Brain-water diffusion coefficients reflect the severity of inherited prion disease.
OBJECTIVE
Inherited prion diseases are progressive neurodegenerative conditions, characterized by cerebral spongiosis, gliosis, and neuronal loss, caused by mutations within the prion protein (PRNP) gene. We wished to assess the potential of diffusion-weighted MRI as a biomarker of disease severity in inherited prion diseases.


METHODS
Twenty-five subjects (mean age 45.2 years) with a known PRNP mutation including 19 symptomatic patients, 6 gene-positive asymptomatic subjects, and 7 controls (mean age 54.1 years) underwent conventional and diffusion-weighted MRI. An index of normalized brain volume (NBV) and region of interest (ROI) mean apparent diffusion coefficient (ADC) for the head of caudate, putamen, and pulvinar nuclei were recorded. ADC histograms were computed for whole brain (WB) and gray matter (GM) tissue fractions. Clinical assessment utilized standardized clinical scores. Mann-Whitney U test and regression analyses were performed.


RESULTS
Symptomatic patients exhibited an increased WB mean ADC (p = 0.006) and GM mean ADC (p = 0.024) compared to controls. Decreased NBV and increased mean ADC measures significantly correlated with clinical measures of disease severity. Using a stepwise multivariate regression procedure, GM mean ADC was an independent predictor of Clinician's Dementia Rating score (p = 0.001), Barthel Index of activities of daily living (p = 0.001), and Rankin disability score (p = 0.019).


CONCLUSIONS
Brain volume loss in inherited prion diseases is accompanied by increased cerebral apparent diffusion coefficient (ADC), correlating with increased disease severity. The association between gray matter ADC and clinical neurologic status suggests this measure may prove a useful biomarker of disease activity in inherited prion diseases.
Hyare
H
H
National Prion Clinic, Box 98, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK, WC1N 3BG. harpreet.hyare@uclh.nhs.uk
Wroe
S
S
Siddique
D
D
Webb
T
T
Fox
N C
NC
Stevens
J
J
Collinge
J
J
Yousry
T
T
Thornton
J S
JS
D000328:Adult; D001834:Body Water; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D009929:Organ Size; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D012044:Regression Analysis; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions