'Too young to sit at home': a qualitative study conducted among employees with young-onset dementia and their relatives.

OBJECTIVES: Young-onset dementia (YOD) symptoms often first present in the workplace, resulting in work performance challenges and eventually loss of employment. This study aims to investigate the experiences, work values, and support needs of employees with YOD and their relatives. METHOD: Semi-structured interviews were conducted to explore the experiences, work values, and support needs of (former) employees with YOD and their relatives. Subsequently, separate focus group discussions were conducted for employees and relatives to review and prioritize interview findings. Inductive thematic analysis was applied to both datasets. RESULTS: A total of 15 interviews (six employees; nine relatives) and four focus group discussions (ten employees; six relatives) were conducted. Six themes emerged, with five revolving around the central theme: desire to work. The other themes represent essential contributing factors, including importance of receiving a YOD diagnosis; knowledge, awareness, and understanding regarding YOD; open communication, joint decision making, and collaboration; work adjustments, involvement, and support; phasing out work and future perspectives. CONCLUSION: The findings highlight a strong desire to work post-YOD diagnosis, serving as a foundation for developing workplace support tools and guidance. This has the potential to help individuals with YOD preserve their self-confidence and identity while working within their capabilities.

Sociodemographic structure and health care-related outcomes of community-dwelling dementia caregiving dyads: a latent class replication study.

BACKGROUND: The identification of dyadic subgroups of individuals living with dementia and their informal caregivers can help to design effective tailored support. In a previous German study, we identified six dementia dyad subgroups by applying Latent Class Analysis (LCA). Results showed sociodemographic heterogeneity as well as differences in health care outcomes (i.e., quality of life, health status, caregiver burden) between subgroups. The objective of this study is to determine if the dyad subgroups from the previous analysis can be replicated in a similar but distinct Dutch sample. METHODS: A LCA 3-step procedure was applied to baseline data from the COMPAS study, a prospective cohort study. LCA is a statistical approach used to identify heterogeneous subgroups within populations based on their pattern of answers on a set of categorical variables. Data comprises 509 community-living individuals with predominantly mild to moderate dementia and their informal caregivers. A narrative analysis was used to compare latent class structures of the original versus the replication study. RESULTS: Six distinct dementia dyad subgroups were identified: A subgroup of "adult-child-parent relation with younger informal caregiver" (31.8%), a "couple with female informal caregiver of older age" group (23.1%), an "adult-child-parent relation with middle-aged informal caregiver" group (14.2%), a "couple with middle-aged female informal caregiver" group (12.4%), a "couple with older male informal caregiver" group (11.2%) and a "couple with middle-aged male informal caregiver" group (7.4%). Quality of life of individuals with dementia was rated better in couples than in adult-child-relationships. Worst health for caregivers was reported by subgroups with female informal caregivers living together with male individuals with dementia in couple relationships. A subgroup with older female informal caregivers in couple relationships report the most severe burden on physical and mental health. In both studies, a model with six subgroups fitted the data best. Although substantive similarities between the subgroups of both studies appeared, considerable differences are also evident. CONCLUSION: This replication study confirmed the existence of informal dementia dyad subgroups. The observed differences between the subgroups provide useful contributions for a more tailored health care services for informal caregivers and individuals living with dementia. Furthermore, it underlines the relevance of dyadic perspectives. To facilitate replication studies and increase the validity of evidence, a standardization of collected data across studies would be beneficial.

Determinants of quality of life in family caregivers in MCI: a comparison with mild dementia.

OBJECTIVES: The aim of the current study was to investigate the health-related quality of life (HRQol) of the family caregiver in MCI, explore possible determinants and study possible differences with mild dementia. METHODS: This secondary data analysis included 145 persons with MCI and 154 persons with dementia and their family caregivers from two Dutch cohort studies. HRQoL was measured with the VAS of the EuroQol-5D-3L version. Regressions analyses were conducted to examine potential demographic and clinical determinants of the caregiver's HRQoL. RESULTS: The mean EQ5D-VAS in family caregivers of persons with MCI was 81.1 (SD 15.7), and did not significantly differ from family caregivers in mild dementia (81.9 (SD 13.0)). In MCI, patient measurements were not significantly associated with caregiver mean EQ5D-VAS. Concerning caregiver characteristics, being a spouse and a lower educational level were associated with a lower mean EQ5D-VAS (in a multiple linear regression model: unstandardized B -8.075, p = 0.013 and unstandardized B -6.162, p = 0.037 resp.). In mild dementia, the NPI item irritability showed an association with caregiver EQ5D-VAS in bivariate linear regression analyses. CONCLUSION: Results indicate that especially family caregiver characteristics seem to influence family caregiver HRQoL in MCI. Future research should include other potential determinants such as burden, coping strategies and relationship quality.

