Abstract
There is currently a lack of non-invasive tools to assess water transport in healthy and pathological brain tissue. Aquaporin-4 (AQP4) water channels are central to many water transport mechanisms, and emerging evidence also suggests that AQP4 plays a key role in amyloid-β (Aβ) clearance, possibly via the glymphatic system. Here, we present the first non-invasive technique sensitive to AQP4 channels polarised at the blood-brain interface (BBI). We apply a multiple echo time (multi-TE) arterial spin labelling (ASL) MRI technique to the mouse brain to assess BBI water permeability via calculation of the exchange time (Texw), the time for magnetically labelled intravascular water to exchange across the BBI. We observed a 31% increase in exchange time in AQP4-deficient (Aqp4−/−) mice (452 ± 90 ms) compared to their wild-type counterparts (343 ± 91 ms) (p = 0.01), demonstrating the sensitivity of the technique to the lack of AQP4 water channels. More established, quantitative MRI parameters: arterial transit time (δa), cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) detected no significant changes with the removal of AQP4. This clinically relevant tool may be crucial to better understand the role of AQP4 in water transport across the BBI, as well as clearance of proteins in neurodegenerative conditions such as Alzheimer's disease.
Highlights
Regulating brain water transport is vital to brain homeostasis and dysfunction is associated with several neurological conditions such as meningitis, traumatic brain injury and cerebral oedema (Papadopoulos and Verkman, 2005; Manley et al, 2000, 2004; Chen et al, 2016)
We have developed a non-invasive technique to assess blood-brain interface (BBI) permeability to water in the mouse brain, using multiple echo time arterial spin labelling (ASL)
Our results suggest that the technique is sensitive to the presence of AQP4, as a 31% reduction of the estimated rate of water flux across the BBI was detected in the absence of these water channels
Summary
Regulating brain water transport is vital to brain homeostasis and dysfunction is associated with several neurological conditions such as meningitis, traumatic brain injury and cerebral oedema (Papadopoulos and Verkman, 2005; Manley et al, 2000, 2004; Chen et al, 2016). Many of the methods for assessing the role of AQP4 in brain clearance pathways are highly invasive and not clinically applicable (Papadopoulos and Verkman, 2005; Iliff et al, 2012; Haj-Yasein et al, 2011); the development of non-invasive tools for the assessment of AQP4 expression/polarisation would be highly beneficial to advance our understanding of AQP4 mediated clearance of waste products and neurotoxic proteins from the brain. This may lead to new approaches for early diagnosis and effective therapeutic intervention in neurodegenerative diseases
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