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1. Pattern of predictive features of continued cannabis use in patients with recent-onset psychosis and clinical high-risk for psychosis

Author

Nora Penzel, Rachele Sanfelici, Linda A. Antonucci, Linda T. Betz, Dominic Dwyer, Anne Ruef, Kang Ik K. Cho, Paul Cumming, Oliver Pogarell, Oliver Howes, Peter Falkai, Rachel Upthegrove, Stefan Borgwardt, Paolo Brambilla, Rebekka Lencer, Eva Meisenzahl, Frauke Schultze-Lutter, Marlene Rosen, Theresa Lichtenstein, Lana Kambeitz-Ilankovic, Stephan Ruhrmann, Raimo K. R. Salokangas, Christos Pantelis, Stephen J. Wood, Boris B. Quednow, Giulio Pergola, Alessandro Bertolino, Nikolaos Koutsouleris, Joseph Kambeitz, and the PRONIA Consortium

Subjects
Psychiatry, RC435-571
Abstract

Abstract Continued cannabis use (CCu) is an important predictor for poor long-term outcomes in psychosis and clinically high-risk patients, but no generalizable model has hitherto been tested for its ability to predict CCu in these vulnerable patient groups. In the current study, we investigated how structured clinical and cognitive assessments and structural magnetic resonance imaging (sMRI) contributed to the prediction of CCu in a group of 109 patients with recent-onset psychosis (ROP). We tested the generalizability of our predictors in 73 patients at clinical high-risk for psychosis (CHR). Here, CCu was defined as any cannabis consumption between baseline and 9-month follow-up, as assessed in structured interviews. All patients reported lifetime cannabis use at baseline. Data from clinical assessment alone correctly classified 73% (p 0.093), and their addition to the interview-based predictor via stacking did not improve prediction significantly, either in the ROP or CHR groups (ps > 0.065). Lower functioning, specific substance use patterns, urbanicity and a lack of other coping strategies contributed reliably to the prediction of CCu and might thus represent important factors for guiding preventative efforts. Our results suggest that it may be possible to identify by clinical measures those psychosis-spectrum patients at high risk for CCu, potentially allowing to improve clinical care through targeted interventions. However, our model needs further testing in larger samples including more diverse clinical populations before being transferred into clinical practice.

Published
2022
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2. Anhedonia as a Potential Transdiagnostic Phenotype With Immune-Related Changes in Recent-Onset Mental Health Disorders.

Author

Lalousis, PA, Malaviya, A, Khatibi, A, Saberi, M, Kambeitz-Ilankovic, L, Haas, SS, Wood, SJ, Barnes, NM, Rogers, J, Chisholm, K, Bertolino, A, Borgwardt, S, Brambilla, P, Kambeitz, J, Lencer, R, Pantelis, C, Ruhrmann, S, Salokangas, RKR, Schultze-Lutter, F, Schmidt, A, Meisenzahl, E, Dwyer, D, Koutsouleris, N, Upthegrove, R, Griffiths, SL, PRONIA Consortium, Lalousis, PA, Malaviya, A, Khatibi, A, Saberi, M, Kambeitz-Ilankovic, L, Haas, SS, Wood, SJ, Barnes, NM, Rogers, J, Chisholm, K, Bertolino, A, Borgwardt, S, Brambilla, P, Kambeitz, J, Lencer, R, Pantelis, C, Ruhrmann, S, Salokangas, RKR, Schultze-Lutter, F, Schmidt, A, Meisenzahl, E, Dwyer, D, Koutsouleris, N, Upthegrove, R, Griffiths, SL, and PRONIA Consortium

Abstract

BACKGROUND: Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes, reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in people with enduring illness, but few have explored inflammatory changes. We sought to identify an inflammatory signal and the associated brain function underlying anhedonia among young people with recent-onset psychosis and recent-onset depression. METHODS: Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from 108 (mean [SD] age = 26.2 [6.2] years; female = 50) participants with recent-onset psychosis (n = 53) and recent-onset depression (n = 55) from the European Union/Seventh Framework Programme-funded PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Time series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and a functional connectivity model were developed to classify participants into an anhedonic group or a normal hedonic group. RESULTS: A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic recent-onset psychosis/recent-onset depression groups with a balanced accuracy of 63.9% and an area under the curve of 0.61. The functional connectivity model produced a balanced accuracy of 55.2% and an area under the curve of 0.57. Anhedonic group assignment was driven by higher levels of interleukin 6, S100B, and interleukin 1 receptor antagonist and lower levels of interferon gamma, in addition to connectivity within the precuneus and posterior cingulate. CONCLUSIONS: We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications

Published
2024

3. Alterations of Functional Connectivity Dynamics in Affective and Psychotic Disorders.

Author

Hoheisel, L, Kambeitz-Ilankovic, L, Wenzel, J, Haas, SS, Antonucci, LA, Ruef, A, Penzel, N, Schultze-Lutter, F, Lichtenstein, T, Rosen, M, Dwyer, DB, Salokangas, RKR, Lencer, R, Brambilla, P, Borgwardt, S, Wood, SJ, Upthegrove, R, Bertolino, A, Ruhrmann, S, Meisenzahl, E, Koutsouleris, N, Fink, GR, Daun, S, Kambeitz, J, PRONIA Consortium, Hoheisel, L, Kambeitz-Ilankovic, L, Wenzel, J, Haas, SS, Antonucci, LA, Ruef, A, Penzel, N, Schultze-Lutter, F, Lichtenstein, T, Rosen, M, Dwyer, DB, Salokangas, RKR, Lencer, R, Brambilla, P, Borgwardt, S, Wood, SJ, Upthegrove, R, Bertolino, A, Ruhrmann, S, Meisenzahl, E, Koutsouleris, N, Fink, GR, Daun, S, Kambeitz, J, and PRONIA Consortium

Abstract

BACKGROUND: Patients with psychosis and patients with depression exhibit widespread neurobiological abnormalities. The analysis of dynamic functional connectivity (dFC) allows for the detection of changes in complex brain activity patterns, providing insights into common and unique processes underlying these disorders. METHODS: We report the analysis of dFC in a large sample including 127 patients at clinical high risk for psychosis, 142 patients with recent-onset psychosis, 134 patients with recent-onset depression, and 256 healthy control participants. A sliding window-based technique was used to calculate the time-dependent FC in resting-state magnetic resonance imaging data, followed by clustering to reveal recurrent FC states in each diagnostic group. RESULTS: We identified 5 unique FC states, which could be identified in all groups with high consistency (mean r = 0.889 [SD = 0.116]). Analysis of dynamic parameters of these states showed a characteristic increase in the lifetime and frequency of a weakly connected FC state in patients with recent-onset depression (p < .0005) compared with the other groups and a common increase in the lifetime of an FC state characterized by high sensorimotor and cingulo-opercular connectivities in all patient groups compared with the healthy control group (p < .0002). Canonical correlation analysis revealed a mode that exhibited significant correlations between dFC parameters and clinical variables (r = 0.617, p < .0029), which was associated with positive psychosis symptom severity and several dFC parameters. CONCLUSIONS: Our findings indicate diagnosis-specific alterations of dFC and underline the potential of dynamic analysis to characterize disorders such as depression and psychosis and clinical risk states.

Published
2024

4. General psychopathology links burden of recent life events and psychotic symptoms in a network approach

Author

Linda T. Betz, Nora Penzel, Lana Kambeitz-Ilankovic, Marlene Rosen, Katharine Chisholm, Alexandra Stainton, Theresa K. Haidl, Julian Wenzel, Alessandro Bertolino, Stefan Borgwardt, Paolo Brambilla, Rebekka Lencer, Eva Meisenzahl, Stephan Ruhrmann, Raimo K. R. Salokangas, Frauke Schultze-Lutter, Stephen J. Wood, Rachel Upthegrove, Nikolaos Koutsouleris, Joseph Kambeitz, and the PRONIA consortium

