Searching for patomechanisms of late life minor depression

The doctoral dissertation: Searching for pathomechanisms of late-life minor depression – a combined MRI, biomarker and meta-analytic study was one of the first studies investigating the underlying pathophysiology of minor depression. The dissertation comprises a systematic review of the prevalence rates of minor depression, two meta-analyses of peripheral BDNF changes in major depressive disorder, as well as two original studies investigating serum BDNF, S100B and NSE levels and gray matter changes in minor depression. The limitations of studies and proposed improvements to the study design are discussed extensively.:1. INTRODUCTION 1.1 Motivation 1.1.1 Minor depression in the spectrum of psychiatric disorders 1.1.2 Minor depression is prevalent but unrecognized. 1.2 Theoretical background 1.2.1 Overview of depression hypotheses 1.2.2 Neurotrophic hypothesis of depressive disorders 1.2.3 Glial hypothesis of depressive disorders 1.2.4 Structural neuroimaging changes in major depression 1.3. Rationale and hypotheses of the empirical studies 1.3.1 Research questions 1.3.2 Research hypotheses 2. EMPIRICAL STUDIES 2.1 The prevalence of minor depression in the late life 2.2 The meta-analysis of BDNF changes in mood disorders 2.3 The meta-analysis of BDNF changes following ECT in depression 2.4 Serum biomarkers in minor depression 2.5 Structural brain imaging in minor depression 3. GENERAL DISCUSSION 3.1 Summary of results 3.2 Implications for research 3.3 Implications for clinical studies SUMMARY REFERENCES APPENDIX A: DECLARATION OF CONTRIBUTION APPENDIX B: STATEMENT OF AUTHORSHIP APPENDIX C: CURRICULUM VITAEAPPENDIX D: ACADEMIC CONTRIBUTIONS APPENDIX E: ACKNOWLEDGMEN

Mindreading From the Eyes Declines With Aging - Evidence From 1,603 Subjects.

Social cognition, in particular mindreading, enables the understanding of another individual's feelings, intentions, desires, and mental states. The Reading the Mind in the Eyes Test (RMET) captures the ability to identify mental states from gaze. We investigated RMET accuracy in the context of age and cognition across the whole adult age-range (19-79 years) in a very large population-based sample (N = 1,603) with linear regression models accounting for cognitive abilities, neurological diseases, and psychiatric disorders. Higher age predicted lower RMET performance in women and men, suggesting difficulties to infer mental states from gaze at older age. Effects remained stable when taking other cognitive abilities and psychiatric disorders or neurological diseases into account. Our results show that RMET performance as a measure of social cognition declines with increasing age

A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests

Behavioral variant frontotemporal dementia (bvFTD) is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011) and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET), Stroop task, Trail Making Test (TMT), Hamasch-Five-Point Test (H5PT), and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test's discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC). bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC) was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD)-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM)-5

Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia. Supplementary data: Motor speech characterization per participant

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Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

© The Author(s) 2022. Springer Nature Switzerland AG. Part of Springer Nature. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Introduction: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail. Methods: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis. Results: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions. Conclusion: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.he Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. RC/CG are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID No 739510. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198).info:eu-repo/semantics/publishedVersio

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

ImportanceThe 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.ObjectiveTo 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 ParticipantsThis 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 MeasuresCase 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.ResultsOf 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 RelevanceNeurobiological 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.</p

Neuroimaging the consciousness of self: Review, and conceptual-methodological framework

We review neuroimaging research investigating self-referential processing (SRP), that is, how we respond to stimuli that reference ourselves, prefaced by a lexical-thematic analysis of words indicative of “self-feelings”. We consider SRP as occurring verbally (V-SRP) and non-verbally (NV-SRP), both in the controlled, “top-down” form of introspective and interoceptive tasks, respectively, as well as in the “bottom-up” spontaneous or automatic form of “mind wandering” and “body wandering” that occurs during resting state. Our review leads us to outline a conceptual and methodological framework for future SRP research that we briefly apply toward understanding certain psychological and neurological disorders symptomatically associated with abnormal SRP. Our discussion is partly guided by William James’ original writings on the consciousness of self

Searching for patomechanisms of late life minor depression

The doctoral dissertation: Searching for pathomechanisms of late-life minor depression – a combined MRI, biomarker and meta-analytic study was one of the first studies investigating the underlying pathophysiology of minor depression. The dissertation comprises a systematic review of the prevalence rates of minor depression, two meta-analyses of peripheral BDNF changes in major depressive disorder, as well as two original studies investigating serum BDNF, S100B and NSE levels and gray matter changes in minor depression. The limitations of studies and proposed improvements to the study design are discussed extensively.:1. INTRODUCTION 1.1 Motivation 1.1.1 Minor depression in the spectrum of psychiatric disorders 1.1.2 Minor depression is prevalent but unrecognized. 1.2 Theoretical background 1.2.1 Overview of depression hypotheses 1.2.2 Neurotrophic hypothesis of depressive disorders 1.2.3 Glial hypothesis of depressive disorders 1.2.4 Structural neuroimaging changes in major depression 1.3. Rationale and hypotheses of the empirical studies 1.3.1 Research questions 1.3.2 Research hypotheses 2. EMPIRICAL STUDIES 2.1 The prevalence of minor depression in the late life 2.2 The meta-analysis of BDNF changes in mood disorders 2.3 The meta-analysis of BDNF changes following ECT in depression 2.4 Serum biomarkers in minor depression 2.5 Structural brain imaging in minor depression 3. GENERAL DISCUSSION 3.1 Summary of results 3.2 Implications for research 3.3 Implications for clinical studies SUMMARY REFERENCES APPENDIX A: DECLARATION OF CONTRIBUTION APPENDIX B: STATEMENT OF AUTHORSHIP APPENDIX C: CURRICULUM VITAEAPPENDIX D: ACADEMIC CONTRIBUTIONS APPENDIX E: ACKNOWLEDGMEN