Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia

Abstract

Background and objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.

Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms.

Results: A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness.

Discussion: We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Figure 1. Multidimensional Scaling of Behavioral and Neuropsychiatric Symptoms and Genetic Cases, Respectively

(A) Two-dimensional spatial representation based on the similarity of variables as revealed by MDS. Variables that have been assigned to a specific 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 the affected gene. C9orf72 = chromosome 9 open reading frame 72; GRN = progranulin; MAPT = microtubule-associated protein tau; MDS = multidimensional scaling; PCA = principal component analysis.

Figure 2. Severity and Frequency of Behavioral and Neuropsychiatric Symptoms and Proportion of the Dominant Clinical Phenotype Depending on the Affected Gene

(A) Comparison of the severity of behavioral and neuropsychiatric symptoms as defined by the sum scores of the individual phenotypes according to the underlying pathogenic variant. (B) Comparison of the frequency of symptom occurrence between pathogenic variant carriers showing behavioral or neuropsychiatric symptoms. Patients may present symptoms of different behavioral or neuropsychiatric phenotypes. Therefore, the sum of frequencies does not add up to 100%. * indicates significant differences. (C) Cases were assigned to the component with the highest PCA-based sum score. As patients may present behavioral and neuropsychiatric symptoms of other phenotypes in addition to the symptoms of the predominating phenotype, Figure 2C is not congruent with Figure 2B.

Figure 3. Correlation of Sum Scores of Behavioral and Neuropsychiatric Phenotypes With Cerebral Atrophy Using Linear Regression Models

T-maps from the analysis of gray and white matter were merged for visualization purposes. (A) Diverse behavioral phenotype, (B) psychotic phenotype, and (C) euphoric/hypersexual phenotype.

Figure 4. Predicted Probability of Developing Symptoms (With 95% CI) vs Estimated Years to Symptom Onset

(A) Predicted probability of developing symptoms of male and female participants separately. 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. (B) Overlay of the probability of the 3 genetic variant career groups and of male and female participants in each group of developing symptoms.

Figure 5. Calculated Sum Scores (With 95% CI) vs Estimated Years to Symptom Onset

Given the exponential nature of the sum score aggregation of symptoms, a logarithmic transformation of the sum score response was applied. The point in time at which the lower 95% CI crosses the x-axis is marked by a vertical bar in the respective color for each group. 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.