Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning
Nikolaos Koutsouleris, Christos Pantelis, Dennis Velakoulis, Philip McGuire, Dominic Dwyer, Maria-Fernanda Urquijo-Castro, Riya Paul, Sen Dong, David Popovic, Oemer Faruk Oeztuerk, Joseph Kambeitz, Raimo K. R. Salokangas, Jarmo Hietala, Alessandro Bertolino, Paolo Brambilla, Rachel Upthegrove, Stephen J. Wood, Rebekka Lencer, Stefan Borgwardt, Carlo Maj, Markus M. Nöthen, Franziska Degenhardt, Maryna Polyakova, Karsten Mueller, Arno Villringer, Adrian Danek, Klaus Faßbender, Klaus Fließbach, Holger Jahn, Johannes Kornhuber, G. Bernhard Landwehrmeyer, Sarah Anderl‐Straub, Johannes Prudlo, Matthis Synofzik, Jens Wiltfang, Lina Riedl, Janine Diehl‐Schmid, Markus Otto, Eva Meisenzahl, Peter Falkai, Matthias L. Schroeter, Shalaila S. Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Aylin Melo, Susanna Muckenhuber-Sternbauer, Yanis Köhler, Ömer Öztürk, Nora Penzel, Adrian Rangnick, Sebastian von Saldern, Moritz Spangemacher, Ana Tupac, Johanna Weiske, Antonia Wosgien, Camilla Krämer, Karsten Blume, Dennis M. Hedderich, Dominika Julkowski, Nathalie Kaiser, Theresa Lichtenstein, Ruth Milz, Alexandra Nikolaides, Tanja Pilgram, Mauro Seves, Martina Wassen, Christina Andreou, Laura Egloff, Fabienne Harrisberger, Ulrike Heitz, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, Sonja Widmayer, Chris Day, Siân Lowri Griffiths, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, Ashleigh Lin, Paris Alexandros Lalousis, Alexander Denissoff, Anu Ellilä, Tiina From, Markus Heinimaa, Tuula Ilonen, Päivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli Mäkela, Janina Paju, Henri Pesonen, Reetta-Liina Säilä, Anna Toivonen, Otto Turtonen
Abstract
Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.