The Institute of Translational Neuroscience is an independent research institution at the Medical Faculty of the University Münster. It is dedicated to provide new options for diagnostic and/or therapeutic strategies for human diseases of the nervous system. This “bench to bedside” approach builds on molecular research pursued during the last 30 years which paved the avenue for novel therapeutic strategies to be assessed in man. It follows the idea that neuroscience is a discipline providing understanding of human disease and eventually its cure, rather than to explain man itself. Translation defines the goal of basic research, the patient. While experimental studies are pursued in close collaboration with the Institute of Anatomy, University of Cologne (Director: Prof. Dr. med. Johannes Vogt), clinical studies are performed in close collaboration with the Institute of Translational Psychiatry, University Münster (Director: Prof. Dr. med. Dr. phil. Udo Dannlowski).

In addition to translational research, philosophical aspects of the mind-body debate are addressed and a focus of the Institute’s teaching activities. The ever-recurring attempts of the neurosciences to explain all mental phenomena in physical terms alone are revised by critical reappraisal of classical concepts, e.g. Wilder Penfield’s “storehouse of memories”. Our analyzes question the idea of a realization of memory in solely naturalistic terms. These studies are performed in part at the Montreal Neurological Institute (Prof. Dr. Richard Leblanc, Prof. Dr. Jack Antel), Quebec, Canada, and in close collaboration with Prof. Dr. med. Frank Stahnisch at the Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.

Flinkenflügel K*, Meinert S*, Hirtsiefer C, Grotegerd D, Gruber M, Goltermann J , Winter NR, Stein F,  Brosch K, Leehr EJ, Böhnlein J, Dohm K, Bauer J, Redlich R, Hahn T, Repple J, Opel N, Nitsch R, Jamalabadi H, Straube B, Alexander N, Jansen A, Nenadić I, van den Heuvel MP, Thiel K, Winter A, Thomas-Odenthal F, Usemann P, Teutenberg L, Pfarr JK, Kircher T, Dannlowksi U (2024). Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study. The Lancet Psychiatry 11(11):899-909 (*equal contribution). (full article)

Background

Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset.

Methods

In the naturalistic, observational, prospective, case-control Marburg-Münster Affective Disorders Cohort Study, individuals aged 18–65 years and of Caucasian ancestry were recruited from local psychiatric hospitals in Münster and Marburg, Germany, and newspaper advertisements. Individuals diagnosed with MDD and individuals without any history of psychiatric disorder (ie, healthy controls) were included in this subsample analysis. Participants had diffusion-weighted imaging, a battery of neuropsychological tests, and detailed clinical data collected at baseline and at 2 years of follow-up. We used linear mixed-effect models to compare changes in cognitive performance and white matter integrity between participants with MDD and healthy controls. Diffusion-weighted imaging analyses were conducted using tract-based spatial statistics. To correct for multiple comparisons, threshold free cluster enhancement (TFCE) was used to correct α-values at the family-wise error rate (FWE; ptfce-FWE). Effect sizes were estimated by conditional, partial R2 values (sr2) following the Nakagawa and Schielzeth method to quantify explained variance. The association between changes in cognitive performance and changes in white matter integrity was analysed. Finally, we examined whether the depressive disease course between assessments predicted cognitive performance at follow-up and whether white matter integrity mediated this association. People with lived experience were not involved in the research and writing process.

Findings

881 participants were selected for our study, of whom 418 (47%) had MDD (mean age 36·8 years [SD 13·4], 274 [66%] were female, and 144 [34%] were male) and 463 (53%) were healthy controls (mean age 35·6 years [13·5], 295 [64%] were female, and 168 [36%] were male). Baseline assessments were done between Sept 11, 2014, and June 3, 2019, and after a mean follow-up of 2·20 years (SD 0·19), follow-up assessments were done between Oct 6, 2016, and May 31, 2021. Participants with MDD had lower cognitive performance than did healthy controls (p<0·0001, sr2=0·056), regardless of timepoint. Analyses of diffusion-weighted imaging indicated a significant diagnosis × time interaction with a steeper decline in white matter integrity of the superior longitudinal fasciculus over time in participants with MDD than in healthy controls (ptfce-FWE=0·026, sr2=0·002). Furthermore, cognitive decline was robustly associated with the decline in white matter integrity over time across both groups (ptfce-FWE<0·0001, sr2=0·004). In participants with MDD, changes in white matter integrity (p=0·0040, β=0·071) and adverse depressive disease course (p=0·0022, β=–0·073) independently predicted lower cognitive performance at follow-up.

Interpretation

Alterations of white matter integrity occurred over time to a greater extent in participants with MDD than in healthy controls, and decline in white matter integrity was associated with a decline in cognitive performance across groups. Our findings emphasise the crucial role of white matter microstructure and disease progression in depression-related cognitive dysfunction, making both priority targets for future treatment development.

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