Brain-water diffusion coefficients reflect the severity of inherited prion disease

Abstract

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.

Figure 1 Whole brain and gray matter histograms in patients and controls (A) Mean whole brain histograms in patients and controls. (B) Mean gray matter histograms in symptomatic patients and controls. ADC = apparent diffusion coefficient.

Figure 2 Positioning of the basal ganglia regions of interest (ROIs) Apparent diffusion coefficient map demonstrating positions of the caudate, putamen, and pulvinar ROIs bilaterally.

Figure 3 Significant correlations between MRI histogram measures and clinical scores Scatterplots of (A) gray matter mean apparent diffusion coefficient (ADC) and Mini-Mental State Examination (MMSE), (B) gray matter mean ADC and Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog), (C) gray matter mean ADC and Clinician's Dementia Rating Scale (CDR), (D) gray matter mean ADC and Clinician's Global Impression of Disease (CGIS), (E) whole brain mean ADC and MMSE, (F) normalized brain volume and MMSE.

Figure 4 Significant correlations between mean region of interest (ROI) apparent diffusion coefficient (ADC) and clinical scores Scatterplots of (A) right and (B) left pulvinar ROI mean ADC and Clinician's Global Impression of Disease.