Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling.
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Young Alexandra L, Bocchetta Martina, Russell Lucy L, Convery Rhian S, Peakman Georgia, Todd Emily, Cash David M, Greaves Caroline V, van Swieten John, Jiskoot Lize, Seelaar Harro, Moreno Fermin, Sanchez-Valle Raquel, Borroni Barbara, Laforce Robert, Masellis Mario, Tartaglia Maria Carmela, Graff Caroline, Galimberti Daniela, Rowe James B, Finger Elizabeth, Synofzik Matthis, Vandenberghe Rik, de Mendonça Alexandre, Tagliavini Fabrizio, Santana Isabel, Ducharme Simon, Butler Chris, Gerhard Alex, Levin Johannes, Danek Adrian, Otto Markus, Sorbi Sandro, Williams Steven C R, Alexander Daniel C, Rohrer Jonathan D, Genetic FTD Initiative (GENFI)
Аннотация
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.