Brain MRI signatures of atrophy in genetic frontotemporal lobar degeneration

Abstract Background Genetic heterogeneity underlying different clinical presentations of the frontotemporal lobar degeneration (FTLD) spectrum hampers the identification of useful biomarkers that may be able to monitor disease progression and/or facilitate the enrolment in clinical trials. The aim of this study was to assess cortical, subcortical and cerebellar grey matter (GM) atrophy using magnetic resonance imaging (MRI) in patients affected by disorders of the FTLD spectrum with known genetic mutations. Method Sixty‐six patients carrying FTLD‐related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty‐one patients with sporadic FTLD (sFTLD) matched for age, sex and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls (HC). A whole‐brain voxel‐based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were also obtained. Result Compared with HC, GM volume loss on VBM was generally greater and more diffuse in genetic FTD (gFTD) cases, followed by sporadic FTD (sFTD) cases and genetic MND (gMND) cases, whereas sporadic MND (sMND) showed very focal atrophy of the motor cortex. Patients carrying GRN and C9ORF72 mutations showed the most widespread cortical volume loss, whereas SOD1 and TARDBP patients were the least atrophic. Greater atrophy of the parietal cortices and thalami was found, globally, in genetic FTLD patients compared with sporadic FTLD and, particularly, in C9‐MND patients compared with sMND. When assessing deep GM volumes, genetic FTLD patients showed significant volume loss compared with sporadic FTLD in the caudate nuclei and thalami. In particular, greater atrophy of the left caudate and right thalamus was found in C9MND compared with sMND. At the cerebellar level, greater atrophy of the right lobule VIIb could discriminate genetic FTLD from sporadic FTLD patients. Conclusion Our data suggest that measures of deep GM and cerebellar involvement might be useful markers of genetic FTLD, particularly C9ORF72‐related disorders, regardless of the clinical presentation within the FTLD spectrum. Supported by: Italian Ministry of Health (RF‐2011‐02351193; GR‐2011‐02351217) and European Research Council (StG‐2016_714388_NeuroTRACK).