Locus Coeruleus Degeneration Differs Between Frontotemporal Lobar Degeneration Subtypes

Abstract

Background: There are few studies on the locus coeruleus (LC) in frontotemporal lobar degeneration (FTLD) and the potential differences in the LC related to the underlying proteinopathy.

Objective: The aim of this study was to investigate the LC in FTLD subgroups.

Methods: Neuropathological cases diagnosed with FTLD were included. The subgroups consisted of FTLD with tau, transactive response DNA-binding protein 43 (TDP) and fused in sarcoma (FUS). Micro- and macroscopical degeneration of the LC were assessed with respect to the number of neurons and the degree of depigmentation. A group of cognitively healthy subjects and a group with vascular cognitive impairment (VCI) served as comparison groups.

Results: A total of 85 FTLD cases were included, of which 44 had FTLD-TDP, 38 had FTLD-tau, and three had FTLD-FUS. The groups were compared with 25 VCI cases and 41 cognitively healthy control cases (N = 151 for the entire study). All FTLD groups had a statistically higher microscopical degeneration of the LC compared to the controls, but the FTLD-tau group had greater micro- and macroscopical degeneration than the FTLD-TDP group. Age correlated positively with the LC score in the FTLD-tau group, but not in the FTLD-TDP group.

Conclusion: A greater microscopical degeneration of the LC was observed in all FTLD cases compared to healthy controls and those with VCI. The LC degeneration was more severe in FTLD-tau than in FTLD-TDP. The macroscopically differential degeneration of the LC in FTLD subgroups may facilitate differential diagnostics, potentially with imaging.

Keywords: Frontotemporal dementia; TDP-43; locus coeruleus; neuronal counts; tau; tauopathy.

Fig. 1

Example image of the locus coeruleus (LC) in neuropathological case diagnosed with frontotemporal lobar degeneration (FTLD) with tau proteinopathy at 13x magnification. Demonstrated in the image is a degenerated LC with a degeneration score of 9 points of 9 possible according to assessment tool introduced in the study. Scale bar representing 0.2 mm.

Fig. 2

Example image of the locus coeruleus (LC) in neuropathological case diagnosed with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein 43 (TDP) proteinopathy at 13x magnification. Demonstrated in the image is the LC with a degeneration score 2 of 9 points possible according to the assessment tool introduced in the study. Scale bar representing 0.2 mm.

Fig. 3

Density plot indicating the distribution of median degeneration score (x-axis) of the locus coeruleus (LC) according to various subgroups (y-axis) of FTLD, VCI, and cognitively healthy control subjects. The subgroups consisted of FTLD-TDP, FTLD-tau, and FTLD-FUS. A scale from 0 to 9 was used for assessment, with 0 being healthy LC and 9 being severely degenerated LC. The scoring system was based on the number of manually counted pigmented cells of the best-preserved nucleus as well as depigmentation. The highest degeneration score of 9 points was for 0–10 counted cells, followed by a score of 8 points for 11–20 counted cells, 6 points for 21–40 counted cells, 4 points for 41–60 counted cells, and 2 points for 61–80 cells. A healthy LC was considered to correspond to≥81 cells. An additional point was given if > 50% of the neurons substantially lacked pigmentation in the cases with a neuron count of 21 or more. The figure was made using Jamovi 2.2.2. FTLD, frontotemporal lobar dementia; FUS, fused in sarcoma; TDP, TAR-DNA binding protein 43; VCI, vascular cognitive impairment.