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The article titled "Theme 10 - Disease Stratification and Phenotyping of Patients" discusses the importance of accurately categorizing and studying patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The authors emphasize the need for precise disease stratification and phenotyping in order to better understand the underlying mechanisms and develop targeted treatments. The article includes contributions from numerous authors and researchers from various institutions, highlighting the collaborative effort in advancing research on ALS and FTD. [Extracted from the article]

Introduction: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype., Methods: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments., Results: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations., Discussion: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients., Highlights: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: German legislation establishes advance directives (ADs) as legally binding instruments that all involved parties need to adhere to. This applies also to family members who have been authorized as official surrogates of the AD's author. As surrogates, they are expected to make sure that the AD is being implemented. Our study aims at uncovering how family members experience their legally assigned role as an advocate of an AD., Research Design and Methods: We conducted 25 episodic interviews with family surrogates of persons living with dementia and used thematic analysis to make sense of our interview data., Results: Family surrogates expressed scepticism toward ADs as instruments for planning end-of-life care. They did not necessarily follow the decisions expressed in the AD. We found cases in which family surrogates intentionally refrained from bringing the ADs to the attention of health care providers as well as cases in which the ADs conflicted with self-related interests of family surrogates., Discussion and Implications: Our findings lead us to critique the legal construction of family surrogates as advocates of the AD. Family members are directly and enduringly affected by the end-of-life care decisions that the AD sets out and are thus no neutral agents who have no stake in the matter. Expecting them to simply transmit decisions formulated in the AD means expecting them to render their own interests irrelevant-which, arguably, might be too much to ask., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer's disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases., Objective: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages., Methods: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models., Conclusions: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design.

The increasing number of melanoma patients makes it necessary to develop best possible strategies for prognosis assessment in order to recommend appropriate therapy and follow-up. The prognostic significance of tumor cell pigmentation has not been fully elucidated. Hematoxylin and eosin (H&E)-stained sections of 775 melanomas diagnosed between 2012 and 2015 were independently assessed for melanin pigment abundance by two investigators, and the impact on melanoma-specific survival was calculated. Unpigmented melanomas (n = 99) had a melanoma-specific survival of 67.7%, melanomas with moderate pigmentation (n = 384) had a melanoma-specific survival of 85.9%, and strongly pigmented melanomas (n = 292) had a melanoma-specific survival of 91.4% (p < .001). In an analysis of melanoma-specific survival adjusted for pT stage and pigmentation, we found a nonsignificant impact of pigmentation abundance with a hazard ratio of 1.277 (p = .74). The study presented here provides evidence in a German cohort that patients with pigmented melanomas have a more favorable prognosis than those diagnosed with nonpigmented melanomas. Moreover, the abundance of pigmentation already seems to provide a first prognostic estimate. However, it does not appear to provide significant additional value for prognostic assessment according to the AJCC 2017 pT classification., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Objectives: Workers on sick-leave due to a mental illness have enormous problems to return to work. The main objective of the present study is to examine, how individuals experience the transition from the mental health system to their workplace., Methods: A qualitative research design guided by a grounded theory approach was used. Narrative interviews with ten workers on sick leave and four semi-structured interviews with return-to-work-experts were conducted., Results: Relevant for returning to work is the interplay between the involved persons. Essential is the interpretation of the transition and as a result, which calls for action are made to the participants., Conclusion: Clinical interventions for returning to work should focus the support on the expectations of the participants and stimulate a common interpretation., Competing Interests: Johannes Hamann erhielt Vortragshonorare von Janssen Cilag, Otsuka/Lundbeck und Rovi. Die anderen Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Only two-thirds of patients admitted to psychiatric wards return to their previous jobs. Return-to-work interventions in Germany are investigated for their effectiveness, but information regarding cost-effectiveness is lacking. This study investigates the cost-utility of a return-to-work intervention for patients with mental disorders compared to treatment as usual (TAU)., Methods: We used data from a cluster-randomised controlled trial including 166 patients from 28 inpatient psychiatric wards providing data at 6- and 12-month follow-ups. Health and social care service use was measured with the Client Sociodemographic and Service Receipt Inventory. Quality of life was measured with the EQ-5D-3L questionnaire. Cost-utility analysis was performed by calculating additional costs per one additional QALY (Quality-Adjusted Life Years) gained by receiving the support of return-to-work experts, in comparison to TAU., Results: No significant cost or QALY difference between the intervention and control groups has been detected. The return-to-work intervention cannot be identified as cost-effective in comparison to TAU., Conclusions: The employment of return-to-work experts could not reach the threshold of providing good value for money. TAU, therefore, seems to be sufficient support for the target group.

Background: In recent years it could be shown that psychosocial working conditions and mental health of employees are closely correlated. One well-established instrument to measure psychosocial stress at work is the COPSOQ (Copenhagen Psychosocial Questionnaire, German Standard Version). It is an 84 item self-rating instrument addressing several domains of psychosocial working conditions and is generally used for risk assessments in companies., Aims: To examine associations between COPSOQ ratings with clinical features and symptoms of employees who currently suffer from an episode of a mental illness requiring inpatient treatment., Method: For 265 inpatients with mental disorders who participated in a cluster randomized trial (RETURN-study) COPSOQ-data were available as part of the baseline data acquisition. These data were compared with the German COPSOQ validation sample of the Freiburg research center for occupational sciences (FFAW; approximately 250,000 participants). For subdomains of the COPSOQ that showed major and significant differences between the two samples regression analyses were done to predict COPSOQ scores within the RETURN-sample., Results: Psychiatric inpatients did not assess their working conditions significantly different compared to the population based FFAW sample. However, with regard to the effects of working conditions (general health, burnout, presenteeism, and intention to leave the job) there were major differences between the two samples with the clinical sample expressing more negative views. In the RETURN sample these were predicted by a greater expression of depressive symptoms., Conclusions: The linkage between work and mental wellbeing is complex. Mental illness is not necessarily a result of poor working conditions, while good working conditions may not in every case prevent symptoms of bad health, even if such associations exist.

In recent years, the scientific community has called for improvements in the credibility, robustness and reproducibility of research, characterized by increased interest and promotion of open and transparent research practices. While progress has been positive, there is a lack of consideration about how this approach can be embedded into undergraduate and postgraduate research training. Specifically, a critical overview of the literature which investigates how integrating open and reproducible science may influence student outcomes is needed. In this paper, we provide the first critical review of literature surrounding the integration of open and reproducible scholarship into teaching and learning and its associated outcomes in students. Our review highlighted how embedding open and reproducible scholarship appears to be associated with (i) students' scientific literacies (i.e. students' understanding of open research, consumption of science and the development of transferable skills); (ii) student engagement (i.e. motivation and engagement with learning, collaboration and engagement in open research) and (iii) students' attitudes towards science (i.e. trust in science and confidence in research findings). However, our review also identified a need for more robust and rigorous methods within pedagogical research, including more interventional and experimental evaluations of teaching practice. We discuss implications for teaching and learning scholarship., Competing Interests: We declare we have no competing interests., (© 2023 The Authors.)

