Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials

Abstract

Objective: To investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).

Methods: We investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.

Results: RSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11).

Conclusions: The RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

© 2020 American Academy of Neurology.

Figures

Figure 1. RSMS score reflects disease severity independently of mutation status

Linear mixed-effects model analysis (n = 475) revealed a significant main effect of CDR Dementia Staging Instrument plus Behavior and Language domains from the National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Module (CDR plus NACC FTLD) (F4,48 = 140.10, p < 0.001), showing that average Revised Self-Monitoring Scale (RSMS) score dropped significantly between asymptomatic (CDR plus NACC FTLD score 0) and very mildly symptomatic (CDR plus NACC FTLD score 0.5) stages (t = 4.99, p < 0.001, estimate 10.58, 95% confidence interval [CI] 6.32–14.85), between very mild (CDR plus NACC FTLD score 0.5) and mild (CDR plus NACC FTLD score 1) stages (t = −5.48, p < 0.001, estimate −12.02, 95% CI −16.43 to −7.61), between mild (CDR plus NACC FTLD score 1) and moderate (CDR plus NACC FTLD score 2) stages (t = 4.46, p < 0.001, estimate 6.50, 95% CI 3.57–9.43), and between moderate and severe stages (t = 2.12, p < 0.039, estimate 4.93, 95% CI 0.25–9.61) in both mutation carriers and noncarriers. Age at first assessment and sex were included as covariates of no interest.

Figure 2. RSMS score shows linear declines over time in behavioral variant frontotemporal dementia

(A) Linear mixed-effects model analysis in the full longitudinal subsample (n = 62) revealed a significant main effect of disease duration (F1,59 = 8.90, p = 0.004, estimate −0.73, 95% confidence interval −1.90 to −0.23), showing that Revised Self-Monitoring Scale (RSMS) score significantly worsened over time. Rate of RSMS score progression did not differ significantly between mutation carriers and noncarriers. (B) When patients were assigned to 3 groups based on their baseline disease stage (very mild, mild, moderate to severe) measured by the CDR plus National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Module, no significant interaction was found between disease duration and disease stage group, suggesting that the RSMS score progresses at a similar rate in patients who are in different disease stages at baseline. Age at symptom onset and sex were included as covariates of no interest.

Figure 3. More rapid decline on the RSMS corresponded to faster progression of salience network atrophy

(A) Voxel-wise analysis in the full longitudinal subsample (n = 62) showed that a higher drop in Revised Self-Monitoring Scale (RSMS) score was significantly associated with more gray matter volume loss in the right anterior insula, dorsal anterior cingulate cortex, and orbitofrontal cortex (p < 0.001, uncorrected). (B) A general linear model confirmed this result by showing that a higher annual drop in RSMS score significantly predicted (F1,56 = 13.47, p < 0.001, estimate 753.96, 95% confidence interval 342.38–1,165.54) more annual volume loss within the binarized statistical t map derived from the voxel-wise analysis. Age at symptom onset, sex, disease duration, and total intracranial volume were included as covariates of no interest.