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

Abstract

BackgroundIn 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.MethodsMagnetic 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).ResultsIntra- 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.ConclusionsThese 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.

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

“…However, patients with the p.P397S MAPT variant showed a significantly older age at disease onset and slower disease progression compared with p.P301L mutation carriers. Neuroimaging of all patients revealed bitemporal atrophy in concordance with the typical atrophy pattern described in FTLD due to MAPT mutations, but with relative preservation of other areas of the brain including frontal areas …”

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

“…Previous cross-sectional MRI studies demonstrated atrophy in the anteromedial temporal lobe and orbitofrontal cortex in asymptomatic MAPT mutation carriers (6,19,20), while others found no difference between asymptomatic MAPT mutation carriers and controls (6,7,33). Recently, two longitudinal studies from a cohort of asymptomatic MAPT mutation carriers have reported that hippocampal volumes decline during a 2-year follow-up, but no cortical atrophy was found in longitudinal analysis with 4 years of follow-up (21,22).…”

“…In asymptomatic C9orf72 mutation carriers, cross-sectional structural MRI studies consistently found a diffuse pattern of atrophy including frontal, temporal, parietal, insular, and posterior cortical regions, as well as subcortical volumes of thalamus, hippocampus, and the cerebellum (6,22,(29)(30)(31)(32), while very few studies reported no difference between asymptomatic C9orf72 mutation carriers and healthy controls (20,68). The atrophy of subcortical regions is estimated to occur as early as 25 years before the expected symptom onset in C9orf72 mutation carriers, and later involves temporal and frontal lobes at around 20 years before the expected symptom onset, and finally involving the cerebellum at around 10 years before the expected symptom onset (19).…”

“…Structural magnetic resonance imaging (sMRI) has captured cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers (6,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Studies of sMRI using different analysis methods, such as region of interest (ROI) in specific brain regions, cortical thickness analysis and voxel-based morphometry (VBM), could capture the gray matter and white matter volumes, cortical thickness, and the subcortical gray matter volume.…”

“…In asymptomatic GRN mutation carriers, the structural MRI studies were inconsistent (24)(25)(26)(27). Although most cross-sectional (6,7,20,32,(55)(56)(57) and longitudinal structural MRI studies (22) reported no gray matter volume differences between asymptomatic GRN mutation carriers and controls, a few recent studies found a gray matter FIGURE 1 | Coronal T1-weighted magnetic resonance imaging (MRI). Brain MRIs (coronal T1-weighted images) of the three familiar FTLD mutation carriers who progressed from the asymptomatic to the symptomatic stage are shown in the timeline with years before and after conversion.…”