Tolcapone Treatment for Cognitive and Behavioral Symptoms in Behavioral Variant Frontotemporal Dementia: A Placebo-Controlled Crossover Study

Abstract

Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD).

Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD.

Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI).

Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078).

Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

Keywords: COMT; dopamine; frontotemporal dementia; tolcapone; treatment.

Fig. 1.

Study design. MRI scans performed at Assessments #2, 3, and 4. Clinical and neuropsychological study measures performed at screening and Assessments #2, 3, and 4. Side effect evaluation, vital signs, physical examination, Liver Function Tests, and AIMS performed at all assessment points. mg po tid, milligrams per oral three times a day.

Fig. 2.

Structure of the N-back test. a) N-back test. b) One block of the N-back. Three counterbalanced blocks were administered. The rest condition had blank screens without a task.

Fig. 3.

Effects of treatment phase on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). a) Mean score at Baseline, Treatment (Tolcapone, in gray), Placebo, and Washout phases. Open circles are individual data points. Error bars represent 95% confidence intervals. b) Mean score during each phase of the trial for Tolcapone first (circle) and Placebo first (square) conditions. Filled symbols indicate active (tolcapone) phase. Error bars represent 95% confidence intervals.

Fig. 4.

Effects of treatment phase on the Neuropsychiatric Inventory-Questionnaire (NPI-Q). a) Mean score at Baseline, Treatment (Tolcapone, in gray), Placebo, and Washout phases. Open circles are individual data points. Error bars represent 95% confidence intervals. b) Mean score during each phase of the trial for Tolcapone first (circle) and Placebo first (square) conditions. Filled symbols indicate active (tolcapone) phase. Error bars represent 95% confidence intervals.

Fig. 5.

Effects of treatment phase on the Clinical Global Impressions Scale. a) Mean score at Treatment (Tolcapone, Gray), Placebo, and Washout phases. CGI of 4 is no change, scores lower than 4 represent improvement, greater than 4 represent worsening. Error bars represent 95% confidence intervals. b) Mean within-subject CGI difference of Treatment - Placebo CGI by genotype. Negative Treatment-Placebo CGI is an improvement. Open circles represent individual data points. Error bars represent standard error of the mean.