Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Key Points

Question  Do psychosis and dementia share brain-behavioral alterations?

Findings  In this diagnostic/prognostic study including 1870 patients, patients with schizophrenia expressed the neuroanatomical pattern of behavioral-variant frontotemporal dementia more strongly (41%) than that of Alzheimer disease (17%), and at lower levels, this difference was also encountered in those with major depression (22% vs 3%). Already in clinical high-risk states for psychosis the high expression of the behavioral-variant frontotemporal dementia pattern was linked to severe phenotypes, unfavorable courses, and elevated polygenic risks for schizophrenia and dementia, with further pattern progression being present in those patients who did not recover over time.

Meaning  Dementia praecox should be revisited as a shared pathophysiological dimension of severe psychosis and frontotemporal disease spectra.

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.

Schizophrenia remains in use as umbrella term for a heterogeneous group of disorders.¹ Up to 25% of patients exhibit a course of profound cognitive functional decline, and this observation inspired Emil Kraepelin’s concept of dementia praecox more than a century ago.^2,3 Based on his pathological examinations, Kraepelin conceptualized dementia praecox as a frontotemporal disorder, but its pathological basis remained elusive.⁴ Recent studies reported a 5-fold increased risk of dementia in schizophrenia^5,6 although postmortem data did not identify Alzheimer disease (AD) or frontotemporal dementia (FTD) pathology in schizophrenia.⁷

Still, frontotemporolimbic alterations and cognitive deficits characterize schizophrenic psychoses⁸ and evolve early in the disease,^3,9,10 supporting the possibility of both neurodevelopmental and neuroprogressive brain processes.^11-14 In addition, temporal, prefrontal, and insular abnormalities predict poor illness courses in psychotic^15-18 and also depressive disorders.¹⁹ Several research lines point to clinical, neuroimaging, pathological, and genetic similarities between schizophrenia and FTD, particularly behavioral-variant FTD (bvFTD).^20-25 The idea of shared neurobiology between psychiatric disorders and bvFTD initially gained traction because of the clinical similarity and diagnostic conundrum caused by the early onset of bvFTD, its prominent negative symptoms, and disinhibited and psychotic manifestations.^26-28 The finding that Chromosome 9 open reading frame 72 (C9orf72) variants—the most frequent genetic cause of bvFTD²⁹—are associated with psychotic and affective disorders in carriers and relatives³⁰ further spurred interest in the association between bvFTD and psychiatric conditions.²⁸ C9orf72 has been linked with an earlier, neuroinflammation-associated onset,³¹ slower progression of bvFTD,³² and prominent psychotic phenotypes.³³ Also, genetic studies of bvFTD have implicated immune system alterations,^34,35 echoing findings in schizophrenia.^36,37 These observations hint at complex overlaps between both conditions, not determined by single genes, localized brain alterations, or isolated symptoms.

Machine learning may facilitate a system-level analysis of these overlaps by encapsulating the neurobiological signatures of bvFTD and schizophrenia into mathematical models.³⁸ Disease similarities and differences can be mapped at the clinical and neurobiological scales via crossover model application. Diagnostic specificity can be further interrogated by applying models across psychotic, affective, and neurodegenerative conditions and associating them to Brain Age Gap Estimation (BrainAGE), a marker of accelerated aging in neurological and psychiatric disorders.^39,40 Furthermore, the genetic underpinnings of models’ predictions can be tested to identify shared and unique features of genetic risk projecting onto brain phenotypes.⁴¹ Finally, by applying models to longitudinal data, the heterogeneity of illness courses can be investigated along neurodegenerative and psychotic disease dimensions.

Using this approach, we tested (1) whether patients with schizophrenia expressed neuroanatomical patterns of bvFTD more prominently than AD patterns, more strongly than patients with major depression (MD), and more pronouncedly in the presence of negative and disinhibitory symptoms; and (2) whether schizophrenia patterns expressed by patients with bvFTD were predicted by psychopathological features, C9orf72 status, and neuroinflammatory markers.^31,35,42 We explored whether disease pattern expression was associated with 2-year functioning in young patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD) and predicted by polygenic risk for FTD, AD, and schizophrenia. Conversely, we evaluated whether functional nonrecovery was linked to 1-year pattern progression in these patients. We also tested whether a structural magnetic resonance imaging (MRI)–based prognostic model of nonrecovery validated diagnostic patterns by predicting neurodegenerative and psychiatric disease expression in the case-control samples. Finally, to probe diagnostic specificity longitudinally, we explored whether neurodegenerative, schizophrenic, or nonrecovery patterns predicted cognitive decline in patients with mild cognitive impairment (MCI) or early-stage AD.

The eMethods section in Supplement 1 details our methods, and eFigure 1 in Supplement 1 schematically describes the overall analysis process. Each patient, participant, caregiver, or legal representative provided written informed consent in the projects providing data for the study. Local research ethics committees approved projects according to the principles of the Declaration of Helsinki. The study followed the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) reporting guideline.

In summary, we used the machine learning software NeuroMiner version 1.05 to generate 4 diagnostic classifiers differentiating between healthy controls (HCs) from patients with bvFTD (n = 108), established AD (n = 44), MCI or early-stage AD (n = 96), and schizophrenia (n = 157) based on age-standardized and cohort-adjusted gray matter volume maps to facilitate transdiagnostic comparisons across the life span (eTable 1 and eFigure 2 in Supplement 1). Gray matter volume maps were extracted from T1-weighted structural MRI scans (eTable 2 in Supplement 1). Trained diagnostic classifiers (eTable 4 in Supplement 1) were applied to all individuals who had not been involved in model derivation. Post hoc analyses were conducted to compare classifiers (McNemar and Quade tests), evaluate possible determinants of classifier predictions (ie, χ² tests, linear and cubic regression, t test, and analysis of variance), and explore their prognostic associations (linear mixed effects models). These analyses were performed in MATLAB version 2020a (MathWorks) and SPSS version 26 (IBM). Statistical significance was determined at α = .05 and 2-sided P values were corrected for multiple comparisons using the false discovery rate and Dunn-Sidak method for pairwise post-hoc tests as required by the respective analysis. Classifiers’ diagnostic signatures, decision score distributions, and patient class predictions were compared in Figure 1, the Table, and eFigures 3 to 4 in Supplement 1 and related to univariate measures in eFigures 5 to 6 in Supplement 1. Then, classifiers’ predictions were probed for confounds, including cohort provenance (eFigure 7 in Supplement 1); age, sex, image quality ratings, and total gray matter volume (eFigure 8 and eTable 5 in Supplement 1); patient subgroup effects (eFigures 9 and 10 in Supplement 1); and spatial nonspecificity, given the varying global brain atrophy present across disease cohorts (eFigure 11 in Supplement 1). Classifiers’ predictions were assessed for nonequality in each patient group (eTable 6 in Supplement 1). In addition, we produced BrainAGE predictions for participants using NeuroMiner to evaluate the specificity of findings against the transdiagnostic effects of accelerated aging (eFigures 12 and 13 in Supplement 1).⁴³ This analysis phase was completed by univariate analyses performed with Statistical Parametric Mapping (SPM12, Wellcome Department of Imaging Neuroscience, University College London) that contrasted topographies of diagnostic signatures while controlling for confounds (eFigures 14 and 15 in Supplement 1).

Next, we standardized decision scores, termed diagnostic expression scores in the following, and tested them for group-level differences (eFigure 16 in Supplement 1), including BrainAGE as covariate (eFigures 17 in Supplement 1). We also generated a differential diagnostic classifier in NeuroMiner to separate bvFTD from patients with established AD and explored how schizophrenia, MD, or MCI/early-stage AD groups were positioned in this neuroanatomical space (eFigure 18 in Supplement 1). Then, NeuroMiner was used to assess the predictability of diagnostic expression scores in bvFTD and schizophrenia samples by applying pattern regression to available sociodemographic, clinical, and biological variables (Figure 2; eTable 3 and eFigures 19 to 21 in Supplement 1).

After completing this analysis phase, we evaluated the prognostic value of diagnostic classifiers and BrainAGE by applying them to young patients with CHR (n = 160) or ROD (n = 161) drawn from the Personalised Prognostic Tools for Early Psychosis Management (PRONIA) study.^9,44 Linear mixed models were used to analyze 2-year functional trajectories in high vs low pattern expression groups (eFigure 22 and eTable 7 in Supplement 1), while accounting for BrainAGE effects (eTable 8 in Supplement 1). Genetic separability of pattern expression groups was explored using NeuroMiner based on polygenic risk scores (PRS) for FTD, AD, and schizophrenia (eFigure 23 in Supplement 1).

Next, we investigated the presence of a life span, transdiagnostic signature of poor disease outcome by training a prognostic classifier in NeuroMiner to separate nonrecovery from preserved recovery courses in patients with CHR or ROD (eFigures 24 to 26 in Supplement 1). We applied this classifier to the case-control samples to test associations with the previously produced diagnostic expression scores (Figure 3A), while controlling for BrainAGE effects (eTable 9 in Supplement 1). Additionally, the nonrecovery classifier underwent sensitivity analyses at more lenient nonrecovery definitions (eTable 10 in Supplement 1) and was diagnostically validated in case-control samples using receiver operating characteristic curve analyses (Figure 3B). Third, we evaluated whether the diagnostic expression scores generated for PRONIA patients could be used as features for an alternative nonrecovery predictor (eFigure 27 in Supplement 1). Fourth, we analyzed stratification effects of all diagnostic or prognostic classifiers on long-term cognitive decline in patients with MCI or early-stage AD (eFigure 28 and eTable 11 in Supplement 1). Finally, in patients with CHR or ROD with longitudinal MRI data (n = 216), 1-year diagnostic pattern progression was compared in patients with nonrecovery vs preserved recovery (Figure 4; eTable 12 in Supplement 1).

Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. Severe cognitive impairment (Clinical Dementia Rating [CDR] score greater than 3) was observed in patients with bvFTD (mean [SD] CDR, 5.6 [3.5]) and established AD (mean [SD] CDR, 5.5 [3.0]), different from patients with MCI or early-stage AD (mean [SD] CDR, 0.7 [2.7]) (eTable 1 in Supplement 1). Psychiatric symptoms differentiated bvFTD from established AD, ie, affective flattening and irritability/impulsivity. Accordingly, compared with patients with AD, patients with bvFTD more frequently received antipsychotics (antipsychotics (31 of 108 [28.7%] vs. 5 of 44 [11.4%]) and antidepressants (51 of 108 [47.2%] vs. 15 of 44 [34.1%]). The MCI/early-stage AD cohort was older (mean [SD] age, 73.3 [7.6] years; F_2,245 = 40.6; P < .001) than patients with established AD (mean [SD] age, 66.5 [8.7] years) who had been age matched to the bvFTD cohort. Most patients with MCI or early-stage AD (65 of 96 [67.7%]) fulfilled MCI criteria (CDR, 0.5) and thus presented early disease conditions.

Patients with schizophrenia were younger than the dementia or MD samples (mean [SD] age, 30.8 [10.0] years; F_4,502 = 373.3; P < .001). Both psychiatric samples had an illness duration of 4.5 years or more and showed moderate to severe symptoms. Most patients with schizophrenia were prescribed antipsychotics (133 of 157 [88.1%]), while only 18 of 102 patients with MD (17.6%) received these treatments (χ²₁ = 125.5; P < .001).

CHR samples (mean [SD] age, 23.8 [5.4] years) and ROD samples (mean [SD] age, 25.8 [6.1] years) were younger than patient cohorts (F_6,821 = 647.5; P < .001). Compared with patients with schizophrenia, they showed a mild disease severity (mean [SD] Positive and Negative Symptoms Scale: CHR, 46.1 [15.4]; ROD, 41.9 [10.8]). Both samples had moderate depression (mean [SD] Beck-Depression Inventory II⁴⁵: CHR, 23.8 [11.0]; ROD, 24.5 [12.3]) and hence less affected than patients with MD. A total of 34 of 160 patients with CHR (21.5%) and 28 of 161 with ROD (17.5%) received antipsychotics.

The highest neuroanatomical case-control separability was found in patients with bvFTD (balanced accuracy [BAC], 85.6%; eTable 4 in Supplement 1) and established AD (BAC, 86.0%), followed by MCI/early-stage AD (BAC, 74.4%) and schizophrenia (BAC, 70.8%). The 4 classifiers’ signatures covered similar extents of insular, middle/superior temporal, and medial temporal lobe structures, while the bvFTD and schizophrenia patterns specifically involved large parts of the cingulate and prefrontal areas as well as the Heschl gyri. The schizophrenia signature was most extended, encompassing cerebellar hemispheres, vermis, and occipital cortices, while the bvFTD signature involved caudate nuclei and putamen (Figure 1A-D; eFigure 3A in Supplement 1). Cross-validation ratio mapping (eMethods in Supplement 1) indicated that prefrontal, orbitofrontal, and insular cortices were most altered in the bvFTD pattern, while the schizophrenia signature showed peak alterations in the medial temporal lobe, occipital and inferior temporal cortices, the cerebellum, and the anterior thalamic nuclei compared with the other signatures (eFigure 4A in Supplement 1). The schizophrenia pattern was most dissimilar to the other signatures, while the 2 AD patterns strongly overlapped (eFigures 3B and 4B in Supplement 1). Classifiers were topographically specific and not biased by confounders (eResults and eFigures 8 to 15 in Supplement 1).

The bvFTD model case-labeled 32 of 44 patients with established AD (72.7%), 54 of 96 with MCI or early-stage AD (56.3%), 65 of 157 with schizophrenia (41.4%), and 22 of 102 with MD (21.6%) (Table). Conversely, the schizophrenia classifier case-labeled 92 of 108 patients with bvFTD (85.5%), 31 of 44 with established AD (70.5%), 63 of 96 with MCI or early-stage AD (65.6%), and 55 of 102 with MD (53.9%). Patients with schizophrenia and patients with MD were labeled 2.3-fold and 7.3-fold, respectively, more often with bvFTD than with established AD (28 of 157 [17.8%] and 3 of 102 [2.9%]) (Table); these patients were labeled 1.4-fold and 1.8-fold more often with bvFTD than with MCI or early-stage AD (47 of 157 [29.9%] and 12 of 102 [11.8%]) (Table; Figure 1). Reflecting a gradient of increasing neuroanatomical heterogeneity, classifiers similarly case-labeled patients with established AD and bvFTD, while they disagreed in patients with schizophrenia or MD (eTable 6 in Supplement 1).

The repeated-measures analysis of variance showed within-patient effects of classifier type (F_2.47 = 28.4; P < .001), between-patient effects of diagnostic group (F₄ = 62.9; P < .001), and interaction effects (F_9.9 = 40.0; P < .001) on diagnostic expression scores. In the post hoc comparisons (eFigure 16B in Supplement 1), patients with schizophrenia had higher bvFTD scores than established AD scores (mean difference [standard error]: 0.431 [0.072]; P < .001) or MCI/early-stage AD scores (0.265 [0.084]; P = .01), but their bvFTD and schizophrenia scores did not differ (−0.098 [0.069]; P = .64). These effects also characterized patients with MD (eFigure 16B in Supplement 1). Correcting for BrainAGE reduced scores in bvFTD and established AD compared with the other samples but did not change main or interaction effects (eFigure 17 in Supplement 1). Finally, the neuroanatomical alignment of schizophrenia and MD was confirmed by the differential-diagnostic classifier, which labeled 113 of 157 (72%) and 80 of 102 (78.5%), respectively, with bvFTD, while 65 of 96 patients with MCI/early-stage AD (67.7%) were labeled with established AD (eFigure 18 in Supplement 1).

Schizophrenia score predictability (R²) in bvFTD measured 0.283 (Figure 2A) and was higher than those patients’ respective AD scores (eFigures 19 and 21 in Supplement 1). C9orf72 carrier status (n = 11), oligoclonal banding in the cerebrospinal fluid (CSF), lower cognitive performance, younger age, and relatively reduced total CSF cell counts predicted higher schizophrenia scores (Figure 2B). Higher BrainAGE was not predicted by CSF markers or C9orf72 but instead by lower cognitive performance, female sex, lower impulsivity, no relationship/partner, and younger age (R² = 0.309; eFigure 19A in Supplement 1).

