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

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-022-11442-y.

Supplementary eTable 1 Motor symptoms included in the GENFI Symptom Scales in the History assessment. Scoring of each symptom is on a scale similar to the CDR i.e. 0 (absent), 0.5 (very mild/questionable), 1 (mild), 2 (moderate), and 3 (severe).
Supplementary eTable 2 Scoring rules to derive the algorithm-based motor score (as per the method used to calculate the CDR ® plus NACC FTLD Global Score) Supplementary eTable 3 Mean (standard deviation) severity of motor symptoms in controls and mutation carriers. Bold items are significantly different to controls using linear regression analysis (p < 0.05). Other differences are shown as a significantly impaired compared to GRN and b significantly impaired compared to MAPT using logistic regression analysis (p < 0.05).
Supplementary eFigure 1 Frequency of each individual motor symptom score within all mutation carriers compared with the equivalent motor examination score. In the left-hand figure for each motor feature, frequency is on the y-axis, and the severity of the motor symptom or examination scores is shown on the x-axis with the following scale: 0 = absent, 0.5 = very mild, 1 = mild, 2 = moderate, 3 = severe. In the right-hand figure, a Sankey diagram illustrates the difference in numbers of cases with a particular severity score, with motor symptoms on the left of each diagram, and motor examination on the right.

Dysarthria
Has the subject had difficulties with articulation?
Possible speech disturbance of questionable significance or very mild.
Detectable speech disturbancemay be asked to repeat statements infrequently.
Becoming less intelligiblefrequently asked to repeat statements.

Dysphagia
Has the subject had difficulties with swallowing?
Rare choking of questionable significance.
Swallowing problems are evident with regular episodes of choking.
Requires changes in dietary consistency.
Needs supplemental tube feeding.

Tremor
Has the subject had rhythmic shaking, especially in the hands, arms, legs or head?
Tremor is infrequently present and of questionable significance or very mild.
Tremor is evident but is generally not distressing to the patient.
Tremor is evident, may be distressing and interferes with many activities.
Tremor interferes with most activities.

Weakness
Has the subject noticed their arms or legs have become weak?
Possible weakness of limbs but of questionable significance or very mild.
Mild weaknessdoes not require assistance with using arms or walking.
Moderate weaknessrequires assistance walking or with activities requiring the arms.
Severe weaknessunable to walk and/or use arms.

Supplementary eTable 2 Scoring rules to derive the algorithm-based motor score (as per the method used to calculate the CDR ® plus NACC FTLD Global Score)
Individual scores Overall score All 0 0 Maximum 0.5 0.5 Maximum > 0.5: Maximum 1, all others 0 0.5 Maximum 2 or 3, all others 0 1 Maximum occurs once, another rating > 0 One level < maximum Maximum occurs > once Maximum score

Supplementary eTable 3 Mean (standard deviation) severity of motor symptoms in controls and mutation carriers. Bold
items are significantly different to controls using linear regression analysis (p < 0.05). Other differences are shown as a significantly impaired compared to GRN and b significantly impaired compared to MAPT using logistic regression analysis (p < 0.05). Supplementary eFigure 1 Frequency of each individual motor symptom score within all mutation carriers compared with the equivalent motor examination score. In the left-hand figure for each motor feature, frequency is on the y-axis, and the severity of the motor symptom or examination scores is shown on the x-axis with the following scale: 0 = absent, 0.5 = very mild, 1 = mild, 2 = moderate, 3 = severe. In the right-hand figure, a Sankey diagram illustrates the difference in numbers of cases with a particular severity score, with motor symptoms on the left of each diagram, and motor examination on the right.