Purpose: Previous research on motor speech disorders (MSDs) in primary progressive aphasia (PPA) has largely focused on patients with the nonfluent/agrammatic variant of PPA (nfvPPA), with few systematic descriptions of MSDs in variants other than nfvPPA. There has also been an emphasis on studying apraxia of speech, whereas less is known about dysarthria or other forms of MSDs. This study aimed to examine the qualitative and quantitative characteristics of MSDs in a prospective sample of individuals with PPA independent of subtype., Method: We included 38 participants with a root diagnosis of PPA according to current consensus criteria, including one case with primary progressive apraxia of speech. Speech tasks comprised various speech modalities and levels of complexity. Expert raters used a novel protocol for auditory speech analyses covering all major dimensions of speech., Results: Of the participants, 47.4% presented with some form of MSD. Individual speech motor profiles varied widely with respect to the different speech dimensions. Besides apraxia of speech, we observed different dysarthria syndromes, special forms of MSDs (e.g., neurogenic stuttering), and mixed forms. Degrees of severity ranged from mild to severe. We also observed MSDs in patients whose speech and language profiles were incompatible with nfvPPA., Conclusions: The results confirm that MSDs are common in PPA and can manifest in different syndromes. The findings emphasize that future studies of MSDs in PPA should be extended to all clinical variants and should take into account the qualitative characteristics of motor speech dysfunction across speech dimensions., Supplemental Material: https://doi.org/10.23641/asha.22555534.

Objective: Patients with mental illnesses often face difficulties when returning to workplace after an episode of inpatient treatment. Available resources intended to support the return-to-work process are often not used. It was the aim of the present study to develop an intervention that facilitates the implementation of patient support at the interface of in- and outpatient care., Methods: We used a structured development process for the establishment of a return-to-work intervention for psychiatric inpatients., Results: The intervention consisted of the use of return-to-work experts who worked on the basis of a manual. In clearly defined modules, patients were given information on social law basics and details of the return process. Difficult situations (e. g., dealing with the disclosure of the diagnosis, return interview) were discussed and rehearsed. After discharge, further care took place, above all with regard to experiences on the first working day, accompaniment to discussions with the employer and support with any other upcoming difficulties., Conclusion: The results of the ongoing study will show whether the chosen approach actually yields the expected results, namely an improvement of the return-to-work process., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenskonflikt besteht, (Thieme. All rights reserved.)

Understanding the relationships between brain structure and language behaviour in primary progressive aphasia provides crucial information about these diseases' pathomechanisms. However, previous investigations have been limited from providing a statistically reliable view of broad language abilities by sample size, variant focus and task focus. In this study, the authors aimed to determine the relationship between brain structure and language behaviour in primary progressive aphasia, to determine the degree to which task-associated regions were atrophied across disease variants and to determine the degree to which task-related atrophy overlaps across disease variants. Participants were 118 primary progressive aphasia patients and 61 healthy, age-matched controls tested from 2011 to 2018 in the German Consortium for Frontotemporal Lobar Degeneration cohort. Diagnosis of primary progressive aphasia required progressive deterioration of mainly speech and language for ≥ 2 years, and variant was diagnosed by the criteria of Gorno-Tempini et al . (Classification of primary progressive aphasia and its variants. Neurology . 2011;76(11):1006-1014). Twenty-one participants not fulfilling a specific subtype were classified as mixed-variant and excluded. Language tasks of interest included the Boston naming test, a German adaptation of the Repeat and Point task, phonemic and category fluency tasks and the reading/writing subtest of the Aachen Aphasia Test. Brain structure was measured by cortical thickness. We observed networks of language task-associated temporal, frontal and parietal cortex. Overlapping task-associated atrophy was observed in the left lateral, ventral and medial temporal lobes, middle and superior frontal gyri, supramarginal gyrus and insula. Some regions, primarily in the perisylvian region, were associated with language behaviour despite showing no significant atrophy. The results crucially extend less powerful studies associating brain and language measures in primary progressive aphasia. Cross-variant atrophy in task-associated regions suggests partially shared underlying deficits, whereas unique atrophy reinforces variant-specific deficits. Language task-related regions that are not obviously atrophied suggest regions of future network disruption and encourage understanding of task deficits beyond clearly atrophied cortex. These results may pave the way for new treatment approaches., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The scholarly debate on advance directives (ADs) in the context of dementia is mainly built around ethical arguments. Empirical studies that shed light into the realities of ADs of persons living with dementia are few and far between and too little is known about the effect of national AD legislation on such realities. This paper offers insight into the preparation phase of ADs according to German legislation in the context of dementia. It presents results from a document analysis of 100 ADs and from 25 episodic interviews with family members. Findings show that drafting an AD involves family members and different professionals in addition to the signatory, whose cognitive impairment differed considerably at the time of preparing the AD. The involvement of family members and professionals is at times problematic, which prompts the question of how much and what kind of involvement of others turns an AD of a person living with dementia into an AD about a person living with dementia. The results invite policy makers to critically review legislation on ADs from the perspective of cognitively impaired persons, who might find it difficult to protect themselves from inappropriate involvement when completing an AD.

Background: If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on "common mental disorders" and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment., Methods: The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued., Results: A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant ( p  = 0.14). Intervention patients returned to their workplace earlier than patients in the control group ( p  = 0.040)., Conclusions: The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

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.

Background: Guidelines for the treatment of behavioral and psychological symptoms of dementia (BPSD) recommend that if antipsychotics are necessary, these should be used only for a limited time and with the lowest possible dose., Objective: In order to raise awareness of the risks of antipsychotic treatment in patients with dementia and the resulting need for time-limited and as low-dose antipsychotic treatment as possible, recommendations for deprescribing of antipsychotics in people with dementia have been developed., Material and Methods: The recommendations were developed in a multistage process: 1. Literature search with special appreciation of agreed guideline recommendations and results of an intervention study (READY study) 2. Discussion and consensus in a panel of experts, 3. Online survey of medical dementia experts working in Germany., Results: From the 51 statements that were initially drafted 32 statements on antipsychotic deprescribing were formulated after the discussion in the multiprofessional expert panel. Of the 32 statements 25 were finally implemented after agreement by the experts in the online survey., Discussion: In Germany, there are so far no specific recommendations for the reduction and discontinuation of antipsychotics used to treat BPSD in people with dementia. The article is intended as recommendations for general practitioners and specialists. The recommendations are not guidelines and do not replace personal responsibility. The individual approach always depends on the individual treatment situation., (© 2022. The Author(s).)

Dysfunctional social communication is one of the most stable characteristics in patients with schizophrenia spectrum disorder (SSD) that severely affects quality of life. Interpreting abstract speech and integrating nonverbal information is particularly affected. Considering the difficulty to treat communication dysfunctions with usual intervention, we investigated the possibility to apply a multimodal speech-gesture (MSG) training. In the MSG training, we offered 8 sessions (60 min each) including perceptive and expressive tasks as well as meta-learning elements and transfer exercises to 29 patients with SSD. In a within-group crossover design, patients were randomized to a TAU-first (treatment as usual first, then MSG training) group (N = 20) or a MSG-first (MSG training first, then TAU only) group (N = 9), and were compared to healthy controls (N = 17). Outcomes were quality of life and related changes in the neural processing of abstract speech-gesture information, which were measured pre-post training through standardized psychological questionnaires and functional Magnetic Resonance Imaging, respectively. Pre-training, patients showed reduced quality of life as compared to controls but improved significantly during the training. Strikingly, this improvement was correlated with neural activation changes in the middle temporal gyrus for the processing of abstract multimodal content. Improvement during training, self-report measures and ratings of relatives confirmed the MSG-related changes. Together, we provide first promising results of a novel multimodal speech-gesture training for patients with schizophrenia. We could link training induced changes in speech-gesture processing to changes in quality of life, demonstrating the relevance of intact communication skills and gesture processing for well-being., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Mental illnesses are among the most common diseases worldwide. Cases of inability to work caused by mental illness are frequent and the related economic burden is immense. A successful reintegration into their work environment of those patients who were on sick leave due to a mental illness is an important prognostic factor for the further course of the disease and helps reducing financial consequences. It was the aim of the present review to give an overview of the status quo of return-to-work interventions in the international literature., Recent Findings: Main themes of interventions addressing return to work of persons with mental illnesses are the provision of psychotherapeutic support with or without combining these approaches with work directed interventions. Personal contact of employees, mental healthcare staff and supervisors may be helpful with regard to facilitating return to work., Summary: Current return to work interventions are mostly elaborate, extensive and expensive without convincing results regarding work related outcome parameters. A variety of reasons might be responsible for this finding, including heterogeneity of outcomes, a poor definition of return-to-work-interventions and the complexity of the issue (involving multiple stakeholders)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Polypharmacy is common in people with dementia. The use of psychotropic drugs (PDs) and other, potentially inappropriate medications is high. The aims of this cross-sectional study were 1) to investigate the use of drugs in people with advanced dementia (PWAD), living at home or in long term care (LTC); 2) to focus on PD use; and 3) to identify determinants of PD use., Methods: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for people in advanced and terminal stages of YOD and LOD in Germany). 191 PWAD were included. All drugs that were administered at the date of the examination were recorded. Multiple logistic regression analysis identified determinants of PD use., Results: 96% of PWAD received medication with a median number of four drugs. 49.7% received five or more drugs. According to the Beers Criteria 39% of PWAD ≥ 65 years received at least one potentially inappropriate medication. 79% of PWAD were treated with PDs. Older PWAD and PWAD living in LTC facilities received significantly more drugs than younger PWAD, and PWAD living at home, respectively. Dementia etiology was significantly associated with the use of antipsychotics, antidepressants and sedative substances. Place of living was associated with the use of pain medication. Behavioral disturbances were associated with the use of antipsychotics and sedative substances., Conclusions: To mitigate the dangers of polypharmacy and medication related harm, critical examination is required, whether a drug is indicated or not. Also, the deprescribing of drugs should be considered on a regular basis., Trial Registration: Clinicaltrial.gov, NCT03364179 . Registered 6 December 2017., (© 2022. The Author(s).)

Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA)., Objective: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA., Method: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed., Results: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%)., Conclusion: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with schizophrenia spectrum disorders (SSD) exhibit an aberrant perception and comprehension of abstract speech-gesture combinations associated with dysfunctional activation of the left inferior frontal gyrus (IFG). Recently, a significant deficit of speech-gesture mismatch detection was identified in SSD, but the underlying neural mechanisms have not yet been examined. A novel mismatch-detection fMRI paradigm was implemented manipulating speech-gesture abstractness (abstract/concrete) and relatedness (related/unrelated). During fMRI data acquisition, 42 SSD patients (schizophrenia, schizoaffective disorder, or other non-organic psychotic disorder [ICD-10: F20, F25, F28; DSM-IV: 295.X]) and 36 healthy controls were presented with short video clips of an actor reciting abstract or concrete sentences accompanied by either a semantically related or unrelated gesture. Participants indicated via button press whether they perceived each gesture as matching the speech content or not. Speech-gesture mismatch detection performance was significantly impaired in patients compared to controls. fMRI data analysis revealed that patients showed lower activation in bilateral frontal areas, including the IFG for all abstract > concrete speech-gesture pairs. In addition, they exhibited reduced engagement of the right supplementary motor area (SMA) and bilateral anterior cingulate cortices (ACC) for unrelated > related stimuli. We provide first evidence that impaired speech-gesture mismatch detection in SSD could be the result of dysfunctional activation of the SMA and ACC. Failure to activate the left IFG disrupts the integration of abstract speech-gesture combinations in particular. Future investigations should focus on brain stimulation of the SMA, ACC, and the IFG to improve communication and social functioning in SSD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Data on suicidal ideation, behavior and the risk factors in patients with dementia is scarce. To evaluate the prevalence of death wishes, suicidal ideation, and suicidal behavior of young (YOD) and late onset dementia (LOD) and to identify risk factors for suicidal ideation and behavior. Methods: We interviewed 157 family caregivers of patients with advanced dementia using questions from the Columbia-Suicide Severity Rating Scale to gather information about suicidal ideation and behavior before the onset of symptoms of dementia, after the onset of dementia and within 30 days prior to the interview. At the time of the interview, we also assessed disease severity, cognitive function, and other psychological, behavioral and physical symptoms of the patients as well as the caregivers' psychological well-being. Results: Forty four (28%) of the patients expressed suicidal ideation or behavior at some time after the onset of symptoms, and 14 (9%) of these within the month prior to the assessment. Two patients had attempted suicide after the onset of dementia. There were no statistically significant differences between patients with and without suicidal ideations or behavior with regards to demographics or age at onset of dementia. In patients with advanced dementia, Alzheimer's disease (rather than frontotemporal lobar degeneration), better cognitive function, more severe psychological, behavioral, and physical symptoms, and a reduced quality of life were associated with the expression of suicidal ideation. Conclusions: According to caregivers' reports, majority of patients with dementia did not express suicidal ideation or show suicidal behavior. Patients who expressed suicidal ideation during early stages of dementia often stopped expressing them in advanced stages. It remains unclear if this was due to reduced communication abilities, a reduction of disease awareness, and/ or an adjustment to their situation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ortner, Riedl, Jox, Hartmann, Roßmeier, Dorn, Kehl, Egert-Schwender, Fischer and Diehl-Schmid.)

Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress., Competing Interests: Declaration of interests Anisha Keshavan is an employee of Octave Bioscience., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany., Objective: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD; 2) To determine whether there are differences between young and late onset dementia (YOD and LOD)., Methods: The study was performed in the context of the project EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of Young-onset and Late-Onset dementia in Germany). Closest relatives of recently deceased patients with advanced YOD (N = 46) and LOD (N = 54) living at home or in long term care were interviewed., Results: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60% of PWAD appeared to be "at peace". Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified., Conclusion: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs' needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established.

Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics., Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort., Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests., Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal., Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.

Background: Advanced stages of dementia are characterized by severe cognitive and physical impairment. It has not yet been investigated whether persons with young onset dementia (YOD) and late onset dementia (LOD) differ in advanced disease stages., Objectives: To compare quality of life (QoL) between persons with advanced YOD and LOD; to explore the determinants of QoL; to investigate whether YOD and LOD differ with regard to symptoms and care., Methods: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of YOD and LOD in Germany). Persons with advanced dementia (PWAD) were assessed and caregivers were interviewed. QoL was measured with the proxy rating Quality of Life in Late Stage Dementia (QUALID) scale., Results: 93 persons with YOD and 98 with LOD were included. No significant differences in QoL were detected. Determinants of QoL were similar in YOD and LOD. Behavioral and psychological symptoms of dementia (BPSD), suffering and other distressing symptoms were associated with a lower QoL. In YOD but not in LOD antipsychotic treatment was associated with low QoL. The group of persons who were younger than 65 years at the time of the study visit experienced significantly more distressing symptoms than older PWAD., Conclusion: Overall, persons with advanced YOD do not appear to be disadvantaged compared to old and oldest PWAD. Special attention, however, must be paid to the group of the very young persons who seem to be particularly vulnerable.

Objective : The aims of our study were to describe the clinical phenotype and to characterize the cerebral glucose metabolism patterns as measured with fluordesoxyglucose-positron emission tomography (FDG-PET) in symptomatic FTLD-patients with different GRN variants. Methods : For this study, data were included from all patients ( n  = 10) of a single-center FTLD registry study who had a pathogenic GRN variant and who had undergone a cerebral FDG-PET scan. Results : An overt variability of clinical phenotypes was identified with half of the cases being not unambiguously classifiable into one of the clinical FTLD subtypes. Furthermore, GRN + patients showed a considerable inter-individual variability of FDG uptake pattern. In half of the GRN + patients, metabolic changes expanded from frontal and temporal brain regions to parietal brain regions including the posterior cingulate cortex. Striking asymmetry without a preference for either hemisphere was overt in half of GRN + cases. Conclusion : We conclude that GRN mutations cause variable patterns of neurodegeneration that often exceed the anatomical boundaries of the frontotemporal brain regions and produce clinical syndromes that cannot clearly be classified into one of the subtypes as defined by the diagnostic criteria.

