Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

Abstract

Background: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

Methods: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point.

Results: Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r_s=-0.77, p<0.001) and within each genetic group (r_s=-0.67 to -0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls -0.1 (6.0) for FRS, -0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers -0.5 (8.2), 0.2 (0.9), prodromal disease -2.3 (9.9), 0.6 (2.7), mild disease -10.2 (18.6), 3.0 (4.1), moderate disease -9.6 (16.6), 4.4 (4.0), severe disease -2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.

Conclusions: Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.

Keywords: frontotemporal dementia.

Figure 1

Mean FRS percentage score according to CDR+NACC FTLD global rating in mutation carriers at baseline. Error bars represent SE of the mean. CDR+NACC FTLD global ratings: GRN 0, N=114; 0.5, N=25; 1, N=19; 2, N=15; 3, N=14; MAPT 0, N=42; 0.5, N=13; 1, N=7; 2, N=8; 3, N=7; C9orf72 0, N=92; 0.5, N=32; 1, N=18; 2, N=26; 3, N=25. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

Figure 2

Scatter plot of FRS percentage scores and CDR+NACC FTLD sum of boxes scores in all mutation carriers at baseline. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

Figure 3

Bar graph and Sankey diagram presenting proportions of participants in each FRS severity category according to CDR+NACC FTLD global rating, in all mutation carriers at baseline. CDR+NACC FTLD global rating 0, N=248; 0.5, N=70; 1, N=44; 2, N=49; 3, N=46. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

Figure 4

(A) Frequencies of CDR+NACC FTLD domains affected (rating ≥0.5) within each FRS severity category, in mutation carriers and non-carrier controls at baseline. FRS severity categories: controls: asymptomatic, N=165; very mild, N=29; mild, N=63; moderate, N=11; severe, N=0; very severe, N=0; profound, N=0; mutation carriers: asymptomatic, N=175; very mild, N=33; mild, N=101; moderate, N=60; severe, N=63; very severe, N=23; profound, N=2. Note that very severe and profound groups were combined for the mutation carriers due to limited cases in the profound group. (B) Mean scores on CDR+NACC FTLD domains within each FRS severity category, in mutation carriers and in non-carrier controls at baseline. Error bars represent SE of the mean. domains are rated using scores of 0 (absent), 0.5 (questionable/very mild), 1 (mild), 2 (moderate) and 3 (severe). CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

Figure 5

Annualised change in FRS percentage score and CDR+NACC FTLD sum of boxes score in mutation carriers according to baseline CDR+NACC FTLD global rating and controls. Baseline values=mean score, follow-up values=(baseline mean score)+(mean annualised change in score). Controls N=145; carriers N=232 (baseline CDR+NACC FTLD global 0, N=140; 0.5, N=30; 1, N=22; 2, N=23; 3, N=16). CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.