Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

Schubert, J. J.; Veronese, M.; Marchitelli, L.; Bodini, B.; Tonietto, M.; Stankoff, B.; Brooks, D. J.; Bertoldo, A.; Edison, P.; Turkheimer, F. E.

doi:10.1101/493734

bioRxiv · 10.1101/493734

Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

Schubert, J. J.·Veronese, M.·Marchitelli, L.·Bodini, B.·Tonietto, M.·Stankoff, B.·Brooks, D. J.·Bertoldo, A.·Edison, P.·Turkheimer, F. E.

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Abstract

Cerebrospinal fluid (CSF) plays an important role in the clearance of solutes and maintenance of brain homeostasis. 11C-PiB PET was recently proposed as a tool for detection of CSF clearance alterations in Alzheimers disease. The current study seeks to investigate the magnitude of 11C-PiB PET signal in the lateral ventricles of an independent group of Alzheimers and mild cognitive impairment subjects. We have also evaluated multiple sclerosis as a model of disease with CSF clearance alterations without amyloid-beta tissue accumulation.\n\nMethodsA set of Alzheimers and mild cognitive impairment subjects and a set of multiple sclerosis subjects with matched healthy controls underwent MRI and dynamic 11C-PiB PET. Manual lateral ventricle regions of interest were generated from MRI data. PET data was analysed using a simplified reference tissue model with cerebellum or a supervised reference region, for the Alzheimers and multiple sclerosis datasets, respectively. Magnitude of 11C-PiB signal in the lateral ventricles was calculated as area under curve from 35 to 80 minutes and standard uptake value ratio (SUVR) from 50 to 70 minutes. Compartmental modelling analysis was performed on a separate dataset containing Alzheimers and matched healthy control data with an arterial input function to further understand the kinetics of the lateral ventricular 11C-PiB signal.\n\nResultsAnalysis of variance revealed significant group differences in lateral ventricular SUVR across the Alzheimers, mild cognitive impairment, and healthy control groups (p=0.004). Additional pairwise comparisons revealed significantly lower lateral ventricular SUVR in Alzheimers compared to healthy controls (p<0.001) and mild cognitive impairment (p=0.029). Lateral ventricular SUVR was also significantly lower in multiple sclerosis compared to healthy controls (p=0.008). Compartmental modelling analysis revealed significantly lower uptake rates of 11C-PiB signal from blood (p=0.005) and brain tissue (p=0.004) to the lateral ventricles in Alzheimers compared to healthy controls. This analysis also revealed significantly lower clearance of 11C-PiB signal out of the lateral ventricles in Alzheimers compared to healthy controls (p=0.002).\n\nConclusionOverall, these results indicate that dynamic 11C-PiB PET can be used to observe pathological changes in cerebrospinal fluid dynamics and that cerebrospinal fluid-mediated clearance is reduced in Alzheimers disease and multiple sclerosis compared to healthy controls.

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Schubert, J. J., Veronese, M., Marchitelli, L., Bodini, B., Tonietto, M., Stankoff, B., Brooks, D. J., Bertoldo, A., Edison, P., Turkheimer, F. E.. 2018-12-13. Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis. https://doi.org/10.1101/493734

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