In patients with schizophrenia, bvFTD scores could be estimated (R² = 0.108), while their AD scores could not (Figure 2A; eFigures 20 and 21 in Supplement 1). Higher scores were determined by higher body mass index, reduced insight, psychomotor retardation, affective disinhibition, and paranoid ideation (Figure 2B). Reduced bvFTD scores were predicted by treatment with first-generation antipsychotics, disorganized behavior, hostility, and poor rapport (Figure 2B). BrainAGE was predicted by higher body mass index and a less specific psychopathological pattern compared with the bvFTD prediction model (R² = 0.074; eFigure 20A in Supplement 1).

Associations between global functioning trajectories and high vs low bvFTD or schizophrenia scores but not AD pattern expression were found in the PRONIA sample (bvFTD: F_1,772.9 = 15.5; P < .001; schizophrenia: F_1,774.6 = 13.6; P < .001) (eTable 7 and eFigure 22 in Supplement 1). bvFTD and schizophrenia pattern expression was associated with PRONIA study group (bvFTD: F_1,778.1 = 8.9; P = .003; schizophrenia: F_1,779.1 = 9.7; P = .002), with patients with CHR driving this effect. These patterns particularly stratified Functional Remission of General Schizophrenia (FROGS)⁴⁶ Daily Life and Relationships trajectories (eTable 7 in Supplement 1), while study group effects were prominent in the Activities and Quality of Adaptation domain. Main effects of BrainAGE on global functioning were detected across all 4 classifiers, but no interactions emerged (eTable 8 in Supplement 1).

The genetic classification analysis of high vs low pattern expression groups demonstrated PRS-based separability only in the bvFTD-defined and schizophrenia-defined strata of patients with CHR (bvFTD: BAC, 65.2%; P = .008; schizophrenia: BAC, 67.9%, P = .008) (eFigure 23 in Supplement 1). Discriminative functions involved transdiagnostic PRS patterns with increased FTD, AD, and schizophrenia PRS predicting high pattern expression at genome-wide thresholds (eFigure 23C in Supplement 1).

Stratification of the PRONIA sample for functional nonrecovery identified a transdiagnostic subgroup of 23 patients (10 with CHR and 13 with ROD) (eFigure 24A in Supplement 1) who did not improve over 2 years. The prognostic structural MRI classifier predicted recovery-related outcomes (BAC, 64.1%; P = .005) (eFigure 24B and C in Supplement 1) and showed topographic specificity (eFigure 26 in Supplement 1). An alternative prognostic model operating on age, sex, diagnostic expression scores, and BrainAGE performed with a BAC of 68.8% (eFigure 27 in Supplement 1), with bvFTD expression and BrainAGE being the most predictive features. The prognostic and diagnostic classifiers (1) overlapped in the prefrontal, cingulate, hippocampal, parahippocampal, insular, and cerebellar cortices (eFigures 24D and 25 in Supplement 1); (2) produced correlated diagnostic expression scores in schizophrenia (R² = 0.85), MCI and early-stage AD (R² = 0.60), established AD (R² = 0.48), and bvFTD (R² = 0.15) (Figure 3A; eTable 9 in Supplement 1); and (3) induced similar areas under the curve as the case-control classifiers in the respective samples (Figure 3B; eTables 4 and 10 in Supplement 1). A sensitivity analysis showed that a more lenient nonrecovery cutoff weakened prognostic-diagnostic associations (eTable 10 in Supplement 1). Finally, prognostic and diagnostic classifiers invariantly predicted 9-year cognitive decline in patients with MCI or early-stage AD (eResults, eTable 12, and eFigure 28 in Supplement 1).

