Putaminal diffusion tensor imaging measures predict disease severity across human prion diseases.
Harpreet HyareEnrico De VitaMarie-Claire PorterIvor SimpsonGerard RidgwayJessica LoweAndrew ThompsonChris CarswellSebastien OurselinMarc ModatLiane Dos Santos CanasDiana CaineZoe FoxPeter RudgeJohn CollingeSimon MeadJohn S ThorntonPublished in: Brain communications (2020)
Therapeutic trials of disease-modifying agents in neurodegenerative disease typically require several hundred participants and long durations for clinical endpoints. Trials of this size are not feasible for prion diseases, rare dementia disorders associated with misfolding of prion protein. In this situation, biomarkers are particularly helpful. On diagnostic imaging, prion diseases demonstrate characteristic brain signal abnormalities on diffusion-weighted MRI. The aim of this study was to determine whether cerebral water diffusivity could be a quantitative imaging biomarker of disease severity. We hypothesized that the basal ganglia were most likely to demonstrate functionally relevant changes in diffusivity. Seventy-one subjects (37 patients and 34 controls) of whom 47 underwent serial scanning (23 patients and 24 controls) were recruited as part of the UK National Prion Monitoring Cohort. All patients underwent neurological assessment with the Medical Research Council Scale, a functionally orientated measure of prion disease severity, and diffusion tensor imaging. Voxel-based morphometry, voxel-based analysis of diffusion tensor imaging and regions of interest analyses were performed. A significant voxel-wise correlation of decreased Medical Research Council Scale score and decreased mean, radial and axial diffusivities in the putamen bilaterally was observed (P < 0.01). Significant decrease in putamen mean, radial and axial diffusivities over time was observed for patients compared with controls (P = 0.01), and there was a significant correlation between monthly decrease in putamen mean, radial and axial diffusivities and monthly decrease in Medical Research Council Scale (P < 0.001). Step-wise linear regression analysis, with dependent variable decline in Medical Research Council Scale, and covariates age and disease duration, showed the rate of decrease in putamen radial diffusivity to be the strongest predictor of rate of decrease in Medical Research Council Scale (P < 0.001). Sample size calculations estimated that, for an intervention study, 83 randomized patients would be required to provide 80% power to detect a 75% amelioration of decline in putamen radial diffusivity. Putamen radial diffusivity has potential as a secondary outcome measure biomarker in future therapeutic trials in human prion diseases.
Keyphrases
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- healthcare
- computed tomography
- randomized controlled trial
- peritoneal dialysis
- high resolution
- endothelial cells
- white matter
- double blind
- multiple sclerosis
- small molecule
- patient reported outcomes
- mild cognitive impairment
- open label
- diffusion weighted
- current status
- phase ii
- human health
- functional connectivity
- resting state
- placebo controlled
- data analysis
- density functional theory
- diffusion weighted imaging
- protein protein
- blood brain barrier
- induced pluripotent stem cells