Transdiagnostic Network Localization of Social, Language, and Motor Symptoms in Patients With Frontotemporal Lobar Degeneration

Abstract

Background and objectives: Frontotemporal lobar degeneration (FTLD) includes different clinical syndromes with distinct patterns of symptoms and neuroanatomical locations of neurodegeneration. However, FTLD is clinically heterogeneous (with overlapping symptoms across several domains) and neuroanatomically heterogeneous (with brain atrophy in different locations in different patients). Traditional methods struggle to fully account for this heterogeneity. In this study, we use a relatively new neuroimaging approach, atrophy network mapping, to localize clinical symptoms in patients with FTLD to specific brain networks transdiagnostically.

Methods: Data were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative and 4-Repeat Tauopathy Neuroimaging Initiative. Inclusion required T1-weighted MRI and a diagnosis of behavioral-variant frontotemporal dementia (bvFTD), semantic-variant primary progressive aphasia (svPPA), nonfluent primary progressive aphasia (nfvPPA), progressive supranuclear palsy Richardson syndrome (PSP-rs), corticobasal syndrome (CBS), or normal cognition. Measures of social cognition (Interpersonal Reactivity Index, Revised Self-Monitoring Scale), language (Boston Naming Test, Animal Fluency), and motor function (Unified Parkinson Disease Rating Scale Part III, PSP Rating Scale) were correlated with neuroimaging measures, including cortical thickness, volume, and atrophy network mapping, a newer method that localizes regions connected to brain atrophy using a functional connectome from cognitively normal persons (n = 1,000).

Results: Fifty-seven patients with bvFTD (age 61.2 ± 6.8 years, 35% female), 41 PSP-rs (age 69.7 ± 7.4 years, 54% female), 39 CBS (age 66.2 ± 6.2 years, 51% female), 37 svPPA (age 63.0 ± 6.0 years, 46% female), and 36 nfvPPA (age 68.3 ± 7.3 years, 53% female) and 135 healthy age-matched controls (age 63.3 ± 7.4 years, 58% female) were included. Compared with atrophy alone, atrophy network mapping showed more consistent neuroimaging results across patients with the same clinical syndrome (Dice index mean 0.68 vs 0.11, paired t = 263.1, df = 4,452, p < 0.001), more strongly explained social cognition (F(1, 84) = 10.2, p = 0.002) and motor symptoms (F(1, 185) = 91.3, p < 0.001) across different syndromes, and showed novel neuroanatomical associations, with the temporal parietal junction relating to social cognition; Wernicke area relating to language symptoms; and association sensorimotor cortex, thalamus, and cerebellum relating to motor symptoms.

Discussion: Atrophy network mapping can improve understanding of brain-behavior relationships in clinically and neuroanatomically heterogeneous disorders such as FTLD.