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

Article type: Research Article

Authors: Fremont, Rachel^a | Manoochehri, Masood^{b; c} | Armstrong, Nicole M.^d | Mattay, Venkata S.^{e; f} | Apud, Jose A.^g | Tierney, Mary C.^h | Devanand, D.P.^a | Gazes, Yunglin^c | Habeck, Christian^c | Wassermann, Eric M.^h | Grafman, Jordan^{i; j} | Huey, Edward D.^{a; b; c; *}

Affiliations: [a] Department of Psychiatry, Columbia University, New York, NY, USA | [b] Taub Institute, Columbia University, New York, NY, USA | [c] Department of Neurology, Columbia University, New York, NY, USA | [d] Laboratory of Behavioral Neuroscience, NIA/NIH, Bethesda, MD, USA | [e] Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA | [f] Departments of Neurology and Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [g] Section on Integrative Neuroimaging, Clinical & Translational Neuroscience Branch, Intramural Research Program, NIMH/NIH, Bethesda, MD, USA | [h] Behavioral Neurology Unit, Intramural Research Program, NINDS/NIH, Bethesda, MD, USA | [i] Department of Physical Medicine and Rehabilitation, Cognitive Neuroscience Laboratory, Brain Injury Research, Shirley Ryan AbilityLab, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA | [j] Departments of Neurology, Psychiatry, and Cognitive Neurology & Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

Correspondence: [*] Correspondence to: Dr. Edward D. Huey, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630 West 168th Street, P&S Box 16, New York, NY 10032, USA. E-mail: [email protected].

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

Keywords: NCT00604591

DOI: 10.3233/JAD-191265

Journal: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1391-1403, 2020