We observed a 1-year progression of diagnostic patterns in patients with nonrecovery CHR and ROD. Significant effects on patients’ diagnostic assignments included recovery type (Wald χ²₁ = 9.0; P = .003), classifier type (Wald χ²₃ = 41.1; P < .001), and time point (Wald χ²₁ = 8.8; P = .003) (eTable 11 in Supplement 1) and were driven by bvFTD or schizophrenia pattern progression (bvFTD. 23.8%; P = .02; schizophrenia, 20%; P = .03) compared with preserved-recovery individuals (bvFTD, 1.0%; P = .40; schizophrenia, 1.0%; P = .54) (Figure 4; eTable 11 in Supplement 1). BrainAGE showed a main effect on diagnostic assignment (Wald χ²₁ = 28.1; P = .003), but no interactions effects.

The comparative machine learning analysis of the neuroanatomical patterns of bvFTD, AD, and schizophrenia revealed a frontotemporal interface between bvFTD and schizophrenia. BrainAGE correction did not alter the specificity of this interface but reduced overall group differences, in line with findings of BrainAGE increasing from affective, over psychotic to neurodegenerative disorders.⁴⁰ Differential diagnostic classification confirmed the alignment of psychiatric cohorts with bvFTD rather than AD and an interaction between BrainAGE and bvFTD pattern expression in patients with MD, extending our previous findings.³⁸ More generally, we observed a gradient of increasing neuroanatomical heterogeneity ranging from bvFTD to schizophrenia and MD due to a stronger differentiation of disease signatures in patients with schizophrenia and MD. Thus, these signatures could provide meaningful intermediate phenotypes of neurofunctional systems differentially affected by bvFTD and AD and facilitate the decomposition of neurobiological heterogeneity in psychiatric disorders.⁴⁷

Brain patterns of schizophrenia and bvFTD were linked to sociodemographic, clinical, and biological variables available in each cohort and could be predicted with higher precision than AD patterns. This observation corroborated our hypothesis of a neuroanatomical interface between the 2 disease groups, which may be associated with shared clinical and biological dimensions; in schizophrenia, bvFTD expression was predicted by body mass index, psychomotor slowing, reduced insight, affective disinhibition, and paranoid ideation. These findings agree with previous reports of prominent prefrontal, limbic, and paralimbic volume reductions in patients with Kraepelinian manifestations, ie, courses characterized by psychosocial disability and treatment-refractory negative symptoms.^3,10,48,49 Conversely, patients with bvFTD with high schizophrenia scores were more likely to be younger, carry the C9orf72 variant, show oligoclonal banding without increased CSF cell count, and have more cognitive deficits. Of note, patients with C9orf72-mediated bvFTD typically present with earlier and more pronounced neurocognitive impairment compared with noncarriers.^33,50

These findings may speculatively point to neuroinflammatory alterations shared by psychotic disorders and bvFTD. Recent studies revealed that the C9orf72 variant activates proinflammatory pathways along the gut-brain axis,³¹ and thus contributes to microglia-mediated inflammation in bvFTD.⁵¹ Data from a recently discovered bvFTD risk-gene network further suggests that pathways involving microglia-initiated immune responses are overexpressed in prefrontal and salience systems, with a predilection for layer V neurons.³⁵ Elevated neuroinflammatory markers have also been reported in schizophrenia,^52-54 pointing to a dysregulation of neural development mediated by low-grade neuroinflammation.³⁷ Hence, neuroinflammatory pathways may be associated with cognitive and functional impairments, potentially driving progressive brain changes in early stages of schizophrenia.^55,56

Following these hypotheses and because of potential chronicity effects in our case-control cohorts,⁵⁷ we applied the diagnostic classifiers to the young PRONIA patients and explored their longitudinal clinical associations. Independent of BrainAGE, we found that bvFTD and schizophrenia pattern expression at baseline, but not AD expression, were associated with reduced 2-year multidomain functioning in patients with CHR. These observations extended our initial cross-sectional findings to the time domain and to psychosis risk syndromes.

Neuroanatomical findings were supported by the genetic separability of high vs low bvFTD and schizophrenia pattern expression individuals in the CHR sample. At stricter genome-wide significance thresholds, increased PRS for FTD, AD, or schizophrenia were predictive of high pattern expression, potentially pointing to pathophysiological overlaps between neurodegenerative and psychotic disorders. These findings require independent replication and further mechanistic exploration using gene expression analysis.

