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Link to original content: https://pubmed.ncbi.nlm.nih.gov/32500143/
Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia - PubMed Skip to main page content
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. 2020 Sep 3;30(10):5387-5399.
doi: 10.1093/cercor/bhaa119.

Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia

Lorenzo Pasquini  1 , Alissa L Nana  1 , Gianina Toller  1 , Jesse A Brown  1 , Jersey Deng  1 , Adam Staffaroni  1 , Eun-Joo Kim  1 , Ji-Hye L Hwang  1 , Libo Li  1   2 , Youngsoon Park  1 , Stephanie E Gaus  1 , Isabel Allen  1 , Virginia E Sturm  1 , Salvatore Spina  1 , Lea T Grinberg  1   3 , Katherine P Rankin  1 , Joel H Kramer  1 , Howard J Rosen  1 , Bruce L Miller  1 , William W Seeley  1   3
Affiliations

Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia

Lorenzo Pasquini et al. Cereb Cortex. .

Abstract

Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

Keywords: empathy; frontoinsular cortex; frontotemporal dementia; salience network; von Economo neurons.

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Figures

Figure 1
Figure 1
Patient assessment. (A) All patients underwent structural MRI. Images were preprocessed, segmented into gray matter tissue intensity maps, and transformed to W-score maps using a multiple regression model trained on healthy older adults (GMcon) to model the voxel-wise relationship between relevant demographic variables and segmented tissue intensity. The model provides a predicted gray matter map for each patient, and the actual and predicted gray matter maps are compared to derive W-score maps, which reflect the deviation at each voxel from the predicted gray matter intensity. To facilitate the interpretation of these maps, the sign of W-score values was inverted, with higher W-score values reflecting higher levels of atrophy. (B) Postmortem, the rate of VENs (blue circles) and fork cells (violet triangles) with TDP-43 pathobiology was quantified in layer 5 of the right FI via unbiased counting on TDP-43 immunostained sections. TDP-43 is normally expressed in the nucleus (brown nucleus in [a.] normal VEN and [b.] normal fork cell), which in patients aggregates into neuronal cytoplasmic inclusions ([c.] TDP-43 inclusion-bearing VEN) while being cleared from the nucleus. A minority of neurons lacks either normal nuclear TDP-43 or a cytoplasmic inclusion ([d.] nuclear TDP-43 depleted VEN). Scale bar in B.a. represents 10 μm. Percentage of (C) TDP-43 inclusion-bearing and (D) TDP-43 depleted VENs (blue) and fork cells (orange) for individual patients. ALS = amyotrophic lateral sclerosis; bvFTD = behavioral variant of frontotemporal dementia; bvFTD-MND = behavioral variant of frontotemporal dementia with motor neuron disease; C9orf72— = C9orf72 expansion noncarriers; C9orf72 + = C9orf72 expansion carriers; dAI = dorsal anterior insula; FI = frontoinsular cortex; IHC = immunohistochemistry; GM = gray matter; POrbG = posterior orbitofrontal gyrus; Predicted = through the healthy adults regression model predicted patient’s gray matter map; Put = putamen; Raw = segmented patient’s gray matter map; SDε = standard deviation of the residuals in the healthy adults model; TDP-43 = transactive response DNA binding protein with 43 kD; VEN = von Economo neuron.
Figure 2
Figure 2
Gray matter atrophy associated with the rate of TDP-43 inclusion-bearing VENs and fork cells in right FI. (A) Brain atrophy in ALS/bvFTD spectrum. Voxel-wise frequency map of gray matter atrophy using W-score maps of all patients. Individual W-score gray matter maps were binarized at a W-score threshold of 2 and summed, such that a higher score at each voxel indicates a larger proportion of subjects with suprathreshold atrophy. Only voxels in which at least 4 patients had a W-score > 2 are shown. (B) Gray matter atrophy associated with the rate of TDP-43 inclusion-bearing VENs and fork cells in right FI was observed in medial frontal, right insular, subcortical, limbic, and dorsomedial thalamic sites. A cluster in anterior limbic areas is seen in the region of the bed nucleus of the stria terminalis, and subcortical areas span posteriorly into the dorsomedial and medial pulvinar thalamic nuclei. Voxel-wise analyses were corrected for C9orf72 mutation status and the interval between MRI scan and death. (C) Atrophy patterns associated with TDP-43 inclusion formation in VENs and fork cells (in red) versus layer 5 neighboring neurons (in blue) of the right FI. The overlap of both patterns (violet) reveals substantial overlap in right insula and thalamus. Notable differences (orange arrows) include gray matter atrophy in medial frontal regions, including the anterior cingulate cortex, specifically associated with inclusion formation in VENs and fork cells. In contrast, gray matter atrophy of the right FI (where neuron counting was performed) was more associated with inclusion formation in neighboring layer 5 neurons. Voxel-wise analyses were performed with a height threshold of P < 0.001 and a cluster-extent threshold of P < 0.05 FWE, corrected. NNs = layer 5 neighboring neurons.
