Non-Invasive Imaging of Glymphatic Clearance: A Novel Strategy for the Early Diagnosis of Alzheimer's Disease

Lead Research Organisation: University College London
Department Name: Medicine


Alzheimer's disease is a devastating illness that causes severe memory loss. Despite the huge social, economic and emotional burden of the condition, there is currently no cure. The development of effective treatments is hindered by the difficulty of accurately identifying the early phase of the disease, years before symptoms become apparent.

Recent evidence has come to light of a previously unrecognised waste removal system that clears excess fluid and toxins from the brain. It is thought that impairment of this pathway, known as the glymphatic system, may be a critical causal factor in the development of Alzheimer's disease. However, currently this pathway cannot be measured in humans.

We will develop the first non-invasive methods to image the glymphatic system using MRI, enabling assessment in the human brain for the first time. The new techniques will be carefully assessed by: i) comparison to existing invasive methods that require the injection of imaging agents into the fluid that surrounds the brain, ii) imaging mouse models of impaired glymphatic clearance and comparison with healthy mice.

Taken together, this proposal may lead to a new method for early detection of Alzheimer's disease and identify a new target for effective treatment.

Planned Impact

The work set out in this proposal has the potential to provide a breakthrough in the early diagnosis of AD. The successful development of the technology may lead to widespread clinical application for patient stratification in the early stages of AD pathogenesis. The ability to accurately identify patients at risk of developing AD may markedly increase the efficacy of emerging treatments to delay or prevent clinical symptoms. By developing a new diagnostic tool using novel MRI sequences, we will help alleviate the burden of this oppressive and prevalent condition within society.

Benefit to the patient: Despite the medical care costs of Alzheimer's disease equalling that of cancer and heart disease combined in the UK, there is currently no cure. There is a clear consensus from the AD research community, however, that if upstream disease processes can be accurately identified, then early interventional treatments may delay or prevent clinical symptoms. A successful clinical strategy for the early diagnosis and treatment of AD would have a hugely beneficial impact on patients by lessening the devastating symptoms (memory loss, cognitive impairment) associated with later stages of disease, which is ultimately fatal.

Benefit to Industry: The successful development and validation of the novel, non-invasive and translatable techniques to assess glymphatic function, may each represent a patentable technology. At the earliest opportunity we will seek to protect the intellectual property that will arise during the course of this program of work in conjunction with UCL and the EPSRC. The successful clinical translation of the MRI techniques for the accurate early staging of AD would then represent a highly valuable technology for hospitals and their industrial partners (e.g Siemens, Philips, GE) around the world. In addition, accurate staging of the disease for patient stratification would provide crucial information for pharmaceutical companies in the drive to uncover effective treatments for the condition, where the efficacy of new drugs may be highly dependent on the time-point of therapeutic intervention within the AD cascade.

Awareness of the public: Industry-academic partnerships in imaging in neurodegenerative disease will increase in the coming years, and public understanding and support will be needed to maximise chances of success. We believe it is vital that scientific breakthrough is communicated to the general public and that the dissemination of these complex ideas is done in a non-reductive, yet accessible way. CABI has led several high profile public engagement programs in recent years including Imaging at the Royal Society and at the Cheltenham Science festival. We will continue to prioritise approaches to improve the public perception of the value of the novel technologies to be developed in this proposal for improved AD diagnosis and successful treatment development.

Collaboration and Capability: This is a collaborative proposal between the UCL Centre for Advanced Biomedical Imaging (Mark Lythgoe), the UCL Centre for Neurodegenerative disease (Elizabeth Fisher), Michael O'Neill (Head of Molecular Pathology, Eli Lilly) and the Leonard Wolfson Experimental Neurology Centre (David Thomas, Nick Fox). This will strengthen existing ties between the centres and provide a translational platform for the new technologies, developed in this proposal.


