Frequency and Longitudinal Course of Motor Signs in Genetic Frontotemporal Dementia

Abstract

Background and objectives: Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) gene. As motor disorders are increasingly recognized as part of the clinical spectrum, the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.

Methods: We analyzed baseline visit data of known carriers of a pathogenic variant in the c9orf72, GRN, or MAPT gene from the Genetic Frontotemporal Dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset.

Results: A total of 322 pathogenic variant carriers were included in the analysis: 122 c9orf72 (79 presymptomatic), 143 GRN (112 presymptomatic), and 57 MAPT (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 motor clusters, which we call progressive supranuclear palsy (PSP)-like, bulbar amyotrophic lateral sclerosis (ALS)-like, mixed/ALS-like, Parkinson disease (PD) like, and corticobasal syndrome-like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. Although the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction influenced motor signs. In c9orf72 pathogenic variant carriers, motor signs could be detected up to 25 years before expected symptom onset.

Discussion: These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinicogenetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Figure 1. Multidimensional Scaling of Motor Signs and Genetic Cases, Respectively

(A) Two-dimensional spatial representation based on the similarity of clinical variables as revealed by MDS. Variables that have been assigned to a specific motor phenotype by PCA are color coded. (B) Two-dimensional spatial representation based on the similarity of cases as revealed by MDS. Cases are color coded according to their affected gene. ALS = amyotrophic lateral sclerosis; c9orf72 = chromosome 9 open reading frame 72; CBS = corticobasal syndrome; GRN = progranulin; MAPT = microtubule-associated protein tau; MDS = multidimensional scaling; MP = motor phenotype; PCA = principal component analysis; PD = Parkinson disease; PSP = progressive supranuclear palsy.

Figure 2. Severity and Frequency of Motor Signs

(A) Comparison of the severity of motor signs as defined by the sum scores of the individual motor phenotypes according to the affected gene. (B) Comparison of the frequency of motor signs between pathogenic variant carriers showing motor signs. Patients may present motor signs of different phenotypes; therefore, the sum of frequencies does not add up to 100%. ALS = amyotrophic lateral sclerosis; c9orf72 = chromosome 9 open reading frame 72; CBS = corticobasal syndrome; GRN = progranulin; MAPT = microtubule-associated protein tau; MP = motor phenotype; PD = Parkinson disease; PSP = progressive supranuclear palsy.

Figure 3. Proportion of the Dominant Clinical Phenotype of Patients With Motor Signs Depending on the Affected Gene

Cases were assigned to the component with the highest PCA-based sum score. As patients may present motor signs of other motor phenotypes in addition to the signs of the predominating motor phenotype, this figure is not congruent with Figure 2B. ALS = amyotrophic lateral sclerosis; c9orf72 = chromosome 9 open reading frame 72; CBS = corticobasal syndrome; GRN = progranulin; MAPT = microtubule-associated protein tau; MP = motor phenotype; PCA = principal component analysis; PD = Parkinson disease; PSP = progressive supranuclear palsy.

Figure 4. Correlation of Sum Scores of Motor Phenotypes With Cerebral Atrophy Using Linear Regression Models

T-maps from the analysis of gray and white matter were merged for visualization purposes. (A) PSP-like motor phenotype, arising from c9orf72, GRN, and MAPT pathogenic variants, not progressive supranuclear palsy pathology. (B) PD-like motor phenotype, arising from c9orf72, GRN, and MAPT pathogenic variants, not PD. (C) Mixed/ALS-like motor phenotype, arising from c9orf72, GRN, and MAPT pathogenic variants. ALS = amyotrophic lateral sclerosis; c9orf72 = chromosome 9 open reading frame 72; CBS = corticobasal syndrome; GRN = progranulin; MAPT = microtubule-associated protein tau; PD = Parkinson disease; PSP = progressive supranuclear palsy.

Figure 5. Calculated Sum Scores and Overall Laterality Index (With 95% CIs), Respectively, vs Estimated Years to Symptom Onset

An early increase of motor signs, up to 25 years before the expected symptom onset, could be detected in c9orf72 pathogenic variant carriers. In MAPT pathogenic variant carriers, motor signs occurred latest. The point in time at which the lower 95% CI of the model crosses the x-axis is marked by a vertical bar in the respective color for each group. Although the severity of motor signs remained highest in c9orf72 pathogenic variant carriers over time, severity of motor signs of GRN and MAPT pathogenic variant carriers progressively converged. Individual data points are not plotted to prevent disclosure of genetic status. However, the time of the examination is marked on the x-axis by a colored dash. ALS = amyotrophic lateral sclerosis; c9orf72 = chromosome 9 open reading frame 72; CBS = corticobasal syndrome; GRN = progranulin; MAPT = microtubule-associated protein tau; MP = motor phenotype; PD = Parkinson disease; PSP = progressive supranuclear palsy.