Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes

Abstract

Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.

Microstructural white matter changes mediate age‐related cognitive decline on the Montreal Cognitive Assessment (MoCA)

“…Knecht, Wersching, Lohmann, Berger, & Ringelstein (2009) reported that up to 11% of age-related changes in memory, executive function, attention, and verbal fluency were linked to systolic blood pressure. It is also consistent with clinical evidence that the MoCA is sensitive to frontal and frontotemporal dementia (Chertkow, Nasreddine, Philips, Litwin, & Whitehead, 2010;Freitas, Simões, Alves, Duro, & Santana, 2012;Miller, Banks, L eger, & Cummings, 2014), as well as MCI and Alzheimer's disease. It is possible to use the MoCA to extract measures related to specific cognitive domains (e.g., episodic memory, executive functioning, and attention; Dong et al, 2010;Nie et al, 2012;Wester, Westhoff, Kessels, & Egger, 2013).…”

Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

“…Identification of effective, evidence-based symptomatic treatments for social cognition and behaviour deficits in FTD and other neuropsychiatric disorders raises several unique challenges for clinical trial design and implementation. These challenges include symptom and behavioural heterogeneity, the nonlinear trajectory of many behavioural symptoms over the course of the disease, lack of harmonisation of assessment and outcome measures across centres, and reliance on subjective caregiver reports for key outcome measures [ 2 – 4 ]. Additional challenges for randomised controlled trials (RCTs) of oxytocin include potential differential responses according to sex, uncertainties around brain penetration of intranasal formulations, lack of dose-finding studies, and confirmation of target engagement [ 5 ].…”

Precision medicine of frontotemporal dementia from genotype to phenotype

“…FTD treatment strategies generally rely on the use of medications for symptomatic management, but most therapies lack quality evidence from randomized, placebo-controlled clinical trials (150). Selective serotonin reuptake inhibitors may be effective in the case of behavioral symptoms, while antipsychotics or antiepileptic drugs are also effective in some case reports, but use of these latter agents is limited by the concern of side effects.…”