Figure 3
Figure 3
Nuclear TDP-43 depletion partially accounts for gray matter atrophy in C9orf72 expansion carriers. (A) Averaged levels of gray matter atrophy in the identified clusters from Figure 2B plotted against the rate of TDP-43 inclusion-bearing VENs and fork cells separately for C9orf72 expansion carriers and noncarriers. The plotted partial residuals for atrophy were derived by regressing out the influence of interval between scan and death, but not the influence of C9orf72 status since we were interested in exploring the distribution of C9orf72 mutation carriers along the regression line. Notably, C9orf72 expansion carriers (orange) distribute less evenly along the regression line due to high levels of gray matter atrophy despite a low proportion of inclusion-bearing neurons compared with nonexpansion carriers (blue). (B) Gray matter atrophy in frontal, subcortical limbic, dorsomedial thalamic, and left angular sites is significantly associated with a composite score of VEN/fork cell TDP-43 pathobiology derived by adding the rates of TDP-43 inclusion formation and nuclear depletion (without inclusion) in the right FI VENs and fork cells (in blue). This pattern overlapped substantially (violet and orange arrows) with the atrophy pattern associated with the rate of TDP-43 inclusion-bearing VENs and fork cells (in red, from Figure 2B). Voxel-wise analyses were corrected for C9orf72 mutation status and time interval between MRI scan and death using a height threshold of P < 0.001 and a cluster-extent threshold of P < 0.05 FWE corrected. (C) VEN and fork cell TDP-43 composite score plotted against averaged atrophy derived from the clusters identified in panel B (blue and violet), after regressing out the influence of interval between scan and death (partial residuals). Combining nuclear TDP-43 depletion with TDP-43 inclusions reveals a more evenly distributed relationship between TDP-43 pathobiology and gray matter atrophy in C9orf72 expansion carriers and noncarriers than seen when using inclusion-bearing VENs and fork cells alone. Geometric shapes depict distinct syndromes. ALS = amyotrophic lateral sclerosis (diamonds); bvFTD = behavioral variant of frontotemporal dementia (triangles); C9orf72 = chromosome 9 open reading frame 72; bvFTD-MND = frontotemporal dementia with motor neuron disease (circles).
Figure 4
Figure 4
Loss of emotional empathy is associated with atrophy in regions related to VEN and fork cell TDP-43 inclusion formation. (A) Gray matter atrophy associated with TDP-43 inclusion-bearing VENs and fork cells (average across clusters identified in Fig. 2B) correlate with deficits in empathic concern. (B) Gray matter atrophy in the right occipital cortex is not significantly associated with deficits in empathic concern. (C) Gray matter atrophy associated with TDP-43 inclusion-bearing VENs and fork cells is not significantly associated with performance on the Boston Naming Test. Spearman partial correlation Rho corrected for C9orf72 mutation status; ***P < 0.0005. BNT = Boston Naming Test; IRI-EC = Interpersonal Reactivity Index, empathic concern subscale.
Figure 5
Figure 5
Atrophy of salience network regions mediates the relationships between neuron type-specific TDP-43 pathobiology and loss of emotional empathy. (A) As shown in previous work, VEN and fork cell TDP-43 inclusion formation predict empathy loss assessed through the empathic concern subscale of the Interpersonal Reactivity Index. (B) The relationship between VEN and fork cell TDP-43 inclusion formation and empathy loss is fully mediated by atrophy of salience network regions, assessed by averaging gray matter W-score values extracted from the clusters identified in Figure 2B. a, b, c, and c’ = regression coefficients; *P < 0.05.
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