Development of quantitative imaging of the glymphatic system by positron emission tomography

Summary

Increasing evidence indicate disturbances of the glymphatic system, the recently discovered central nervous system waste clearance system, may be a critical factor in the aetiology of neurodegenerative disorders (1). This has driven a need for further investigation into the system.

Presently there are no sensitive/robust biomarkers to measure the glymphatic system in vivo. Currently studies of glymphatic function in human mostly use MRI with contrast agents. However, such approaches, are not sensitive to small changes brain barriers permeability nor uses kinetic models that allow accurate quantification of the essential parameterization of glymphatic function, 

Presently the only gold standard methods that can be used to quantify glymphatic function are limited to pre-clinical research on animals using ex-vivo approaches that consist of autoradiography of brain slices using [14C]labelled polysaccharides.

However, using the same polysaccharides, radiolabelled with positron-emitting radioisotopes  opens the ability to use them for in vivo positron-emitting tomography (PET) imaging in humans in addition to animal models. Therefore, for the first time undertake quantitative assessment of the glymphatic system in vivo. 

Critically a method for using the polysaccharide [18F]sorbitol can be readily developed in our laboratory . For this [18F]sorbitol has major advantages:  i) can be readily produced from the widely available radiotracer [18F]FDG; 2) its small molecular weight bestows good sensitivity to brain barriers permeability changes; and 3) has appropriate brain uptake and kinetic profile. 

Project aims

The aim of our project is to develop accurate quantitative PET methodology for the quantification of [18F]Sorbitol data in animals using previously tested compartmental models. Therefore, establishing a method that can then be translated to clinical research in patients. 

The project objectives will consist of :

• Developing the in-vivo [18F]sorbitol PET methodology for the quantitative assessment of glymphatic function by undertaking  radiochemistry, in vivo imaging  and  kinetic modelling.
• Testing  the sensitivity of the [18F]sorbitol PET method to changes in the glymphatic space caused by known pharmacological modulators.

References

1.   JJ Iliff et al., Sci Transl Med, vol. 4, p. 147ra111, 2012

Contact details

Professor Franklin Aigbirhio - fia20@medschl.cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD