Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights

Abstract

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.

Keywords: copathology; frontotemporal dementia; hallucinations; psychiatric symptoms; subcortical.

Figure 1

Overview of concomitant pathologies across FTLD pathological subtypes. The inner circle represents the main pathological diagnosis, the outer circle represents the proportion of different concomitant pathologies, where minimal pathology burden in a single brain region was also scored.

Figure 2

Whole-brain clinicopathological partial correlations between neuropsychiatric symptoms and regional pathology burden. Neuropsychiatric symptoms are shown on the left, brain regions are shown at the top, and pathological proteins are shown on the bottom. Partial correlation coefficients are represented with a colour gradient (top left). Red boxes represent positive correlations, purple boxes represent negative correlations. All correlations are significant at the 0.01 level. lFDR = local FDR threshold; sub nigra = substantia nigra; l coeruleus = locus coeruleus; m oblongata = medulla oblongata; pers/comp = perseverative/compulsive.

Figure 3

Quantification of TDP-43 burden in the granular layer of the hippocampal dentate gyrus. (A) TDP-43 stained sections of the middle hippocampus from two FTLD donors, one from the FTLD-Hal+ group (left) and one from the FTLD-Hal− group (right). Scale bar = 50 µm. (B) Differential distribution of TDP-43 pathology burden—measured with ImageJ software as the percentage of pixels showing TDP-43 pathology—between FTLD-Hal+ and FTLD Hal− brain donors.