Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

Abstract

Objective: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD).

Methods: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR^® plus NACC FTLD was investigated (CDR^® plus NACC FTLD-M).

Results: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR^® plus NACC FTLD to form the CDR^® plus NACC FTLD-M. Individual global scores were more severe with the CDR^® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR^® plus NACC FTLD alone).

Conclusions: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Keywords: C9orf72; Frontotemporal dementia; Genetics; Motor; Progranulin; Tau.

Fig. 1

Frequency of participants with a motor diagnosis compared to those with motor symptoms, in asymptomatic (CDR^® plus NACC FTLD 0), prodromal (0.5) and symptomatic (≥ 1) mutation carriers. Specific motor diagnoses in the mutation carrier groups are shown below: ALS—amyotrophic lateral sclerosis, PD—Parkinson’s disease, PSP—progressive supranuclear palsy, CBS—corticobasal syndrome

Fig. 2

Comparison of the standard CDR^® plus NACC FTLD with a new CDR^® plus NACC FTLD plus Global Motor Score (CDR^® plus NACC FTLD-M). Top figure shows the change in global score in individual participants and bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR^® plus NACC FTLD, right shows new CDR^® plus NACC FTLD-M). Diagnoses: bvFTD, behavioural variant frontotemporal dementia; PPA, Primary Progressive Aphasia; ALS/FTD-ALS, Amyotrophic Lateral Sclerosis; Parkinsonism (Progressive Supranuclear Palsy, Corticobasal Syndrome or Parkinson’s Disease)