Increased blood–brain barrier permeability to water in the aging brain detected using noninvasive multi‐TE ASL MRI

Ohene, Yolanda; Harrison, Ian F.; Evans, Phoebe; Thomas, David L.; Lythgoe, Mark F.; Wells, Jack A.

doi:10.1002/mrm.28496

Cited by 21 publications

(30 citation statements)

References 37 publications

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“…Unfortunately, other factors affecting BBB integrity such as tight junction expression were not assessed, making it difficult to interpret the underlying cause of increased water permeability. Furthermore, the changes in PS w observed in our study are much larger than in the study by Ohene et al 31 (113% between 13 and 21 months vs. 32% between 7 and 27 months). The reason for this difference is not clear but may be due to differences in water exchange between species, or it could reflect differences in the MRI method used to quantify water exchange.…”

Section: Discussioncontrasting

confidence: 79%

“…Our results of increased PS w with age agree with a recent multi-TE ASL MRI study conducted by Ohene et al in young and old C57B1/6JRj mice. 31 Age-related reductions in the water-exchange time (increases in the water-exchange rate) were accompanied by an increase in aquaporin-4 mRNA expression but a decrease in α-synotrophin mRNA, a protein responsible for anchoring aquaporin-4 to astrocyte end feet. Unfortunately, other factors affecting BBB integrity such as tight junction expression were not assessed, making it difficult to interpret the underlying cause of increased water permeability.…”

Section: Discussionmentioning

confidence: 99%

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Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

et al. 2021

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The effects of Alzheimer's disease (AD) and ageing on blood-brain barrier (BBB) breakdown are investigated in TgF344-AD and wild-type rats aged 13, 18 and 21 months. Permeability surface area products of the BBB to water (PS w ) and gadolinium-based contrast agent (PS g ) were measured in grey matter using multiflip angle multiecho dynamic contrast-enhanced MRI. At 13 months of age, there was no significant difference in PS w between TgF344-AD and wild-types (p = 0.82). Between 13 and 18 months, PS w increased in TgF344-AD rats (p = 0.027), but not in wildtypes (p = 0.99), leading to significantly higher PS w in TgF344-AD rats at 18 months, as previously reported (p = 0.012). Between 18 and 21 months, PS w values increased in wild-types (p = 0.050), but not in TgF344-AD rats (p = 0.50). These results indicate that BBB water permeability is affected by both AD pathology and ageing, but that changes occur earlier in the presence of AD pathology. There were no significant genotype or ageing effects on PS g (p > 0.05). In conclusion, we detected increases in BBB water permeability with age in TgF344-AD and wild-type rats, and found that changes occurred at an earlier age in rats with AD pathology.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

et al. 2021

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“…The increased BBB permeability to water may also represent the dysregulation of the aquaporin‐4 (AQP4) channels on the astrocyte endfeet 56 . Both increased AQP4 expression and reduction of AQP4 polarization have been reported in aging and AD, which may have different effects on the water permeability 12,57,58 . Future studies are needed to further understand the specific role of AQP4 in BBB dysfunction in dementia.…”

Section: Discussionmentioning

confidence: 99%

Blood–Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease

Lin

Sur

Liu

et al. 2021

Annals of Neurology

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Objective: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. Methods: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined. Results: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. Interpretation: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance.

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“…In the context of pathological alterations in BBB permeability, it was reported that BBB permeability to water can change by 28.2% in diabetes, 13 19.5% in hypercholesterolemia, 13 31.0% in multiple sclerosis, 34 and 93.8% in brain tumor 34 . It has also been reported that BBB permeability to water could increase by 32% in aging mice 60 and 50% to 100% in rat models of Alzheimer disease 33 . Thus, the reliability of the WEPCAST measure is expected to be sufficient for detection of the BBB abnormalities in diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, WEPCAST MRI is a global technique but does not provide regional information of BBB permeability in the present implementation. Therefore, compared to regional BBB techniques proposed in the literature, 13,[24][25][26]28,29,33,60 this method may not be sensitive to diseases that only affect a small region of the brain such as brain tumor or that detect early focal changes occurring in small structures such as hippocampus in early Alzheimer disease. Future studies shall focus on the measurement of WEPCAST signal in smaller draining veins such as internal cerebral veins and straight sinus, which may provide region-specific information of BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

Noncontrast assessment of blood–brain barrier permeability to water: Shorter acquisition, test–retest reproducibility, and comparison with contrast‐based method

Lin

Jiang

Liu

et al. 2021

Magnetic Resonance in Med

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Purpose: Assessment of the blood-brain barrier (BBB) permeability without the need for contrast agent is desirable, and the ability to measure the permeability to small molecules such as water may further increase the sensitivity in detecting diseases. This study proposed a time-efficient, noncontrast method to measure BBB permeability to water, evaluated its test-retest reproducibility, and compared it with a contrast agent-based method. Methods: A single-delay water extraction with phase-contrast arterial spin tagging (WEPCAST) method was devised in which spatial profile of the signal along the superior sagittal sinus was used to estimate bolus arrival time, and the WEPCAST signal at the corresponding location was used to compute water extraction fraction, which was combined with global cerebral blood flow to estimate BBB permeability surface area product to water. The reliability of WEPCAST sequence was examined in terms of intrasession, intersession, and inter-vendor (Philips [Ingenia, Best, the Netherlands] and Siemens [Prisma, Erlangen, Germany]) reproducibility. Finally, we compared this new technique to a contrast agent-based method. Results: Single-delay WEPCAST reduced the scan duration from approximately 20 min to 5 min. Extract fraction values estimated from single-delay WEPCAST showed good consistency with the multi-delay method (R = 0.82, P = .004). Group-averaged permeability surface area product values were found to be 137.5 ± 9.3 mL/100 g/min. Intrasession, intersession, and inter-vendor coefficient of variation of the permeability surface area product values were 6.6 ± 4.5%, 6.9 ± 3.7%, and 8.9 ± 3.0%, respectively. Finally, permeability surface area product obtained from WEPCAST MRI showed a significant correlation with that from the contrast-based method (R = .73, P = .02).

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Increased blood–brain barrier permeability to water in the aging brain detected using noninvasive multi‐TE ASL MRI

Cited by 21 publications

References 37 publications

Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

Blood–Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease

Noncontrast assessment of blood–brain barrier permeability to water: Shorter acquisition, test–retest reproducibility, and comparison with contrast‐based method

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