Background: Patients with mental illnesses often have massive difficulties returning to work after inpatient treatment at a psychiatric clinic and are often at risk of losing their jobs. The psychosocial support for this patient group at the interface of clinic/outpatient care is often insufficient., Methods/design: The RETURN-study prospectively assesses and surveys 200 patients with mental disorders in a cluster randomized intervention study, i.e. treatment teams and patients from intervention wards receive a return-to-work (RTW) intervention. Patients in control wards obtain treatment as usual (TAU). Pairs of comparable wards (similar patient population, similar staff density) have been identified and then randomized for control and intervention (n = 14 for each condition). On intervention wards return-to-work experts (RTW experts) who focus treatment on the workplace-related needs of patients with mental illnesses have been established. These RTW experts ensure the use of available resources within the framework of work-related discharge management and should lead to a more successful return to the workplace. The days at work in the year after release will be evaluated in a mixed methods approach as well as the return rate in the year after release, disability days in the year after return, relapse rate after 12 months, cost-benefit ratio of the intervention, analysis of the predictors / barriers for a successful return to the workplace (e.g. psychopathology, cognition, stigma, social-psychiatric support, company support, etc.), possibilities to implement the concept of RTW experts in standard psychiatric care (TAU - treatment as usual), the impact of the RTW experts' approach on the treatment process in standard psychiatric care., Discussion: This approach is already internationally established in the field of somatic rehabilitation and supported employment [Am J Psychiatry 171:1183-90, 2014; Lancet 370:1146-52, 2007; Cochrane Database Syst Rev, doi:10.1002/14651858.CD006237.pub3, 2014]; the innovative aspect of this project is to implement and evaluate it in standard psychiatric care in Germany. This project requires no new interventions to be developed and tested, as the techniques of the case manager/job coach is applied to the field of return to work., Trial Registration: The study was registered in Deutsches Register Klinische Studien searchable via its Meta-registry (http://apps.who.int/trialsearch/), Trial registration number: DRKS00016037, Date of registration: 21/12/2018, URL of trial registry record.

Background: Since people with advanced dementia are usually not able to make complex decisions, it is usually the family caregivers, as proxies, who have to decide on treatments and their termination. However, these decisions are difficult for the caregivers to make, as they are often inadequately informed and cannot properly assess the consequences; moreover, they are concerned about harming the sick person. We aimed to first develop an informative booklet about palliative care issues for caregivers of people with advanced dementia. Secondly, we aimed to investigate a change in family caregivers' knowledge regarding palliative care issues and caregivers' involvement in medical and care decisions before and after studying this booklet., Methods: A first version of the booklet was drafted by an experienced psychiatrist and palliative care specialist based on existing booklets and guidelines; necessary cultural adaptions were taken into consideration. A nominal group process was conducted to develop the informative guide. In order to investigate the acceptance of the booklet and the possibility to implement it, 38 patient-caregiver dyads were recruited, and caregivers were interviewed both before receiving the booklet and after 3 months of receiving the booklet., Results: Experts from various disciplines collaborated on a German booklet for family caregivers of people with advanced dementia as an information aid regarding issues of palliative care. The subsequent test showed that all caregivers had experienced a personal benefit from the booklet. Caregivers had a significant gain of knowledge after provision of the booklet. A large proportion of caregivers who had not previously considered and/or discussed medical topics reported that they had done so within 3 months after obtaining the booklet, or planned to do so in the near future., Conclusions: The caregivers valued the comprehensible, concise and well-structured information guide on palliative care issues in advanced dementia. They agreed it increases knowledge and prompts decision making and therefore should be developed in many languages and disseminated among family caregivers of people with dementia., Trial Registration: clinicaltrial.gov, NCT03548142. Retrospectively registered 7 June 2018.