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.
| Original language | English |
|---|---|
| Journal | JAMA Psychiatry |
| Volume | 79 |
| Issue number | 9 |
| Pages (from-to) | 907-919 |
| Number of pages | 13 |
| ISSN | 2168-622X |
| DOIs | |
| Publication status | Published - 01.09.2022 |
Funding
Conflict of Interest Disclosures: Dr Koutsouleris has patent US20160192889A1 issued. Dr Pantelis has received grants from the Australian National Health & Medical Research Council during the conduct of the study as well as grants from Lundbeck Foundation and personal fees from Lundbeck Australia outside the submitted work. Dr Upthegrove has received grants from European Union FP7 during the conduct of the study; grants from Medical Research Council and National Institute for Health Research; and personal fees from Sunovion and Vivalyfe outside the submitted work. Dr Lencer has received personal fees from Laboratorios Farmacéuticos ROVI, S.A., and Johnson & Johnson outside the submitted work. Dr Nöthen has received grants from the European Commission during the conduct of the study as well as personal fees from Life & Brain GmbH and HMG Systems Engineering GmbH outside the submitted work. Dr Jahn has received grants from German Federal Ministry of Education and Research during the conduct of the study. Dr Kornhuber has received grants from German Federal Ministry of Education and Research during the conduct of the study. Dr Landwehrmeyer has received grants from CHDI Foundation during the conduct of the study; grants from Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft, and the European Commission outside the submitted work; and serves on scientific advisory boards for Hoffmann-LaRoche, Novartis, PTC Therapeutics, Teva, and Triplet Therapeutics. Dr Wiltfang has received personal fees from Abbott, Biogen, Boehringer-Ingelheim, Immungenetics, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Actelion, Amgen, Beejing Yibai Science and Technology, and Roboscreen outside the submitted work and has a patent for PCT/EP 2011 001724 issued and a patent for PCT/EP 2015 052945 issued. Dr Diehl-Schmid has received grants from German Ministry for Education and Research during the conduct of the study. Dr Meisenzahl has a patent for US 2016/ 0192889 A1. Dr Schroeter has received grants from the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (grant FKZ01GI1007A) during the conduct of the study as well as grants from German Research Foundation and eHealthSax Initiative of the Sächsische Aufbau bank outside the submitted work. No other disclosures were reported.
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
DFG Research Classification Scheme
- 2.23-03 Experimental and Theoretical Network Neuroscience
- 1.22-01 General, Cognitive and Mathematical Psychology
- 2.23-08 Human Cognitive and Systems Neuroscience
