The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer’s disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer’s disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer’s disease, and possibly other neurodegenerative diseases alike.

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 (Texwtrue), 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.

The glymphatics system describes a CSF-mediated clearance pathway for the removal of potentially harmful molecules, such as amyloid beta, from the brain. As such, its components may represent new therapeutic targets to alleviate aberrant protein accumulation that defines the most prevalent neurodegenerative conditions. Currently, however, the absence of any non-invasive measurement technique prohibits detailed understanding of glymphatic function in the human brain and in turn, it’s role in pathology. Here, we present the first non-invasive technique for the assessment of glymphatic inflow by using an ultra-long echo time, low b-value, multi-direction diffusion weighted MRI sequence to assess perivascular fluid movement (which represents a critical component of the glymphatic pathway) in the rat brain. This novel, quantitative and non-invasive approach may represent a valuable biomarker of CSF-mediated brain clearance, working towards the clinical need for reliable and early diagnostic indicators of neurodegenerative conditions such as Alzheimer’s disease.

The blood–cerebrospinal fluid barrier (BCSFB) is a highly dynamic transport interface that serves brain homeostasis. To date, however, understanding of its role in brain development and pathology has been hindered by the absence of a non-invasive technique for functional assessment. Here we describe a method for non-invasive measurement of BSCFB function by using tracer-free MRI to quantify rates of water delivery from arterial blood to ventricular cerebrospinal fluid. Using this method, we record a 36% decrease in BCSFB function in aged mice, compared to a 13% decrease in parenchymal blood flow, itself a leading candidate biomarker of early neurodegenerative processes. We then apply the method to explore the relationship between BCSFB function and ventricular morphology. Finally, we provide proof of application to the human brain. Our findings position the BCSFB as a promising new diagnostic and therapeutic target, the function of which can now be safely quantified using non-invasive MRI.

The blood-brain barrier (BBB) is a dynamic and regulatory interface that protects the brain parenchyma from deleterious infiltration. 1 Its composition includes endothelial cells, tight junction proteins, pericytes, and aquaporin-4 (AQP4) water channels that reside on astrocytic end feet. Dysfunction of the BBB is an early occurring

Chronic hypertension is a major risk factor for the development of neurodegenerative disease, yet the etiology of hypertension-driven neurodegeneration remains poorly understood. Forming a unique interface between the systemic circulation and the brain, the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP) has been proposed as a key site of vulnerability to hypertension that may initiate downstream neurodegenerative processes. However, our ability to understand BCSFB’s role in pathological processes has, to date, been restricted by a lack of non-invasive functional measurement techniques. In this work, we apply a novel Blood-Cerebrospinal Fluid Barrier Arterial Spin Labeling (BCSFB-ASL) Magnetic resonance imaging (MRI) approach with the aim of detecting possible derangement of BCSFB function in the Spontaneous Hypertensive Rat (SHR) model using a non-invasive, translational technique. SHRs displayed a 36% reduction in BCSFB-mediated labeled arterial water delivery into ventricular cerebrospinal fluid (CSF), relative to normotensive controls, indicative of down-regulated choroid plexus function. This was concomitant with additional changes in brain fluid biomarkers, namely ventriculomegaly and changes in CSF composition, as measured by T1 lengthening. However, cortical cerebral blood flow (CBF) measurements, an imaging biomarker of cerebrovascular health, revealed no measurable change between the groups. Here, we provide the first demonstration of BCSFB-ASL in the rat brain, enabling non-invasive assessment of BCSFB function in healthy and hypertensive rats. Our data highlights the potential for BCSFB-ASL to serve as a sensitive early biomarker for hypertension-driven neurodegeneration, in addition to investigating the mechanisms relating hypertension to neurodegenerative outcomes.

A technique for quantifying regional blood-brain barrier (BBB) water exchange rates using contrast-enhanced arterial spin labelling (CE-ASL) is presented and evaluated in simulations and in vivo. The two-compartment ASL model describes the water exchange rate from blood to tissue, kb, but to estimate kbin practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference in T1values. Here, a gadolinium-based contrast agent is used to increase this T1difference and enable the signal components to be disentangled. The optimal post-contrast blood T1(T1post) at 3 T was determined in a sensitivity analysis, and the accuracy and precision of the method quantified using Monte Carlo simulations. Proof-of-concept data were acquired in six healthy volunteers (five female, age range 24-46 years). The sensitivity analysis identified the optimal T1postat 3 T as 0.8 s. Simulations showed kbcould be estimated in individual cortical regions with a relative error ε < 1 % and coefficient of variation CoV = 30 %; however, a high dependence on blood T1was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit time tA= 1.15±0.49 s, cerebral blood flow f = 58.0±14.3 ml blood / min / 100 ml tissue, water exchange rate kb= 2.32±2.49 s-1. CE-ASL can provide regional BBB water exchange rate estimates; however, the clinical utility of the technique is dependent on the achievable accuracy of measured T1values.

Single beam Fourier transform digital holographic quantitative phase microscopy Appl. Phys. Lett.