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Abnormal Blood-Brain Barrier Water Permeability in Major Depressive Disorder1Biomedical Engineering, Stony Brook University, Stony Brook, NY, United States, 2Radiology, Stony Brook University, Stony Brook, NY, United States, 3Psychology, Stony Brook University, Stony Brook, NY, United States, 4Psychiatry, Stony Brook University, Stony Brook, NY, United States
Synopsis
Blood-brain barrier (BBB) disruption may be the key mechanism leading to neuronal dysfunction and neuroinflammation in major depressive disorder (MDD). Active pathways account for a large portion of trans-membrane water exchange, providing a link between BBB water permeability and metabolism. In this study alterations in BBB water permeability parameters, water extraction fraction (Ew) and water permeability surface area product (PSw), in patients with MDD were investigated using the recently developed Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) technique. Compared to healthy subjects, MDD patients exhibited significantly lower PSw and Ew with no differences in cerebral blood flow.
Introduction
Major depressive disorder (MDD) is the most prevalent and disabling form of depression and affects ~121 million people worldwide1. The mechanisms underlying the development and progression of MDD are only partially known. A recent study in postmortem subjects has demonstrated that the blood-brain barrier (BBB) disruption may be the key mechanism leading to neuronal dysfunction in MDD and other psychiatric disorders2-6. Because trans-capillary water exchange is mainly facilitated by active transport mechanisms7-9, assessing BBB water permeability parameters, water extraction fraction (Ew) and water permeability surface area product (PSw), could provide a direct and sensitive assessment of subtle BBB disruption. In this study we investigate differences in BBB water permeability between patients with MDD and healthy subjects using the recently developed Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) technique10,11.Methods
Fourteen healthy subjects and fourteen MDD patients were recruited with IRB approval and informed consent. Depression symptom severity was assessed with the Beck’s Depression Index (see Table 1 for study population demographics). All studies were performed on a Siemens 3T Prisma MRI with 64-channel head/neck coil. In the IDEALS paradigm, intravascular and extravascular water in an arterial spin labeling (ASL) experiment are separated by their different diffusion sensitivities at two segmentation factors in 3D-GRASE acquisition12. The MRI parameters were: TR/TE/Label Time 4500/16.12/1600 ms, FA=120°, matrix of 64×64×32, FOV of 256×256×128 mm3, iPAT2. Two segmentation schemes (4PAR×2PE and 1PAR×2PE) and two post labeling delays (PLDs) (1000 and 2000 ms) were used for a total of 4 sets of ASL images with total acquisition time ~15 min. The arterial transit time (ATT) was estimated from the 1000 ms PLD data. CBF, Ew, and PSw were subsequently estimated from the 2000 ms PLD data. High resolution MPRAGE images were acquired for segmentation of gray matter (GM) and white matter (WM), and spatial normalization. Four regions of interest (ROIs) implicated in MDD were evaluated: anterior cingulate cortex (ACC), amygdala, dorsolateral prefrontal cortex (DLPFC), and hippocampus. Analysis of covariance (ANCOVA) was used to evaluate group differences between BBB water permeability parameters within the 4 ROIs while controlling for age and gender; p < 0.05 was considered significant.Results
Figure 1 displays the group averaged IDEALS parameter maps. Without correcting for age and gender differences, MDD patients showed lower global GM PSw (82.7 ± 17.4 vs 108.0 ± 26.0 mL/100g/min), Ew (77.7% ± 2.3% vs 81.4% ± 4.3%), and CBF (56.3 ± 13.2 vs 64.0 ± 15.3 mL/100g/min) compared to healthy subjects. Box plots with individual data points for PSw, Ew, and CBF within ROIs are shown in Figure 2. Figure 3 displays the mean values after adjusting for age and gender. No significant differences in CBF between healthy subjects and MDD patients were. Significantly lower Ew was observed in the amygdala, ACC, DLPFC, and hippocampus of MDD patients compared to healthy subjects. Significantly lower PSw was observed in the amygdala and hippocampus of MDD patients compared to healthy subjects.pared to healthy subjects.Discussion
We observed significantly lower BBB water permeability in GM regions implicated in MDD. Although CBF, Ew, and PSw are intimately liked, as described by the Renkin-Crone equation13,14 (PSw = -CBF×log[1-Ew]), we did not observe any significant differences in CBF between MDD patients and healthy subjects. Therefore, the observed differences in PSw were driven by changes in Ew, demonstrating that the IDEALS approach is sensitive to BBB disruption and provides complementary information to CBF. With active trans-membrane water cycling pathways, such as NaK-ATPase, accounting for a large fraction of water exchange15,16, the lower BBB water permeability observed in MDD patients suggests BBB disruption and cerebral metabolic deficits17.Conclusion
Significantly lower BBB PSw was observed in the amygdala and hippocampus of MDD patients compared to healthy subjects. These differences were driven by lower Ew with no significant differences observed for CBF.Acknowledgements
No acknowledgement found.References
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