Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia

Abstract

Introduction: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.

Methods: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51).

Results: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy.

Discussion: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Keywords: Interpersonal Reactivity Index; behavioral variant frontotemporal dementia; clinical trials; cognitive empathy; emotional empathy; volumetric MRI.

Fig. 1.

EC and PT scores reflect disease severity measured by the global CDR^® plus NACC FTLD score regardless of pathogenic variant status, and worsen at a similar rate over time in pathogenic variant carriers and non-carriers. (A) LME model analysis in the full sample (n=594) revealed a significant main effect of CDR^® plus NACC FTLD (p<0.001) with regard to the EC score, showing that the score changes as a function of disease stage from asymptomatic to very mild (estimate=4.38, 95%CI=[2.79, 5.97], p<0.001), very mild to mild (estimate=−3.52, 95%CI=[−5.19, −1.84], p<0.001), and mild to moderate/severe (estimate=2.93, 95%CI=[1.71, 4.14], p<0.001) disease. The interaction between CDR^® plus NACC FTLD and pathogenic variant status did not reach statistical significance. (B) Similar to the EC subscale, CDR^® plus NACC FTLD significantly predicted the PT score (p<0.001), showing that the score significantly worsened between asymptomatic and very mild (estimate=5.64, 95%CI=[3.81, 7.48], p<0.001), very mild and mild (estimate=−3.24, 95%CI=[−4.82, −1.13], p=0.002), as well as between mild and moderate/severe (estimate=1.49, 95%CI=[0.18, 2.79], p=0.023) disease stage. The interaction CDR^® plus NACC FTLD by disease stage at baseline did not reach statistical significance for predicting the PT score. (C) In the fully longitudinal sample (n=91), disease duration significantly predicted (estimate=−0.29, 95%CI=[−0.59, −0.00], p=0.049) the EC score, demonstrating that patients with longer disease duration had lower EC score compared to patients with shorter disease duration. However, the interaction disease duration by pathogenic variant status was not statistically significant. (D) The PT score was significantly predicted by disease duration (estimate=−0.49, 95%CI=[−0.90, −0.09], p=0.019), showing that the score significantly decreased over time with longer disease duration. The interaction between disease duration and pathogenic variant status did not reach statistical significance for predicting the PT score. Age at symptom onset and sex were included as covariates of no interest in each analysis. CDR^® plus NACC FTLD=CDR^® Dementia Staging Instrument plus Behavior and Language domains from the NACC FTLD Module.

Fig. 2.

EC and PT scores of patients with early and more advanced disease stages at baseline significantly decline at a similar rate over time. (A) The EC score was significantly predicted by disease duration (estimate=−0.42, 95%CI=[−0.98, 0.13], p=0.061), but the interaction disease duration by disease severity at baseline (very mild/mild versus moderate/severe) was not significant. This shows that patients who are in both early and more advanced disease stages show similar rates of decline on the EC subscale. (B) Disease duration significantly predicted the PT score in the main effect model (estimate=−0.21, 95%CI=[−0.57, 0.15], p=0.074). However, the interaction between disease duration and disease severity at baseline (very mild/mild versus moderate/advanced) did not reach statistical significance, demonstrating that rate of decline on the PT subscale is independent from disease severity at baseline. Age at symptom onset and sex were added to each model as covariates of no interest. CDR^® plus NACC FTLD=CDR^® Dementia Staging Instrument plus Behavior and Language domains from the NACC FTLD Module.