An update on semantic dementia: genetics, imaging, and pathology

Abstract

Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD. Task-related fMRI have also demonstrated the relative preservation of frontal and parietal regions alongside preserved memory performance. In addition, recent longitudinal studies have demonstrated that, with disease progression, atrophy encroaches into the contralateral temporal pole and medial prefrontal cortices, which reflects emerging changes in behaviour and social cognition. Notably, unlike other frontotemporal dementia subtypes, recent research has demonstrated strong clinicopathological concordance in SD, with TDP43 type C as the most common pathological subtype. Moreover, an underlying genetic cause appears to be relatively rare in SD, with the majority of cases having a sporadic form of the disease. The relatively clear diagnosis, clinical course, and pathological homogeneity of SD make this syndrome a promising target for novel disease-modifying interventions. The development of neuroimaging markers of disease progression at the individual level is an important area of research for future studies to address, in order to assist with this endeavour.

Keywords: Frontotemporal dementia; Primary progressive aphasia; Semantic-variant primary progressive aphasia.

Fig. 1

Axial MRI scans showing typical anterior and middle temporal structural abnormalities in early left and right lateralised SD. L left, R right, SD semantic dementia

Fig. 2

Brain imaging findings in SD at presentation and with disease progression. a Cross-sectional multimodal imaging findings in 10 SD patients versus 21 healthy controls: reduced regional grey matter density (top row), reduced FDG-PET (second row), increased radial diffusivity (third row), and composite of multimodal findings (fourth row). From Acosta-Carbonero et al. [31] with permission. b Baseline and longitudinal changes in cortical thickness in 22 left SD vs 9 right SD patients. From Kumfor et al. [14, 38] with permission. c Longitudinal white matter changes from baseline in 11 SD patients. From Lam et al. [40] with permission. FA fractional anisotropy, FDG-PET fluorodeoxyglucose positron emission tomography, FDR, L left, MD mean diffusivity, R right, RadialD radial diffusivity, SD semantic dementia, TBSS tract-based spatial statistics, VBM voxel-based morphometry, FDR false discovery rate

Fig. 3

llustration of the FTLD-TDP subtypes. From Tan et al. [63] with permission