Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort

Abstract

Introduction: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

Methods: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants.

Results: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation.

Discussion: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency.

Highlights: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.

Keywords: disease severity; frontotemporal dementia/amyotrophic lateral sclerosis; motor impairment; outcome measures.

FIGURE 1

(A) Sankey diagram showing participants in each CDR + NACC FTLD global score and CDR FTLD‐M global score categories. (B) Sankey diagram showing participants in each CDR + NACC FTLD global score and MIR global score categories. (C) Sankey diagram showing ALS participants in each CDR + NACC FTLD global score and CDR FTLD‐M global score categories. (D) Sankey diagram showing ALS participants in each CDR + NACC FTLD global score and MIR global score categories. (E) Agreement between CDR FTLD SB and CDR + NACC FTLD‐M SB. (F) Agreement between CDR + NACC FTLD SB and MIR SB. (G) Agreement between CDR FTLD‐M SB and MIR SB. The disease severity scales are transformed to a range of 0 to 100 because of differences in scale ranges. Compared to CDR + NACC FTLD SB, all subjects had a higher CDR FTLD‐M SB and MIR SB; however, the transformation resulted in a lower CDR FTLD‐M SB and MIR SB relative values for some of the subjects. Orange circles indicate ALS diagnosis. Mean SB is indicated by the red circle. The Sankey diagrams were created using SankeyMATIC. ALS, amyotrophic lateral sclerosis; CDR, Clinical Dementia Rating; FTLD, frontotemporal lobar degeneration; MIR, Multidomain Impairment Rating; NACC, National Alzheimer's Coordinating Center; SB, sum of boxes.

FIGURE 2

Power analysis comparing the number of subjects required in each arm in a theoretical clinical trial to detect a range of mean differences using CDR + NACC FTLD, CDR FTLD‐M, or MIR as the outcome measure. CDR, Clinical Dementia Rating; MIR, Multidomain Impairment Rating; FTLD, frontotemporal lobar degeneration; NACC, National Alzheimer's Coordinating Center.