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.
Highlights
Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD)
There are a number of biomarkers that should be considered for use in randomized clinical trials (RCTs) for FTD, discussion of such measures is beyond the scope and aims of this paper
Conclusions not intended to be a comprehensive, nor exhaustive listing, Table 2, provides an overview of tools that could be considered for FTD trials, describing their roles, as well as potential strengths and limitations
Summary
Cognition and functioning; previously used in clinical trials; demonstrated sensitivity to change. Sensitive to expressive language impairments; previous use in clinical trials limited sensitivity to speech abnormalities; no alternate forms; prone to ceiling effects. The DRS and RBANS are two similar, brief cognitive batteries that have been used in clinical trials, neither provides adequate coverage of the executive domain and would need to be supplemented with additional measures. The NPI and Frontal Behavioral Inventory (FBI) [62,63] have both been shown to reliably differentiate between FTD subtypes at baseline [40] and have shown sensitivity to change over time [26] In some circumstances, these measures may need to be supplemented with additional behavioral assessment tools due to their emphasis on more “positive” behavioral disturbances (e.g., agitation, irritability, disinhibition) over “negative” behaviors (e.g., apathy, indifference), which are among the core features of FTD. Development of behavioral assessment methods that allow for greater objectivity and validation of caregiver reports may be beneficial
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