A frontotemporal dementia–like phenotype in schizophrenia: links to striatal dopamine and iron accumulation

Abstract Some schizophrenia patients share characteristics with behavioral variant frontotemporal dementia (bvFTD) including gray matter volume (GMV) similarities, suggesting overlapping brain mechanisms that may contribute to disease heterogeneity in schizophrenia. However, it is not yet understood whether schizophrenia patients with a bvFTD-like GMV signature also show additional features of bvFTD. Seventy-six patients with schizophrenia (mean age 31.2 years; 71% male) from a previous clinical trial (NCT04038957) underwent structural magnetic resonance imaging (MRI) to measure GMV. Healthy controls ( n = 79) were used for age-related dynamic standardisation. Subsets of patients also completed ¹⁸F-DOPA positron emission tomography (PET; n = 40) for striatal dopamine synthesis, neuromelanin-sensitive MRI (NM-MRI; n = 68) for midbrain dopaminergic integrity, and quantitative susceptibility mapping (QSM; n = 69) for brain iron accumulation. A previously validated machine-learning–based GMV classifier quantified bvFTD-like pattern expression in each schizophrenia patient. Associations with neurochemical, clinical, and medication measures were examined using correlation analyses. Higher bvFTD scores were associated with lower striatal dopamine synthesis capacity ( r = –0.343, p = 0.032) and higher striatal QSM values ( r = 0.282, p = 0.020), but showed no significant association with QSM or NM-MRI values in the dopaminergic midbrain ( p = 0.903 and p = 0.102, respectively). No significant associations were found with negative symptom severity or with medication. Schizophrenia patients expressing a stronger bvFTD-like GMV pattern show lower striatal dopamine synthesis and elevated striatal iron, both hallmark features of bvFTD. This contrasts with the hyperdopaminergic model of schizophrenia and suggests distinct, potentially neurodegenerative mechanisms.