Based on these findings, we explored the neuroanatomical continuum between diagnostic and prognostic disease patterns via the clinical stratification of PRONIA patients into individuals with vs without 2-year functional recovery. We found that a prognostic signature of nonrecovery was topographically aligned with diagnostic classifiers, and accordingly, it explained diagnostic expression score variation in patients with established disorders. These effects remained significant after controlling for BrainAGE, suggesting that accelerated aging⁴³ only partly accounted for these correlations. These findings were supported by the fair to excellent accuracy with which the prognostic model separated cases from controls. These results were sensitive to the strictness of the nonrecovery cutoff, indicating that only PRONIA patients with the worst functional outcomes were neuroanatomically aligned with bvFTD, AD, or schizophrenia.

Furthermore, in our longitudinal MRI analysis, we found heightened bvFTD and schizophrenia expression in patients with nonrecovery, which further increased over 1 year and was independent of BrainAGE-related variation. In contrast to these specific effects in young patients, we found that all diagnostic, prognostic, and BrainAGE patterns invariably predicted faster 9-year cognitive decline in patients with MCI or early-stage AD. This global effect may point to a life span brain signature of risk for cognitive decline, potentially constituting the neuroanatomical surrogate of increased dementia risk reported across different psychiatric disorders.^5,6,25,58-61

Our results support the reciprocity of brain signatures of early functional nonrecovery and neuropsychiatric illnesses. This reciprocity may point to a common final pathway of prefrontal and salience system disruption onto which diverse and potentially unrelated disease mechanisms converge. This final pathway may originate in the von Economo neurons (VEN), which occupy cortical layer V of the human salience system, including the anterior insula, cingulate cortex, and subcortical structures.⁶² VEN are believed to be involved in interpersonal functioning, empathy, and cognitive control.^63,64 In bvFTD, they are affected early,⁶⁵ with links between salience network atrophy and loss of empathy.⁶⁶

Salience network abnormalities are well-replicated in psychiatric research^67,68 and may progress early in psychosis.^17,18 These alterations may moderate cognitive and functional deficits by impairing the integration of internal and task-oriented mental activity.⁶⁹ Despite neuroimaging-based findings, histological studies of the salience network in psychiatric disorders are still rare. Two post mortem studies reported reduced density of and increased lysosomal aggregations in VEN in schizophrenia but not bipolar disorder.^70,71 VEN abnormalities may characterize bvFTD and schizophrenia-spectrum disorders but not bipolar disorders⁷¹ or behavioral-variant AD.⁷² Taken together, these and our findings may point to VEN alterations across psychosis and frontotemporal dementia, which warrant careful histopathological and transcriptomic exploration in post-mortem samples.

Our study has several limitations. First, the follow-up interval of the PRONIA sample was shorter (2 years) compared with the OASIS-3 cohort (9 years), which may have reduced our ability to detect prognostic associations produced by AD patterns in the former sample. Second, the robustness of the nonrecovery signature might be limited because of training sample size, although its validation in the case-control cohorts speak for the opposite. Third, we cannot exclude that the potential alignment of bvFTD and psychosis-related brain patterns might have been partly confounded by overlapping treatment effects in both disease cohorts.⁷³ However, we found that antipsychotic treatment predicted lower bvFTD pattern expression in schizophrenia and did not associate with schizophrenia expression in bvFTD. Finally, bvFTD encompasses different disease pathologies, producing heterogeneous cognitive-behavioral phenotypes.³⁴ Because of training sample size limitations, we could not quantify how this heterogeneity influenced our results.

In summary,⁷⁴ we identified specific overlaps between macroscopic brain signatures of schizophrenia and bvFTD. These overlaps mediated aspects of the clinical-behavioral heterogeneity of both conditions, ie, a negative avolitional syndrome in the former, and a potentially neuroinflammation-associated phenotype involving neurocognitive dysfunction in the latter. We found that the presence of bvFTD and schizophrenia patterns in patients with psychosis risk syndromes predicted impaired functional recovery. Finally, our study revealed that young patients with poor functional outcomes overexpressed these brain patterns over time, in line with Kraepelin’s concept of dementia praecox as a progressive frontotemporal disorder. Further studies into molecular disease pathways are needed to clarify how different pathophysiological processes project on overlapping neural alterations in bvFTD and schizophrenia-spectrum disorders.