Teaching the Virtual Brain.

As a complex three-dimensional organ, the inside of a human brain is difficult to properly visualize. Magnetic Resonance Imaging provides an accurate model of the brain of a patient, but its medical or educational analysis as a set of flat slices is not enough to fully grasp its internal structure. A virtual reality application has been developed to generate a complete three-dimensional model based on MRI data, which users can explore internally through random planar cuts and color cluster isolation. An indexed vertex triangulation algorithm has been designed to efficiently display large amounts of complex three-dimensional vertex clusters in simple mobile devices. Feedback from students suggests that the resulting application satisfactorily complements theoretical lectures, as virtual reality allows them to better observe different structures within the human brain.

Functional connectivity of the hippocampus and its subfields in resting-state networks.

Many neuroimaging studies have shown that the hippocampus participates in a resting-state network called the default mode network. However, how the hippocampus connects to the default mode network, whether the hippocampus connects to other resting-state networks and how the different hippocampal subfields take part in resting-state networks remains poorly understood. Here, we examined these issues using the high spatial-resolution 7T resting-state fMRI dataset from the Human Connectome Project. We used data-driven techniques that relied on spatially-restricted Independent Component Analysis, Dual Regression and linear mixed-effect group-analyses based on participant-specific brain morphology. The results revealed two main activity hotspots inside the hippocampus. The first hotspot was located in an anterior location and was correlated with the somatomotor network. This network was subserved by co-activity in the CA1, CA3, CA4 and Dentate Gyrus fields. In addition, there was an activity hotspot that extended from middle to posterior locations along the hippocampal long-axis and correlated with the default mode network. This network reflected activity in the Subiculum, CA4 and Dentate Gyrus fields. These results show how different sections of the hippocampus participate in two known resting-state networks and how these two resting-state networks depend on different configurations of hippocampal subfield co-activity.

The Dynamics of Speech Motor Control Revealed with Time-Resolved fMRI.

Holding a conversation means that speech must be started, maintained, and stopped continuously. The brain networks that underlie these aspects of speech motor control remain poorly understood. Here we collected functional magnetic resonance imaging (fMRI) data while participants produced normal and fast rate speech in response to sequences of visually presented objects. We took a non-conventional approach to fMRI data analysis that allowed us to study speech motor behavior as it unfolded over time. To this end, whole-brain fMRI signals were extracted in stimulus-locked epochs using slice-based fMRI. These data were then subjected to group independent component analysis to discover spatially independent networks that were associated with different temporal activation profiles. The results revealed two basic brain networks with different temporal dynamics: a cortical network that was activated continuously during speech production, and a second cortico-subcortical network that increased in activity during the initiation and suppression of speech production. Additional analyses explored whether key areas involved in motor suppression such as the right inferior frontal gyrus, sub-thalamic nucleus and pre-supplementary motor area provide first-order signals to stop speech. The results reveal for the first time the brain networks associated with the initiation, maintenance, and suppression of speech motor behavior.

Improving the signal detection accuracy of functional Magnetic Resonance Imaging.

A major drawback of functional Magnetic Resonance Imaging (fMRI) concerns the lack of detection accuracy of the measured signal. Although this limitation stems in part from the neuro-vascular nature of the fMRI signal, it also reflects particular methodological decisions in the fMRI data analysis pathway. Here we show that the signal detection accuracy of fMRI is affected by the specific way in which whole-brain volumes are created from individually acquired brain slices, and by the method of statistically extracting signals from the sampled data. To address these limitations, we propose a new framework for fMRI data analysis. The new framework creates whole-brain volumes from individual brain slices that are all acquired at the same point in time relative to a presented stimulus. These whole-brain volumes contain minimal temporal distortions, and are available at a high temporal resolution. In addition, statistical signal extraction occurred on the basis of a non-standard time point-by-time point approach. We evaluated the detection accuracy of the extracted signal in the standard and new framework with simulated and real-world fMRI data. The new slice-based data-analytic framework yields greatly improved signal detection accuracy of fMRI signals.

