Developing novel non-invasive MRI techniques to assess cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange

The pathological cascade of events in Alzheimer’s disease (AD) is initiated decades prior to the onset of symptoms. Despite intensive research, the relative time-course/interaction of these events is yet to be determined. Recent evidence suggests that impairments to brain clearance (facilitated by the compartmental exchange of cerebrospinal-fluid (CSF) with interstitial-fluid (ISF)), contributes to the build-up of amyloid and tau (AD hallmarks). Therefore, abnormalities in CSF-ISF exchange dynamics, may represent an early driver of downstream events. Clinical evaluation of this hypothesis is hampered due to the lack of non-invasive CSF-ISF exchange assessment techniques. In this thesis, the primary aim was to develop a physiologically relevant, non-invasive CSF-ISF exchange assessment technique that would circumvent the limitations associated with current procedures (primarily their invasiveness). Towards this goal, animal studies were conducted to investigate the feasibility of a contrast enhanced-magnetic resonance imaging (CE-MRI) approach as a potential non-invasive CSF-ISF exchange imaging technique. Another aim of this thesis was to investigate whether the proposed MRI platform could detect abnormalities in CSF-ISF exchange, a condition hypothesised to occur in the early stages of AD. As such, pharmacological intervention studies were conducted to alter CSF-ISF exchange dynamics. CE-MRI, in conjunction with high-level image post-processing, demonstrated high sensitivity to physiological CSF-ISF exchange. This novel, non-invasive platform, captured dynamic, whole-brain infiltration of contrast agent from the blood to the CSF and into the parenchyma, via a pathway named ‘VEntricular-Cerebral TranspORt (VECTOR)’. Additionally, the platform detected significant abnormalities in CSF-ISF exchange following pharmacological intervention, demonstrating the potential of VECTOR in the study of the parenchymal accumulation of aberrant proteins. Development of this platform is a breakthrough step towards the clinical assessment of CSF-ISF exchange abnormalities to study its role in disease onset/progression, an approach that may inform understanding of the causal sequence of pathological events that occurs in AD development

All data from study in achieved folder.

Data from each subject (rat) saved as individual nifti file. part 1: multi_direction_diffusion_weighted (MDDW, n=10); part 2: diffusion tensor imaging (DTI, n=6); part 3: ECG gated (n=5); part 4: dobutamine (n=6). For the ECG data (part 3) the imaging data is saved as a 4D array with the 4th dimension equal to 2. The first element corresponds to the 36ms delay to the r wave (i.e arterial pulsation) and the second element corresponds to the 116ms delay (i.e diastole). For the dobutamine data (part 4), the data is also saved as a 4D array with the same dimensions. The first element of the 4th dimension corresponds to the baseline measurement and the second element corresponds to the measurement after dobutamine (rats 1-3) or saline vechicle (rats 4-6)

Data from: Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with DTI MRI

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

Non-invasive MRI of brain clearance pathways using multiple echo time arterial spin labelling: an aquaporin-4 study

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 ( 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

Impaired glymphatic function and clearance of tau in an Alzheimer's disease model

Abstract 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