Accepted for Publication: June 12, 2022.

Published Online: August 3, 2022. doi:10.1001/jamapsychiatry.2022.2075

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Koutsouleris N et al. JAMA Psychiatry.

Corresponding Author: Nikolaos Koutsouleris, MD, Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstr 7, D-80336 Munich, Germany (nikolaos.koutsouleris@med.uni-muenchen.de); Matthias L. Schroeter, MD, MA, PhD, Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr 1A, 04103 Leipzig, Germany (schroet@cbs.mpg.de).

Author Contributions: Dr Koutsouleris had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Koutsouleris, Velakoulis, McGuire, Kambeitz, Salokangas, Hietala, Bertolino, Brambilla, Borgwardt, Mueller, Landwehrmeyer, Wiltfang, Schroeter.

Acquisition, analysis, or interpretation of data: Koutsouleris, Pantelis, Dwyer, Urquijo-Castro, Paul, Dong, Popovic, Oeztuerk, Kambeitz, Hietala, Brambilla, Upthegrove, Wood, Lencer, Borgwardt, Maj, Nöthen, Degenhardt, Polyakova, Mueller, Villringer, Danek, Fassbender, Fliessbach, Jahn, Kornhuber, Landwehrmeyer, Anderl-Straub, Prudlo, Synofzik, Wiltfang, Riedl, Diehl-Schmid, Otto, Meisenzahl, Falkai, Schroeter.

Drafting of the manuscript: Koutsouleris, Velakoulis, Schroeter.

Critical revision of the manuscript for important intellectual content: Koutsouleris, Pantelis, McGuire, Dwyer, Urquijo-Castro, Paul, Dong, Popovic, Oeztuerk, Kambeitz, Salokangas, Hietala, Bertolino, Brambilla, Upthegrove, Wood, Lencer, Borgwardt, Maj, Nöthen, Degenhardt, Polyakova, Mueller, Villringer, Danek, Fassbender, Fliessbach, Jahn, Kornhuber, Landwehrmeyer, Anderl-Straub, Prudlo, Synofzik, Wiltfang, Riedl, Diehl-Schmid, Otto, Meisenzahl, Falkai, Schroeter.

Statistical analysis: Koutsouleris, Popovic, Maj, Schroeter.

Obtained funding: Koutsouleris, Pantelis, Brambilla, Upthegrove, Borgwardt, Jahn, Diehl-Schmid, Otto, Schroeter.

Administrative, technical, or material support: Koutsouleris, McGuire, Paul, Dong, Kambeitz, Hietala, Brambilla, Upthegrove, Lencer, Degenhardt, Polyakova, Mueller, Jahn, Kornhuber, Landwehrmeyer, Anderl-Straub, Riedl, Diehl-Schmid, Schroeter.

Study supervision: Kambeitz, Salokangas, Hietala, Bertolino, Brambilla, Upthegrove, Borgwardt, Nöthen, Fassbender, Jahn, Landwehrmeyer, Prudlo, Wiltfang, Meisenzahl, Schroeter.

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.

Funding/Support: This study was supported by the European Commission and the German Federal Ministry of Education and Research.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

International FTD-Genetics Consortium (IFGC), the German Frontotemporal Lobar Degeneration (FTLD) Consortium, and the PRONIA Consortium: A complete list of the members of the IFGC, the German FTLD Consortium, and the PRONIA Consortium appears in Supplement 2.

Additional Contributions: We thank the principal investigators Tammie Benzinger, MD, PhD, and Daniel S. Marcus, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, for making the OASIS-3 data openly available for analysis. No compensation was provided. We thank the PRONIA collaborators listed in Supplement 2, who performed the screening, recruitment, rating, examination, and follow-up of the PRONIA study participants. We are grateful to the German Frontotemporal Lobar Degeneration (FTLD) Consortium, which gave us access to their database of participants with behavioral-variant frontotemporal dementia and Alzheimer disease as well as healthy controls. Finally, we thank the International FTD-Genetics Consortium (IFGC) that made the summary statistics for the computation of the frontotemporal dementia polygenic risk scores publicly available.