Alzheimer's disease pathology is associated with earlier alterations to blood-brain barrier water permeability compared with healthy ageing in TgF344-AD rats - PubMed (original) (raw)

Comparative Study

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

Ben R Dickie et al. NMR Biomed. 2021 Jul.

Abstract

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 (PSw ) and gadolinium-based contrast agent (PSg ) were measured in grey matter using multiflip angle multiecho dynamic contrast-enhanced MRI. At 13 months of age, there was no significant difference in PSw between TgF344-AD and wild-types (p = 0.82). Between 13 and 18 months, PSw increased in TgF344-AD rats (p = 0.027), but not in wild-types (p = 0.99), leading to significantly higher PSw in TgF344-AD rats at 18 months, as previously reported (p = 0.012). Between 18 and 21 months, PSw 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 PSg (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.

Keywords: ageing, Alzheimer's disease, BBB breakdown, BBB dysfunction, BBB permeability, blood-brain barrier, MRI, TgF344-AD.

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Figures

FIGURE 1

Example superior sagittal sinus (SSS) vascular input function (VIF), regions of interest (ROIs) and model fits to MFAME‐DCE MRI data. (A) Example C b(t) estimate and the corresponding biexponential fit used to define the VIF from the SSS. The biexponential fit was used to infer blood contrast agent concentration during acquisition of multiflip angle data. The procedure of extracting a VIF was performed individually for each rat to capture interindividual variability in cardiac output, renal clearance and total blood volume. (B) Example segmentations of hippocampus, cortex, striatum and thalamus ROIs. These ROIs were combined to form a composite ROI for statistical analyses; (C) example two‐site water‐exchange model fits to multiflip angle data yielding estimates of PS w; and (D) example Patlak model fits to single flip angle data yielding estimates of PS g. SPGR, spoiled gradient echo

FIGURE 2

Correlation (A) and Bland–Altman (B) plots showing the agreement between regional scan‐rescan measurements of PS w and PS g . PS w and PS g had coefficient of determination values (R 2) of 0.82 (p < 10−12) and 0.96 (p < 10−16), respectively. Solid lines in the Bland‐Altman plots show the mean difference between scan 1 and scan 2. Dashed lines show the limits of agreement within which 95% of scan‐rescan differences lie. Hipp, hippocampus; Ctx, cortex; Stri, striatum; Thal, thalamus

FIGURE 3

Composite region of interest (ROI) estimates of the permeability surface area product of the blood–brain barrier (BBB) to water, PS w (A) and gadolinium‐based contrast agent, PS g (B) for TgF344‐AD and wild‐type (WT) rats aged 13, 18 and 21 months. Bar heights show the group means. Points correspond to measurements made in individual rats. Error bars denote standard error of the mean. *statistically significant pairwise comparisons from Tukey post hoc tests (p < 0.05)

FIGURE 4

Regional estimates of the permeability surface area product of the blood–brain barrier (BBB) to water, PS w (A) and gadolinium‐based contrast agent, PS g (B) for TgF344‐AD and wild‐type (WT) rats aged 13, 18 and 21 months. Bar heights show the group means. Points correspond to measurements made in individual rats. Error bars denote standard error of the mean. Ctx, cortex; Hipp, hippocampus; Stri, striatum; Thal, thalamus

FIGURE 5

Relationship between composite region of interest (ROI) estimates of PS w and PS g. Regression analysis was applied separately to 13‐, 18‐ and 21‐month data and did not reveal any significant trends between PS w and PS g (p > 0.05). The lack of relationship between PS w and PS g indicates that in the rat model and age groups studied, blood–brain barrier (BBB) water exchange and BBB leakage of gadoteric acid occur by different mechanisms

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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 - PubMed (original) (raw)