Basal forebrain atrophy in frontotemporal dementia

Abstract

Background: The basal forebrain is a subcortical structure that plays an important role in learning, attention, and memory. Despite the known subcortical involvement in frontotemporal dementia (FTD), there is little research into the role of the basal forebrain in this disease. We aimed to investigate differences in basal forebrain volumes between clinical, genetic, and pathological diagnoses of FTD.

Methods: 356 patients with FTD were recruited from the UCL Dementia Research Centre and matched on age and gender with 83 cognitively normal controls. All subjects had a T1-weighted MR scan suitable for analysis. Basal forebrain volumes were calculated using the Geodesic Information Flow (GIF) parcellation method and were compared between clinical (148 bvFTD, 82 svPPA, 103 nfvPPA, 14 PPA-NOS, 9 FTD-MND), genetic (24 MAPT, 15 GRN, 26 C9orf72) and pathological groups (28 tau, 3 FUS, 35 TDP-43) and controls. A subanalysis was also performed comparing pathological subgroups of tau (11 Pick's disease, 6 FTDP-17, 7 CBD, 4 PSP) and TDP-43 (12 type A, 2 type B, 21 type C).

Results: All clinical subtypes of FTD showed significantly smaller volumes than controls (p ≤ 0.010, ANCOVA), with svPPA (10% volumetric difference) and bvFTD (9%) displaying the smallest volumes. Reduced basal forebrain volumes were also seen in MAPT mutations (18%, p < 0.0005) and in individuals with pathologically confirmed FTDP-17 (17%), Pick's disease (12%), and TDP-43 type C (8%) (p < 0.001).

Conclusion: Involvement of the basal forebrain is a common feature in FTD, although the extent of volume reduction differs between clinical, genetic, and pathological diagnoses. Tauopathies, particularly those with MAPT mutations, had the smallest volumes. However, atrophy was also seen in those with TDP-43 type C pathology (most of whom have svPPA clinically). This suggests that the basal forebrain is vulnerable to multiple types of FTD-associated protein inclusions.

Keywords: Frontotemporal dementia; MRI, Basal forebrain; Volumetry.

Fig. 1

Representative figure of the basal forebrain and its anatomy, based on Ding et al. (2016). The basal forebrain segmentation is mapped on to the T1-weighted ICBM152 2009c nonlinear symmetric - 1 × 1 × 1 mm template (McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University). PO = preoptic area, BN = bed nucleus, DB = nucleus of the diagonal band, nbM = basal nucleus of Meynert, OlfA = olfactory area, OlfT = olfactory tract, SI = substantia innominata. The coronal slice corresponds to MNI y = 131.

Fig. 2

Overview of the study cohort, showing how patients were stratified in to clinical, genetic, and pathological groups and further divided in to pathological subtypes.

Fig. 3

Volume of the basal forebrain, as a percentage of total intracranial volume, between FTD patients and controls, by clinical, genetic, and pathological diagnosis.