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Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity.

ABSTRACT: Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched controls. Voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) were subsequently performed. Clinical assessment using the Unified Dystonia Rating Scale (UDRS) and Unified Huntington's Disease Rating Scale (UHDRS) was undertaken in all patients. VBM detected significant tissue changes within the substantia nigra, midbrain and dentate together with significant cerebellar atrophy in patients (FWE, p < 0.05). Iron deposition in the caudate head and cavitation in the lateral globus pallidus correlated with UDRS score (p < 0.001). There were no differences between groups with VBR. Our data show that progressive iron accumulation in the caudate nucleus, and cavitation of the globus pallidus correlate with disease severity in neuroferritinopathy. We also confirm sub-clinical cerebellar atrophy as a feature of the disease. We suggest that VBM is an effective technique to detect regions of iron deposition and cavitation, with potential wider utility to determine radiological markers of disease severity for all NBIA disorders.

SUBMITTER: Keogh MJ

PROVIDER: S-EPMC6558265 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity.

Keogh M J MJ Aribisala B S BS He J J Tulip E E Butteriss D D Morris C C Gorman G G Horvath R R Chinnery P F PF Blamire Andrew M AM

Journal of neurology 20150704 10

Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched ...[more]

PMID: 26142024

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Project description: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.

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Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity.

Publications

Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity.

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