by 24 h postinjury, and was primarily associated with the cortex immediately adjacent to the region of necrosis at the impact site. This region consisted of darkly immunostained neurons, glia, and blood vessels. Immunostaining within the region of necrosis was restricted to blood vessels. HSP72-like immunoreactivity was also noted in a limited number of neurons and glia in other brain regions, including the parasagittal cortex, deep cortical layer VI, and CA3 in the posterior hippocampus. Immunoreactive cells in these areas were not apparent until 24 h postinjury. By 7 days postinjury, HSP72-like immunoreactivity was minimal or absent in these injured brains and notable cell loss was apparent only in the impact site. This study demonstrates an early and pronounced expression of HSP72 at the impact site and a more delayed and less prominent expression of this protein in other regions of the brain. These findings parallel the temporal and regional pattern of breakdown of the blood–brain barrier after a similar head injury.

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