Promising therapies for the treatment of frontotemporal dementia clinical phenotypes: from symptomatic to disease-modifying drugs

ABSTRACT

Introduction: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility.

Areas covered: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs.

Expert opinion: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.

KEYWORDS:

• Dementia
• frontotemporal dementia
• tau protein
• acetylcholinesterase inhibitors
• SSRIs
• TDP-43
• FUS
• C9orf72
• progranulin
• lifestyle

Article Highlights

• FTD encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and the most common syndrome is the behavioral variant of FTD (bvFTD).

• There are frequent clinical and neuropathological overlaps with progressive supranuclear palsy (PSP), corticobasal degeneration, and amyotrophic lateral sclerosis.

• Acetylcholinesterase inhibitors are not effective treatments in FTD or progressive supranuclear palsy syndrome patients and may exacerbate behavioral or motor symptoms, respectively.

• Memantine is not an effective treatment for FTD and may also hasten cognitive decline.

• Symptomatic treatments of challenging behaviors with selective serotonin reuptake inhibitors or antipsychotics have yielded mixed results.

• A recently completed Phase III trial of a compound targeting tau protein aggregation (LMTM) in bvFTD patients showed negative findings.

• Further evidence on disease-modifying treatments will come from ongoing Phase I and II trials of novel drugs targeting prevention or removal of protein aggregates, inhibition of tau phosphorylation/acetylation, and rescue of selected loss of function in individual genes mutated in FTD.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Dr. Roberta Stallone and Dr. Carla Piccininni for their help in revising the final manuscript.

Declaration of interest

BP Imbimbo is an employee of Chiesi Farmaceutici. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.