Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Genetics; Motor neuron disease; Neuroimaging; Presymptomatic.

Fig. 1

Genes whose mutations are associated with FTD-ALS spectrum disorders. Reprinted from Kumar et al. (2016) with permission from Elsevier.

Fig. 2

Comparison of grey matter atrophy patterns in three FTD syndromes. Patients with bvFTD, svPPA, nfvPPA were compared to healthy age-matched control subjects using voxel-based morphometry. Maps are thresholded at p < 0.001 uncorrected and superimposed on a study-specific template. BvFTD, behavioral variant frontotemporal dementia; SD, semantic dementia, also known as semantic variant PPA; PNFA, progressive nonfluent aphasia, also known as nonfluent variant PPA; GMV, grey-matter volume. Adapted from Zhang et al. (2013).

Fig. 3

White-matter involvement in sporadic ALS revealed by a multi-site DTI study. FA decreases were found along the corticospinal tracts, frontal lobe, brainstem and hippocampi. Red circles indicate deficits only significant with correction for site differences. ALS, amyotrophic lateral sclerosis; WBSS, whole-brain-based spatial statistics; FA, fractional anisotropy; FDR, false discovery rate. Adapted from Müller et al. (2016) with permission from BMJ Publishing Group Ltd.

Fig. 4

Gray matter deficits in FTD mutation carriers measured by voxel-based morphometry. In both affected (symptomatic) and presymptomatic stages of disease, carriers of the C9orf72 expansion, MAPT and GRN mutations each exhibited distinct atrophy patterns with overlap in frontotemporal cortex and insula. Both C9orf72 and GRN feature parieto-occipital atrophy in addition to frontotemporal atrophy, while MAPT targets the mesial temporal lobe. In the presymptomatic C9orf72 group, circles indicate significantly low gray matter volume in the thalamus. Maps illustrate brain regions with reduced grey matter probability in affected (p < 0.05 FWE-corrected) and presymptomatic (p < 0.001 uncorrected) carriers compared to noncarriers. FTD, frontotemporal dementia; FWE, familywise error rate. Reprinted from Cash et al. (2018).