Research Article: Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales

Date Published: May 24, 2018

Publisher: BioMed Central

Author(s): Giorgio G. Fumagalli, Paola Basilico, Andrea Arighi, Martina Bocchetta, Katrina M. Dick, David M. Cash, Sophie Harding, Matteo Mercurio, Chiara Fenoglio, Anna M. Pietroboni, Laura Ghezzi, John van Swieten, Barbara Borroni, Alexandre de Mendonça, Mario Masellis, Maria C. Tartaglia, James B. Rowe, Caroline Graff, Fabrizio Tagliavini, Giovanni B. Frisoni, Robert Laforce, Elizabeth Finger, Sandro Sorbi, Elio Scarpini, Jonathan D. Rohrer, Daniela Galimberti.


In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms.

Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas).

Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers.

These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Partial Text

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized clinically by changes in behaviour or language. Up to one-third of cases are caused by mutations in one of three major causal genes identified so far: microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72) [1–3].

Using simply applied visual rating scales, we have identified typical patterns of atrophy for each group of mutation carriers: anterior and medial temporal for MAPT, asymmetric frontal (orbitofrontal, cingulate, frontoinsular) and parietal for GRN and widespread for C9ORF72 (see Fig. 2). This is consistent with previous studies on patients with genetic FTD using voxel-based morphometry [6, 9, 10], even with the limitations of a semiquantitative assessment of atrophy. We also validated the visual rating scales using voxel-based morphometry, with each scale correlating with the specific brain region that the scale was designed to assess.

We have demonstrated differences among groups of mutations using a simple-to-use, reproducible and validated set of visual rating scales. Patterns of atrophy can be useful to help differentiate these groups and help predict the presence of a gene mutation in subjects with FTD. Clinicians can integrate the information obtained using MRI data with clinical features (e.g., psychosis in C9ORF72) and family history to tailor an approach to genetic testing [9, 14]. Further studies of visual rating scales of other important regions (such as subcortical areas) may add to our findings in improving differentiation between different mutations in FTD.




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