Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Abstract

Background and objective: Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular MAPT mutation is less well-characterized. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature.

Methods: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study.

Results: Eighty-two MAPT mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of MAPT mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction.

Conclusion: Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.

Figure 1. Subtype Progression Patterns Identified by Subtype and Stage Inference (SuStaIn)

Each progression pattern consists of a set of stages at which regional brain volumes in MAPT mutation carriers (symptomatic and presymptomatic) reach different z scores relative to noncarriers. (A) Spatial distribution and severity of atrophy at each SuStaIn stage based on the most likely subtype progression patterns predicted by the SuStaIn algorithm. (B) Uncertainty in the SuStaIn subtype progression patterns for each region, where each region is shaded according to the probability a particular z score is reached at a particular SuStaIn stage, ranging from 0 (white) to 1 (red for a z score of 1, magenta for a z score of 2, blue for a z score of 3, and black for a z score of 5). Visualizations in subfigure A were generated using BrainPainter. Ant = anterior; Cing = cingulate; DLPFC = dorsolateral prefrontal cortex; FRP = frontal pole; Post = posterior; VMPFC = ventromedial prefrontal cortex.

Figure 2. Stage Progression at Follow-Up Visits

Each point represents an individual’s Subtype and Stage Inference (SuStaIn) stage at baseline and follow-up, with the color indicating the time between baseline and follow-up.