title: Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases.
abstract: In clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR) diffusion-weighted images (DWIs) is a marker of sporadic Creutzfeldt-Jakob Disease (sCJD). MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann-Sträussler-Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of patients and healthy subjects. Analysis of the raw DWI signal allows us to suggest the following acquisition parameters for optimized detection of CJD lesions: b = 3000 s/mm(2) and TE = 103 ms. In conclusion, these results provide the first in vivo estimate of mean vacuole size, new insight on the mechanisms of DWI signal changes in prionopathies and open the way to designing an optimized acquisition protocol to improve early clinical diagnosis and subtyping of sCJD.
authors.affiliation: Neuroradiology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy ; Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Figini
authors.affiliation: Centre for Medical Image Computing, Department of Computer Science, University College London, London, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Alexander
authors.affiliation: Neuropathology, Fondazione IRCCS Istituto Neurologico, Parma, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Redaelli
authors.affiliation: Department of Neuroscience, Università degli Studi di Parma, Parma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fasano
authors.affiliation: Neuroradiology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Grisoli
authors.affiliation: Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Baselli
authors.affiliation: National Prion Disease Pathology Surveillance Center, Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: Neuropathology, Fondazione IRCCS Istituto Neurologico, Parma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Neuroradiology, Humanitas Research Hospital IRCCS, Rozzano, Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bizzi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping / Q000379:methods*; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D017096:Prion Diseases / Q000473:pathology*
keywords: ADC, apparent diffusion coefficient; BIC, Bayesian information criterion; Biophysical models; CJD, Creutzfeldt–Jakob disease; CNR, contrast to noise ratio; Creutzfeldt–Jakob disease; DWI, diffusion weighted imaging; Diffusion MRI; EEG, electroencephalogram; EPI, echo-planar imaging; FOV, field of view; GSS, Gerstmann–Sträussler–Scheinker syndrome; MPRAGE, magnetization-prepared rapid acquisition gradient-echo; PrPC, prion protein cellular; PrPSc, prion protein scrapie; Prion disease; ROI, region of interest; RPE, rapidly progressive encephalopathy; SS-SE, single shot spin-echo; Spongiform degeneration; TE, echo time; TI, inversion time; TR, repetition time; sCJD, sporadic Creutzfeldt–Jakob disease