scholarly journals Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease

2016 ◽  
Vol 37 (2) ◽  
pp. 644-656 ◽  
Author(s):  
Susana Muñoz Maniega ◽  
Francesca M Chappell ◽  
Maria C Valdés Hernández ◽  
Paul A Armitage ◽  
Stephen D Makin ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Mean Diffusivity ◽  
Signal Enhancement ◽  
Brain Barrier ◽  
Normal Appearing White Matter ◽  
Tissue Interactions ◽  
Blood Brain

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

scholarly journals Baseline Blood-Brain Barrier Leakage and Longitudinal Microstructural Tissue Damage in the Periphery of White Matter Hyperintensities

Neurology ◽  
2021 ◽  
Vol 96 (17) ◽  
pp. e2192-e2200
Author(s):  
Danielle Kerkhofs ◽  
Sau May Wong ◽  
Eleana Zhang ◽  
Julie Staals ◽  
Jacobus F.A. Jansen ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Blood Brain ◽  
Diffusion Technique ◽  
Bbb Permeability ◽  
Motion Imaging

ObjectiveTo investigate the 2-year change in parenchymal diffusivity, a quantitative marker of microstructural tissue condition, and the relationship with baseline blood-brain barrier (BBB) permeability, in tissue at risk, i.e., the perilesional zone surrounding white matter hyperintensities (WMH) in patients with cerebral small vessel disease (cSVD).MethodsPatients with sporadic cSVD (lacunar stroke or mild vascular cognitive impairment) underwent 3T MRI at baseline, including dynamic contrast-enhanced MRI to quantify BBB permeability (i.e., leakage volume and rate) and intravoxel incoherent motion imaging (IVIM), a diffusion technique that provides parenchymal diffusivity D. After 2 years, IVIM was repeated. We assessed the relation between BBB leakage measures at baseline and change in parenchymal diffusivity (∆D) over 2 years in the perilesional zones (divided in 2-mm contours) surrounding WMH.ResultsWe analyzed 43 patients (age 68 ± 12 years, 58% male). In the perilesional zones, ∆D increased 0.10% (confidence interval [CI] 0.07–0.013%) (p < 0.01) per 2 mm closer to the WMH. Furthermore, ∆D over 2 years showed a positive correlation with both baseline BBB leakage volume (r = 0.29 [CI 0.06–0.52], p = 0.013) and leakage rate (r = 0.24 [CI 0.02–0.47], p = 0.034).ConclusionBBB leakage at baseline is related to the 2-year change in parenchymal diffusivity in the perilesional zone of WMH. These results support the hypothesis that BBB impairment might play an early role in subsequent microstructural white matter degeneration as part of the pathophysiology of cSVD.

scholarly journals Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Imama Naqvi ◽  
Emi Hitomi ◽  
Richard Leigh
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Stroke ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Blood Brain ◽  
History Of ◽  
Iv Tpa

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.

The effects of blood–brain barrier disruption on glial cell function in multiple sclerosis

2009 ◽  
Vol 37 (1) ◽  
pp. 329-331 ◽  
Author(s):  
Stephen McQuaid ◽  
Paula Cunnea ◽  
Jill McMahon ◽  
Una Fitzgerald
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Cell Function ◽  
Brain Barrier ◽  
Blood Brain Barrier Disruption ◽  
Normal Appearing White Matter ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
Brain Barrier Disruption

Dysfunction of the BBB (blood–brain barrier) is a major hallmark of MS (multiple sclerosis). Studies in our laboratories over the last decade have shown that increased BBB permeability is associated with decreased expression of TJ (tight junction) proteins in brain capillary endothelial cells. Results have revealed that TJ abnormalities were most common in active lesions (42% of vessels affected), but were also present in inactive lesions (23%) and in MS normal-appearing white matter (13%). Importantly, TJ abnormality was also positively associated with leakage of the serum protein fibrinogen which has recently been shown to be an activator of microglia. TJ abnormality and the resultant vascular permeability in both lesional and non-lesional white matter may impair tissue homoeostasis, which may have effects on disease progression, repair mechanisms and drug delivery.

