White matter hyperintensities mediate the association between blood-brain barrier leakage and information processing speed

Freeze, Whitney M.; Jacobs, Heidi I.L.; Jong, Joost J. de; Verheggen, Inge C.M.; Gronenschild, E. H. B. M.; Palm, Walter M.; Hoff, Erik I.; Wardlaw, Joanna M.; Jansen, Jacobus F.A.; Verhey, Frans R.J.; Backes, Walter H.

doi:10.1016/j.neurobiolaging.2019.09.017

Cited by 53 publications

(52 citation statements)

References 57 publications

(83 reference statements)

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“…Burns have been shown to induce cognitive impairment and abnormal behavior (4,(8)(9)(10)(11)(12). Given the fact that BBB dysfunction is the key factor in cognitive impairment (50)(51)(52)(53)(54)(55)(56)(57) and that MSCs can effectively improve the integrity of BBB, we investigated whether burns could induce BBB dysfunction and neuroinflammation as well as evaluated its potential mechanism and the best time point for intervention to improve these effects after burn.…”

Section: Discussionmentioning

confidence: 99%

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Yang

Zhang

et al. 2020

Front. Immunol.

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Neurological syndromes are observed in numerous patients who suffer burns, which add to the economic burden of societies and families. Recent studies have implied that bloodbrain barrier (BBB) dysfunction is the key factor that induces these central nervous system (CNS) syndromes in peripheral traumatic disease, e.g., surgery and burns. However, the effect of burns on BBB and the underlying mechanism remains, largely, to be determined. The present study aimed to investigate the effect of burns on BBB and the potential of umbilical cord-derived mesenchymal stem cells (UC-MSCs), which have strong antiinflammatory and repairing ability, to protect the integrity of BBB. BBB permeability was evaluated using dextran tracer (immunohistochemistry imaging and spectrophotometric quantification) and western blot, interleukin (IL)-6, and IL-1b levels in blood and brain were measured by enzyme-linked immunosorbent assay. Furthermore, transmission electron microscopy (TEM) was used to detect transcellular vesicular transport (transcytosis) in BBB. We found that burns increased mouse BBB permeability to both 10-kDa and 70-kDa dextran. IL-6 and IL-1b levels increased in peripheral blood and CNS after burns. In addition, burns decreased the level of tight junction proteins (TJs), including claudin-5, occludin, and ZO-1, which indicated increased BBB permeability due to paracellular pathway. Moreover, increased vesicular density after burns suggested increased transcytosis in brain microvascular endothelial cells. Finally, administering UC-MSCs at 1 h after burns effectively reversed these adverse effects and protected the integrity of BBB. These results suggest that burns increase BBB permeability through both paracellular pathway and transcytosis, the potential mechanism of which might be through increasing IL-6 and IL-1b levels and decreasing Mfsd2a level, and appropriate treatment with UC-MSCs can reverse these effects and protect the integrity of BBB after burns.

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Section: Discussionmentioning

confidence: 99%

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Yang

Zhang

et al. 2020

Front. Immunol.

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“…We assume that microstructural brain damage subsequent to increased BBB permeability leads to cognitive decline. However, cross-sectional studies investigating this association are sparse and have yielded inconsistent results [9,13].…”

Section: Introductionmentioning

confidence: 99%

Blood–brain barrier leakage at baseline and cognitive decline in cerebral small vessel disease: a 2-year follow-up study

et al. 2021

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Blood–brain barrier (BBB) dysfunction is one of the pathophysiological mechanisms in cerebral small vessel disease (SVD). Previously, it was shown that BBB leakage volume is larger in patients with SVD compared with controls. In this study, we investigated the link between BBB leakage and cognitive decline over 2 years in patients with cSVD. At baseline, 51 patients with clinically overt cSVD (lacunar stroke or mild vascular cognitive impairment) received a dynamic contrast-enhanced MRI scan to quantify BBB permeability in the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical grey matter (CGM), and deep grey matter (DGM). Cognitive function in the domain executive function, information processing speed, and memory was measured in all patients at baseline and after 2 years. The association between baseline BBB leakage and cognitive decline over 2 years was determined with multivariable linear regression analysis, corrected for age, sex, educational level, baseline WMH volume, and baseline brain volume. Regression analyses showed that higher baseline leakage volume and rate in the NAWM and CGM were significantly associated with increased overall cognitive decline. Furthermore, higher baseline leakage volume in the NAWM and CGM, and higher baseline leakage rate in the CGM were significantly associated with increased decline in executive function. This longitudinal study showed that higher BBB leakage at baseline is associated with stronger cognitive decline, specifically in executive function, over 2 years of follow-up in patients with cSVD. These results emphasize the key role of BBB disruption in the pathophysiology and clinical progression of cSVD.

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“…As the APOE4 allele greatly increases the risk of a neurodegenerative disorder, especially AD [40], this indicates that BBB disruption in the hippocampus might be more involved in pathological ageing and might explain why the current study, focusing on successful ageing, obtained a different result. However, another previous study, not only investigating normal controls but also individuals with mild cognitive impairment and AD, found no significant relation between BBB disruption in the hippocampus and cognitive performance [73]. The authors suggest that, at a later stage of neurodegeneration, the effect of microvascular damage on cognitive performance might be negligible compared to the effect of neurodegenerative processes.…”

Section: Discussionmentioning

confidence: 75%

Imaging the role of blood–brain barrier disruption in normal cognitive ageing

et al. 2020

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To investigate whether blood–brain barrier (BBB) disruption is a potential mechanism of usual age-related cognitive decline, we conducted dynamic contrast–enhanced (DCE) MRI to measure BBB leakage in a healthy sample, and investigated the association with longitudinal cognitive decline. In a sample of neurologically and cognitively healthy, older individuals, BBB leakage rate in the white and grey matter and hippocampus was measured using DCE MRI with pharmacokinetic modelling. Regression analysis was performed to investigate whether the leakage rate was associated with decline in cognitive performance (memory encoding, memory retrieval, executive functioning and processing speed) over 12 years. White and grey matter BBB leakages were significantly associated with decline in memory retrieval. No significant relations were found between hippocampal BBB leakage and cognitive performance. BBB disruption already being associated with usual cognitive ageing, supports that this neurovascular alteration is a possible explanation for the cognitive decline inherent to the ageing process. More insight into BBB leakage during the normal ageing process could improve estimation and interpretation of leakage rate in pathological conditions. The current results might also stimulate the search for strategies to maintain BBB integrity and help increase the proportion people experiencing successful ageing. Netherlands Trial Register number: NL6358, date of registration: 2017-03-24.

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White matter hyperintensities mediate the association between blood-brain barrier leakage and information processing speed

Cited by 53 publications

References 57 publications

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Blood–brain barrier leakage at baseline and cognitive decline in cerebral small vessel disease: a 2-year follow-up study

Imaging the role of blood–brain barrier disruption in normal cognitive ageing

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