SQSTM1 MUTATIONS IN FRONTOTEMPORAL DEMENTIA ARE ASSOCIATED WITH ASYMMETRICAL FOCAL TEMPORAL LOBE ATROPHY

Abstract

FTD is a common cause of young onset dementia and in around a third of cases is genetic. Recently mutations in SQSTM1 have been shown to be a rare cause of familial FTD. Little is known about the clinical or neuroanatomical phenotype at present. In this study, we investigated the pattern of grey matter atrophy in a group of patients with SQSTM1-associated FTD. SQSTM1 variants known to be a cause of familial FTD, or strongly increase risk, were found in four patients in the UCL FTD DNA cohort (n=440): two P392L, 1 E155K and 1 E396 frameshift mutation. The patient with the E396fs mutation was also found to have a C9orf72 expansion. The clinical diagnoses in the four patients were behavioural variant FTD, FTD with motor neurone disease, corticobasal syndrome and primary progressive aphasia. The mean (standard deviation) age at onset was 59.0 (5.9). All patients had undergone a T1-weighted magnetic resonance imaging scan acquired on a 3T Siemens Trio scanner: age at scan 65.8 (6.4). Their imaging was compared with 24 age- and gender-matched healthy controls (age: 66.5 (5.2)). We undertook a voxel-based morphometry (VBM) analysis comparing the SQSTM1 mutation carriers and the controls, correcting for age, gender and total intracranial volume. Statistical parametric maps were thresholded at p<0.05 after family-wise error correction and rendered on a study-specific average group T1-weighted MRI template image in MNI space. Grey matter atrophy was asymmetrical with three patients having right-sided dominant atrophy and one left-sided. For the analysis we flipped the scan in the midsagittal plane of the patient with left-sided atrophy so that the hemisphere in which there was predominant atrophy was the same in all four cases. The VBM analysis showed evidence of focal involvement of the antero-inferior-medial temporal lobe, particularly affecting the temporal pole, amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. There was an anterior-posterior gradient of atrophy as well as inferior-superior and medial-lateral gradients. In summary, patients with SQSTM1 mutations can have a varied clinical phenotype but appear to be particularly associated with focal temporal lobe atrophy that can predominantly affect the right or left hemisphere.