Preparing for the age of therapeutic trials in Frontotemporal lobar degeneration

BREIF SENTENCE:

There is a rapidly growing field of therapeutic development for familial forms of FTLD and Peakman et al address the important need for adequate clinical tools to measure treatment effect in this issue of JNNP.

Frontotemporal lobar degeneration (FTLD) comprises a spectrum of heterogenous clinicopathological neurodegenerative disorders and neuropathologic examination at autopsy remains the gold-standard for diagnosis¹. However, detection of pathogenic mutations in genes known to associate with either FTLD-Tau or FTLD-TDP neuropathology in ~20–30% of all FTLD with familial disease provides an accurate antemortem molecular diagnosis in these individuals, even in the presymptomatic stage. Therefore, several clinical trials for agents targeting disease-specific mechanisms associated with forms of familial FTLD are planned or currently underway. Reliable clinical outcome measures to detect and track early disease are crucial to facilitate the success of these efforts. In this issue, Peakman and colleagues² perform a detailed cross-sectional and longitudinal analysis of two commonly used clinical rating scales [i.e. extended clinical dementia rating scale (CDR®+NACC-FTLD) and the Frontotemporal Dementia Rating Scale (FRS)] in the large international Genetic FTD Initiative (GENFI) cohort to address this critical issue.

The main findings include overall good correlation of the scales with each other, and with other metrics of disease severity. However, there was some disagreement between scales in classifying early disease stages. In longitudinal analysis over approximately one-year of follow-up, there was measurable decline on both FRS and CDR®+NACC-FTLD sum-of-boxes score, particularly in mild to moderate global CDR®+NACC-FTLD symptomatic stages (scores=1–2). Notably, annualized change was low for both in the presymptomatic 0.5 stage and did not differ from controls. Finally, the authors find relatively large sample sizes may be needed to detect a moderate effect size on both scales in a proof-of-concept power analysis using presymptomatic stage 0.5 patient data. While both scales have been highly influential and important in improving diagnosis and research in symptomatic patients, this data suggests additional approaches may be needed in presymptomatic familial FTLD.

This is a rigorous and important study that is exemplary of the importance of coordinated international collaborative efforts to facilitate success of therapeutic trials in FTLD, including GENFI and other ongoing FTLD clinical trial readiness programs such as ALLFTD (NCT04363684) and the FTD disorders registry (www.ftdregistry.org). The authors clearly articulate the potential limitations of the study, including the relative few presymptomatic patients who became symptomatic (i.e. undergo phenoconversion) during observation and the lack of individual-item responses in FRS to help resolve discrepancies between scales. Moreover, they thoughtfully posit that augmentation of clinical assessments to include motor and neuropsychiatric features may improve the characterization of presymptomatic disease. Indeed, the clinical heterogeneity of FTD results in varying overlapping clinical features¹ thus, interdisciplinary collaborations are needed across neurologic and psychiatric subspecialties to improve clinical assessments in FTLD. Emerging digital technologies to objectively measure clinical outcomes may be another avenue to track early disease progression³, such as automated speech analysis⁴. The power analyses performed in this study used a traditional 1:1 randomization design and thus, did not account for the diverse and complex clinical trial strategies currently proposed³ or implemented in FTLD trials⁵. As such, the authors suggest a stratification process using biomarkers of underlying neurodegeneration⁶ to enrich presymptomatic familial FTLD cohorts with those individuals at highest risk for phenoconversion may improve statistical power. Future longitudinal analysis that includes more phenoconversion data, when available, will help clarify this important issue. While this study focused on familial FTLD, it is important to note that the majority of patients with sporadic FTLD are often excluded from therapeutic trials, in part, due to poor diagnostic accuracy for underlying pathology. Thus, brain donation and translational research using postmortem human brain tissue to validate and develop novel tissue-sensitive biomarkers for specific forms of FTLD neuropathology are critical to accelerate discoveries and prepare for the rapidly growing field of therapeutic trials in FTLD.