Subjects
Psychiatry, RC435-571
Abstract

Abstract Recent life events have been implicated in the onset and progression of psychosis. However, psychological processes that account for the association are yet to be fully understood. Using a network approach, we aimed to identify pathways linking recent life events and symptoms observed in psychosis. Based on previous literature, we hypothesized that general symptoms would mediate between recent life events and psychotic symptoms. We analyzed baseline data of patients at clinical high risk for psychosis and with recent-onset psychosis (n = 547) from the Personalised Prognostic Tools for Early Psychosis Management (PRONIA) study. In a network analysis, we modeled links between the burden of recent life events and all individual symptoms of the Positive and Negative Syndrome Scale before and after controlling for childhood trauma. To investigate the longitudinal associations between burden of recent life events and symptoms, we analyzed multiwave panel data from seven timepoints up to month 18. Corroborating our hypothesis, burden of recent life events was connected to positive and negative symptoms through general psychopathology, specifically depression, guilt feelings, anxiety and tension, even after controlling for childhood trauma. Longitudinal modeling indicated that on average, burden of recent life events preceded general psychopathology in the individual. In line with the theory of an affective pathway to psychosis, recent life events may lead to psychotic symptoms via heightened emotional distress. Life events may be one driving force of unspecific, general psychopathology described as characteristic of early phases of the psychosis spectrum, offering promising avenues for interventions.

Published
2020
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5. Prevalence of cognitive impairments and strengths in the early course of psychosis and depression

Author

PRONIA Consortium and PRONIA Consortium

Abstract

Background Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. Methods A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. Results Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. Conclusions These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.

Published
2023

6. The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study

Author

Oeztuerk, Oemer Faruk, Pigoni, Alessandro, Wenzel, Julian, Haas, Shalaila S, Popovic, David, Ruef, Anne, Dwyer, Dominic B, Kambeitz-Ilankovic, Lana, Ruhrmann, Stephan, Chisholm, Katharine, Lalousis, Paris, Griffiths, Sian Lowri, Lichtenstein, Theresa, Rosen, Marlene, Kambeitz, Joseph, Schultze-Lutter, Frauke, Liddle, Peter, Upthegrove, Rachel, Salokangas, Raimo K R, Pantelis, Christos, Meisenzahl, Eva, Wood, Stephen J, Brambilla, Paolo, Borgwardt, Stefan, Falkai, Peter, Antonucci, Linda A, Koutsouleris, Nikolaos, and PRONIA Consortium

Subjects
mental disorders
Abstract

Background: Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. Methods: 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Results: The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (p fdr < 0.001) and role (p fdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (p fdr < 0.001) and phonological verbal fluency (p fdr < 0.001), short-term verbal memory (p fdr = 0.002) and abstract thinking (p fdr = 0.010), in comparison to FTD-Low group. Conclusions: Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.

Published
2021

7. The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study

Author

PRONIA Consortium, Oeztuerk, Oemer Faruk, Pigoni, Alessandro, Wenzel, Julian, Haas, Shalaila S, Popovic, David, Ruef, Anne, Dwyer, Dominic B, Kambeitz-Ilankovic, Lana, Ruhrmann, Stephan, Chisholm, Katharine, Lalousis, Paris, Griffiths, Sian Lowri, Lichtenstein, Theresa, Rosen, Marlene, Kambeitz, Joseph, Schultze-Lutter, Frauke, Liddle, Peter, Upthegrove, Rachel, Salokangas, Raimo K R, Pantelis, Christos, Meisenzahl, Eva, Wood, Stephen J, Brambilla, Paolo, Borgwardt, Stefan, Falkai, Peter, Antonucci, Linda A, Koutsouleris, Nikolaos, PRONIA Consortium, Oeztuerk, Oemer Faruk, Pigoni, Alessandro, Wenzel, Julian, Haas, Shalaila S, Popovic, David, Ruef, Anne, Dwyer, Dominic B, Kambeitz-Ilankovic, Lana, Ruhrmann, Stephan, Chisholm, Katharine, Lalousis, Paris, Griffiths, Sian Lowri, Lichtenstein, Theresa, Rosen, Marlene, Kambeitz, Joseph, Schultze-Lutter, Frauke, Liddle, Peter, Upthegrove, Rachel, Salokangas, Raimo K R, Pantelis, Christos, Meisenzahl, Eva, Wood, Stephen J, Brambilla, Paolo, Borgwardt, Stefan, Falkai, Peter, Antonucci, Linda A, and Koutsouleris, Nikolaos

Abstract

Background: Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. Methods: 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Results: The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (p fdr < 0.001) and role (p fdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (p fdr < 0.001) and phonological verbal fluency (p fdr < 0.001), short-term verbal memory (p fdr = 0.002) and abstract thinking (p fdr = 0.010), in comparison to FTD-Low group. Conclusions: Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.

Published
2021

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

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. 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.

Published
2022

10. Clinical, brain, and multilevel clustering in early psychosis and affective stages

Author

Dwyer, Dominic B., Buciuman, Madalina-Octavia, Ruef, Anne, Kambeitz, Joseph, Sen Dong, Mark, Stinson, Caedyn, Kambeitz-Ilankovic, Lana, Degenhardt, Franziska, Sanfelici, Rachele, Antonucci, Linda A., Lalousis, Paris Alexandros, Wenzel, Julian, Urquijo-Castro, Maria Fernanda, Popovic, David, Oeztuerk, Oemer Faruk, Haas, Shalaila S., Weiske, Johanna, Hauke, Daniel, Neufang, Susanne, Schmidt-Kraepelin, Christian, Ruhrmann, Stephan, Penzel, Nora, Lichtenstein, Theresa, Rosen, Marlene, Chisholm, Katharine, Riecher-Rössler, Anita, Egloff, Laura, Schmidt, André, Andreou, Christina, Hietala, Jarmo, Schirmer, Timo, Romer, Georg, Michel, Chantal, Rössler, Wulf, Maj, Carlo, Borisov, Oleg, Krawitz, Peter M., Falkai, Peter, Pantelis, Christos, Lencer, Rebekka, Bertolino, Alessandro, Borgwardt, Stefan, Noethen, Markus, Brambilla, Paolo, Schultze-Lutter, Frauke, Meisenzahl, Eva, Wood, Stephen J., Davatzikos, Christos, Upthegrove, Rachel, Salokangas, Raimo K. R., Koutsouleris, Nikolaos, Mackintosh, Amatya, Kaiser, Nathalie, Lichtenstein, Thorsten, Seves, Mauro, Chisholm, Katie, Reniers, Renate, Stainton, Alexandra, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Tuominen, Lauri, Luutonen, Sinikka, Paju, Janina, Tikka, Maria, Armio (Säilä), Reetta-Liina, Toivonen, Anna, Walta, Maija, Fabbro, Franco, Balestrieri, Matteo, Bonivento, Carolina, Garzitto, Marco, Cabras, Giuseppe, Piccin, Sara, Castellani, Umberto, Bellani, Marcella, Maieron, Marta, Girometti, Rossano, Zuiani, Chiara, Skafidas, Stan, Velakoulis, Dennis, Everall, Ian, Merritt, Antonia, Jovicevic, Michael, Plicht, Manuel, Bequé, Dirk, Solana Sánchez, Ana Beatriz, Hehn, Nicolas, Herrmann, Katrin, Burke, Michael X., Fernandez, Brice, Altamura, Carlo, Rango, Mario, Ferro, Adele, Belleri, Marika, Maggioni, Eleonora, Squarcina, Letizia, Re, Marta, Delvecchio, Giuseppe, Meneghelli, Anna, Monzani, Emiliano, Sassi, Roberto, Sberna, Maurizio, Gennari, Luciana, Torremante, Patrizia, Surmann, Marian, Dannlowski, Udo, Bienek, Olga, Blasi, Giuseppe, Pergola, Giulio, Quarto, Tiziana, Andriola, Ileana, Romano, Raffaella, Gelao, Barbara, Fazio, Leonardo, Korda, Alexandra, Rohner, Henrik, Mann, Matthias, Geyer, Phillip, Treit, Peter, Müller, Johannes, Frackowiak, Richard, Wasserman, Danuta, Maier, Wolfgang, Binder, Elisabeth, Woopen, Christiane, Spranger, Tade Matthias, Möhrmann, Karl-Heinz, and PRONIA Consortium

Subjects
Adult, Male, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Medizin, Brain, Cluster Analysis, Humans, Female, Longitudinal Studies, 610 Medizin und Gesundheit, Original Investigation
Abstract

Importance Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. Objective To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. Design, Setting, and Participants A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. Main Outcomes and Measures A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. Results There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. Conclusions and Relevance The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.

Published
2022

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