Distinct and shared multimodal neuroimaging patterns in clinical frontotemporal dementia syndromes

Clinical syndromes of frontotemporal dementia present both distinct and overlapping neuroimaging abnormalities and, consequently, domains of impairment. The aim of this study was to determine how well covariance patterns from multiple neuroimaging modalities discriminate across clinical frontotemporal dementia syndromes. Four-hundred participants with a clinical frontotemporal dementia diagnosis, including behavioural variant of frontotemporal dementia, semantic variant of primary progressive aphasia, right temporal variant of frontotemporal dementia, primary progressive aphasia, apraxia of speech with agrammatic aphasia, primary progressive apraxia of speech, progressive supranuclear palsy and corticobasal syndrome, and 109 cognitively unimpaired participants underwent extensive neurological and neuropsychological assessments, structural magnetic resonance imaging (MRI), flortaucipir-PET for tau and [¹⁸F] fluorodeoxyglucose-PET. Multimodal imaging covariance was investigated at the voxel-level using principal component analysis after adjusting for age and sex effects. Linear regression models were fit to investigate the relationship between principal components and clinical scores. Multinomial logistic regression models were used to investigate the ability of imaging principal components to discriminate across syndromes. The first principal component, which describes the largest source of variability in the data, was a pattern of widespread cortical atrophy (21% variability explained) and of frontoparietal and temporal hypometabolism (21%): scores were lowest in the behavioural variant of frontotemporal dementia and correlated with general cognitive impairment. On tau-PET, the first principal component (43% of variability) did not significantly differ among syndromes and captured a widespread cortical tau uptake, with a focus on the temporal lobe. In all three modalities, the second principal component captured temporal lobe imaging abnormalities, contrasting the motor and semantic clinical syndromes. Subsequent components described smaller variability. In cross-validation, the classifiers based on principal components from MRI (multiclass area under the receiver operating characteristic: 0.76) and [¹⁸F]fluorodeoxyglucose-PET (0.79) outperformed tau-PET (0.71). In cross-validation, the sensitivity of the image-based classifiers was heterogeneous across syndromes and modalities, with the highest values for progressive supranuclear palsy and semantic variant of primary progressive aphasia and the lowest for primary progressive aphasia and corticobasal syndrome. Our study found that the covariance components of structural and molecular neuroimaging underlying frontotemporal dementia clinical syndromes exist both as a continuum and with syndrome-specific patterns. More than one imaging model was able to correctly classify several frontotemporal dementia clinical syndromes with good specificity and sensitivity, highlighting the value of imaging in aiding patient diagnosis.