10 25 50
Description Understanding of the molecular underpinnings of the glymphatic system
Exploitation Route Targeting the the glymphatic system as both a biomarker of neurological disorders such as Alzheimer's disease, and for possible future treatment strategies for such disorders.
Sectors Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

Description Eli Lilly 
Organisation Eli Lilly & Company Ltd
Country United Kingdom 
Sector Private 
PI Contribution Our partners at Eli Lilly work within the Neurodegenerative Diseases Drug Hunting Team at Eli Lilly in the UK, and Tailored Therapeutics at Eli Lilly in the USA. The collaboration was originally established in order to develop and implement non-invasive in vivo biomarkers of neurodegeneration, to characterise the rTg4510 mouse model of tauopathy, with the intention of expanding the project to assess the efficacy of novel tau-targeting therapeutics. Since starting the collaboration, we have developed non-invasive in vivo magnetic resonance imaging (MRI) biomarkers to characterize the rTg4510 mouse model of tauopathy. These biomarkers were selected as they may show sensitivity to different pathological processes in this model, including cerebral blood flow, protein accumulation and microstructural changes. We conducted a single timepoint study, where the sensitivity of these biomarkers was initially assessed in an aged cohort of rTg4510 animals and wildtype controls. In addition, we have conducted two longitudinal studies to monitor the neurodegenerative process over time. Within these longitudinal studies, we administered doxycycline to a subset of rTg4510 animals to effectively 'halt' the pathological process. We were then able to assess the sensitivity of our biomarkers not only to early pathology in these animals, but to therapeutic intervention. We continue our collaboration with Eli Lilly who provide their expertise and knowledge regarding the rTg4510 mouse model and interpretation of the results we have acquired. In addition, since the rTg4510 transgenic mouse is licences by Eli Lilly and company, they provide us with research animals and histological services.
Collaborator Contribution Our partners at Eli Lilly have provided their expertise and knowledge regarding the rTg4510 mouse model and interpretation of the results we have acquired. They have provided the candidate drugs for therapeutic assessment with our imaging biomarkers. In addition, they have processed the brain tissues which were harvested from the animals after the experiment was completed, for immunohistochemistry.
Impact We have published the following peer reviewed journal articles: [1] Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy [2] In Vivo Imaging of Tau Pathology Using Magnetic Resonance Imaging Textural Analysis [3] Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease [4] Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease [5] Imaging the accumulation and suppression of tau pathology using multiparametric MRI [6] In vivo imaging of tau pathology using multi-parametric quantitative MRI [7] Increased cerebral vascular reactivity in the tau expressing rTg4510 mouse: evidence against the role of tau pathology to impair vascular health in Alzheimer's disease
Start Year 2011
Description Elizabeth Fisher 
Organisation University College London
Department Department of Neurodegenerative Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration was established in order to investigate the role of chromosome 21 genes in the development of Alzheimer's disease. Our collaborators at the UCL Institute of Neurology have developed a novel mouse model of neurodegeneration which they were keen to characterize using non-invasive in vivo imaging. We applied MRI techniques to investigate phenotypic alterations in this mouse.
Collaborator Contribution Our collaborators at the Institute of Neurology have brought their expertise in mouse models of neurodegeneration, providing key advice on the interpretation of the MRI data and its importance in the context of Alzheimer's disease research. In addition, they have conducted histology to validate the MRI findings.
Impact Histology is still underway to investigate the MRI findings. This data has resulted in several successful conference abstracts, notably an oral presentation at the International Society of Magnetic Resonance in Medicine annual meeting in Milan in 2014.
Start Year 2012
Description Cheltenham Science Festival - Brain Wash LIVE - 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interactive live demonstration of the glymphatic system - 1 hour program item
Year(s) Of Engagement Activity 2017
Description Cheltenham Science Festival 2018 - Your Unbelievable Brain: Wine, Sleep And Exercise 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Evening lecture at Cheltenham Science festival exploring the way in which the glymphatic system works in the brain, and how we can harness its power to develop possible treatments for Alzheimer's disease.

Is it possible to cleanse your brain with alcohol, detoxify the mind with sleep or even run the blues away? Faced with the discovery of a revolutionary new brain pathway, the glymphatic system, neuroscientists Mark Lythgoe, Jack Wells and Ian Harrison look at the impact this has on how we look after our minds and whether this is a game-changer for the discovery of new medicines.
Year(s) Of Engagement Activity 2018