The Evolution of White Matter Hyperintensities

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 10 ◽  
Author(s):  
Vanessa G Young ◽  
Jillian J Kril ◽  
◽  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Elderly Subjects ◽  
Vascular Integrity ◽  
Blood Brain ◽  
Mri Scans ◽  
Mri Changes

White matter hyperintensities (WMHs) are a common finding on magnetic resonance imaging (MRI) scans of elderly subjects. Despite their frequency, the clinical correlates and etiology of WMH remain controversial, with many conflicting results published. This is due, in part, to the varied populations studied. Nevertheless, the prevailing opinion is that these lesions are of vascular origin due to the strong associations with vascular risk factors and stroke. Neuropathological studies have also yielded varied results. Interestingly, while a number of associations with variables such as demyelination and gliosis have been reported, no single pathological variable has been found to account for the MRI changes. The most consistent associations are with reduced vascular integrity and increased blood–brain barrier permeability. Further studies investigating the blood–brain barrier may assist in elucidating the origin of these common abnormalities.

scholarly journals Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease

Neurology ◽  
2019 ◽  
Vol 92 (15) ◽  
pp. e1669-e1677 ◽  
Author(s):  
Sau May Wong ◽  
Jacobus F.A. Jansen ◽  
C. Eleana Zhang ◽  
Erik I. Hoff ◽  
Julie Staals ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Brain Barrier ◽  
Small Vessel ◽  
Dynamic Susceptibility ◽  
Vessel Disease ◽  
Blood Brain ◽  
Bbb Permeability

ObjectiveTo investigate the link between blood-brain-barrier (BBB) permeability and cerebral blood flow (CBF) and the relation with white matter hyperintensities (WMH) in cerebral small vessel disease (cSVD).MethodsTwenty-seven patients with cSVD received dynamic susceptibility contrast and dynamic contrast-enhanced MRI to determine CBF and BBB permeability (expressed as leakage rate and volume), respectively. Structural MRI were segmented into normal-appearing white matter (NAWM) and WMH, for which a perilesional zone was defined. In these regions, we investigated the BBB permeability, CBF, and their relation using Pearson correlation r.ResultsWe found a decrease in CBF of 2.2 mL/min/100 g (p < 0.01) and an increase in leakage volume of 0.7% (p < 0.01) per mm closer to the WMH in the perilesional zones. Lower CBF values correlated with higher leakage measures in the NAWM and WMH (−0.53 < r < −0.40, p < 0.05). This relation was also observed in the perilesional zones, which became stronger in the proximity of WMH (p = 0.03).ConclusionBBB impairment and hypoperfusion appear in the WMH and NAWM, which increase in the proximity of the WMH, and are linked. Both BBB and CBF are regulated in the neurovascular unit (NVU) and the observed link might be due to the physiologic regulation mechanism of the NVU. This link may suggest an early overall deterioration of this unit.

Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study

2001 ◽  
Vol 7 (2) ◽  
pp. 75-82 ◽  
Author(s):  
N C Silver ◽  
P S Tofts ◽  
M R Symms ◽  
G J Barker ◽  
A J Thompson ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Resonance Imaging ◽  
Post Contrast ◽  
Time Points ◽  
Normal Appearing White Matter ◽  
Blood Brain

Gadolinium enhanced magnetic resonance imaging detects focal blood-brain barrier breakdown in new inflammatory multiple sclerosis lesions, but such lesions do not correlate with disease progression. To explore whether the latter might relate to subtle but widespread blood-brain barrier (BBB) breakdown with low grade inflammation mediating tissue damage, quantitative techniques were used to detect subtle gadolinium enhancement within otherwise normal-appearing white matter and within lesions not showing visible enhancement. T1-weighted imaging was performed prior to and at 5, 20 and 40 min following injection of 0.3 mmol/kg gadopentate dimeglumine in 33 patients with multiple sclerosis and five healthy control subjects. In healthy controls, a significant increase in white matter signal 5 min following contrast injection was observed (1.8%, P < 0.0005); the signal returned to baseline values by 20 min. In multiple sclerosis patients, a non-significant trend was noted for signal to remain elevated in normal-appearing white matter at the 20 and 40 min post-contrast time points; this was most apparent in primary progressive multiple sclerosis. Significant increases in signal intensity were noted at all time points post contrast in apparent non-enhancing lesions. The transient post contrast signal increase in controls is likely due to intravascular gadopentate dimeglumine. The persistent increases in signal intensity in non-enhancing lesions suggest more widespread abnormalities in BBB than is visually apparent, but substantiation of BBB leakage in normal appearing white matter will require further study using more sensitive methods.

scholarly journals Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Rikesh M. Rajani ◽  
Julien Ratelade ◽  
Valérie Domenga-Denier ◽  
Yoshiki Hase ◽  
Hannu Kalimo ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Brain Barrier ◽  
Perivascular Spaces ◽  
Pericyte Coverage ◽  
Blood Brain ◽  
Post Mortem Brain ◽  
Pericyte Loss

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.

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