Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

Abstract

Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.

Keywords: Behavioral variant frontotemporal dementia; FTLD-TDP; FTLD-tau; Frontotemporal dementia; Frontotemporal lobar degeneration; Magnetic resonance imaging; Neuroimaging; Nonfluent agrammatic variant primary progressive aphasia; Positron emission tomography; Progressive nonfluent aphasia; Semantic dementia; Semantic variant primary progressive aphasia; TDP-43; Tau.

Fig. 1

Patterns of atrophy and hypometabolism associated with FTD clinical syndromes. Group-level maps depicting gray matter atrophy compared to controls are shown on three-dimensional renders of the brain. Hypometabolism on FDG-PET is shown for individual patients, represented as Z score maps depicting abnormalities compared to controls. Adapted with permission from Whitwell 2019 [258]

Fig. 2

Neuroimaging of bvFTD associated with FTLD-TDP type A and B (top row: structural MRI; bottom row: FDG-PET). The variability in patterns of degeneration attributed to FTLD-TDP neuropathology is readily seen in these two cases of bvFTD. In the case of bvFTD associated with FTLD-TDP type A, degeneration and hypometabolism of the bilateral frontal lobes are present; however, the left is significantly more impacted than the right and extends to the left parietal lobe. In bvFTD associated with FTLD-TDP type B, significant degeneration of the bilateral frontal lobes is seen; however, in contrast to type A, the parietal lobes are less affected and atrophy is relatively symmetrical

Fig. 3

Neuroimaging patterns associated with FTLD-TDP type C. FTLD-TDP type C typically exhibits significant anterior temporal lobe degeneration, which strongly lateralizes to either the left or right hemisphere. In cases of left lateralization, the clinical syndrome is typically consistent with svPPA, whereas in cases of right lateralization, there is a greater degree of behavioral symptoms, and language deficits are not typically the initial symptoms

Fig. 4

Gray matter atrophy associated with FTLD-TDP type C: left and right variants. All patients had pathology-proven TDP-C but were classified as having either a left- (n = 18) or right- (n = 12) predominant pattern of atrophy on ante mortem MRIs. At baseline, both groups show asymmetric but bilateral volume reduction in the temporal lobes, with a strong predominance in anterior and medial areas. In patients with multiple MRIs (n = 13 left- and 4 right-predominant cases), longitudinal analyses revealed that in both subgroups, atrophy progressed to the contralateral hemisphere and to more posterior temporal areas. Adapted with permission from Borghesani 2020 [179]

Fig. 5

Neuroimaging patterns associated with Pick’s disease (FTLD-tau, 3R). Structural MRI and FDG-PET demonstrating the variability in patterns of atrophy and hypometabolism attributed to Pick’s disease (3R tau) neuropathology. In the case of bvFTD, significant bilateral frontal lobe atrophy and hypometabolism is seen. In the case of nfvPPA, atrophy and hypometabolism is lateralized and is greatly impacting the left frontal lobe more so than the right.

Fig. 6

Neuroimaging patterns associated with 4R tauopathies (FTLD-tau). Structural MRI and FDG-PET demonstrating the variability in patterns of atrophy and hypometabolism attributed to 4R tauopathies, CBD and PSP