Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study

Abstract

PurposeMRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment.MethodsTwenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2–6 examinations per subject, interval range 0.1–3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied.ResultsIn the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score.ConclusionsUsing 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.

Multimodal MRI staging for tracking progression and clinical-imaging correlation in sporadic Creutzfeldt-Jakob disease

“…We will now address why our MRI Disease-Staging scale, combining MD and Volume changes, works better for clinical-imaging correlation than Volume changes alone. Volume loss by visual assessment is usually not noted in sCJD and other prion diseases, and when evident, it is usually only in late disease stages, and often in patients with long courses ( Uchino et al, 1991 , Finkenstaedt et al, 1996 , De Vita et al, 2017 ). Therefore, atrophy might not be expected to correlate with focal clinical deficits in early stages, but in later stages could correlate with focal deficits and general function.…”

“…Symptoms present at the onset are likely to be associated with the initial histopathological alterations of the disease (vacuolation and PrP Sc deposition) more than neuronal loss, which develop in later stages. In a longitudinal VBM analysis of a subcohort of 21 subjects with prion disease (mostly with slowly progressive genetic forms and only 2 sCJD cases) whom had serial imaging with interscan intervals of > 3 months, De Vita et al found Volume loss in each of several brain regions correlated with functional decline ( De Vita et al, 2017 ). In a different study, the same research group performed VBM on 23 cases of various forms of PrDs (mostly gPrD, unclear how many sCJD) who had detailed neurocognitive assessment.…”

“…Brain atrophy usually is not an obvious early radiological finding by standard visual assessment in sCJD ( De Vita et al, 2017 , Finkenstaedt et al, 1996 ) and seems to occur only in the intermediate/late stages of the disease, particularly in subjects with prolonged disease courses ( Finkenstaedt et al, 1996 , Galvez and Cartier, 1984 , Uchino et al, 1991 , Ukisu et al, 2005 ). Quantitative volume assessment methods such as voxel-based morphometry (VBM) or cortical thickness evaluation, however, are more sensitive for detecting atrophy in sCJD or other prion diseases ( Alner et al, 2011 , Cohen et al, 2009 , De Vita et al, 2013 , De Vita et al, 2017 , Grau-Rivera et al, 2017 ).…”

ACR Appropriateness Criteria® Movement Disorders and Neurodegenerative Diseases

“…A hallmark of the disease is the prominence of gray matter involvement with relative sparing of the underlying white matter on conventional MRI [16]. T1weighted imaging is typically normal initially, with volume loss noted later in the disease course [17].…”

Personalized brain MRI revealed distinct functional and anatomical disruptions in Creutzfeldt‐Jakob disease and Alzheimer's disease

“…DWI studies revealed white matter abnormalities in CJD 11,12 . Progressive brain atrophy was also associated with the deterioration of clinical symptoms in CJD 13 . However, diffusive and structural MRI modalities cannot capture brain functional changes.…”