Intermanual transfer in an artist with Parkinson's disease.

A professional right-handed painter with Parkinson's disease (PD) broke his right arm and continued to paint with his left hand, showing an intact intermanual transfer of skills. This neurocognitive process is related to the supplementary motor area, a brain region that has also been shown to be involved in PD. This observation raises questions about the exact neural underpinnings of intermanual transfer and the possible impact of neurodegenerative disease and medication.

Tracking the Time Course of Competition During Word Production: Evidence for a Post-Retrieval Mechanism of Conflict Resolution.

Producing a word is often complicated by the fact that there are other words that share meaning with the intended word. The competition between words that arises in such a situation is a well-known phenomenon in the word production literature. An ongoing debate in a number of research domains has concerned the question of how competition between words is resolved. Here, we contributed to the debate by presenting evidence that indicates that resolving competition during word production involves a postretrieval mechanism of conflict resolution. Specifically, we tracked the time course of competition during word production using electroencephalography. In the experiment, participants named pictures in contexts that varied in the strength of competition. The electrophysiological data show that competition is associated with a late, frontally distributed component that arises between 500 and 750 ms after picture presentation. These data are interpreted in terms of a model of word production that relies on a mechanism of cognitive control.

Task influences on the production and comprehension of compound words.

Studies of compound word processing have revealed effects of the compound's constituents in a wide variety of word production and comprehension tasks. Surprisingly, effects of the compound's constituents were not found in a recent word production study using the picture-naming task. Here, we examined whether these contrasting constituent effects reflect methodological differences or whether they reflect the influence of task-specific characteristics on compound processing. A large set of compounds was used to elicit picture-naming latencies in Experiment 1 and visual lexical decision latencies in Experiment 2. Regression analyses revealed surface frequency effects in picture naming and lexical decision and constituent effects only in lexical decision. These results rule out methodological differences as the basis for the contrasting constituent effects observed between the various tasks and imply that constituent effects are best understood as arising out of task-specific characteristics.

Age-related constraints on the spatial geometry of the brain.

Age-related structural brain changes may be better captured by assessing complex spatial geometric differences rather than isolated changes to individual regions. We applied a novel analytic method to quantify age-related changes to the spatial anatomy of the brain by measuring expansion and compression of global brain shape and the distance between cross-hemisphere homologous regions. To test how global brain shape and regional distances are affected by aging, we analyzed 2,603 structural MRIs (range: 30-97 years). Increasing age was associated with global shape expansion across inferior-anterior gradients, global compression across superior-posterior gradients, and regional expansion between frontotemporal homologues. Specific patterns of global and regional expansion and compression were further associated with clinical impairment and distinctly related to deficits in various cognitive domains. These findings suggest that changes to the complex spatial anatomy and geometry of the aging brain may be associated with reduced efficiency and cognitive dysfunction in older adults.

The subcortical default mode network and Alzheimer's disease: a systematic review and meta-analysis.

The default mode network is a central cortical brain network suggested to play a major role in several disorders and to be particularly vulnerable to the neuropathological hallmarks of Alzheimer's disease. Subcortical involvement in the default mode network and its alteration in Alzheimer's disease remains largely unknown. We performed a systematic review, meta-analysis and empirical validation of the subcortical default mode network in healthy adults, combined with a systematic review, meta-analysis and network analysis of the involvement of subcortical default mode areas in Alzheimer's disease. Our results show that, besides the well-known cortical default mode network brain regions, the default mode network consistently includes subcortical regions, namely the thalamus, lobule and vermis IX and right Crus I/II of the cerebellum and the amygdala. Network analysis also suggests the involvement of the caudate nucleus. In Alzheimer's disease, we observed a left-lateralized cluster of decrease in functional connectivity which covered the medial temporal lobe and amygdala and showed overlap with the default mode network in a portion covering parts of the left anterior hippocampus and left amygdala. We also found an increase in functional connectivity in the right anterior insula. These results confirm the consistency of subcortical contributions to the default mode network in healthy adults and highlight the relevance of the subcortical default mode network alteration in Alzheimer's disease.

Exploring self-experience practices in dementia care: A scoping review.

BACKGROUND: Recognised as essential for high-quality dementia service, person-centred care aims to understand and respect the unique needs of each individual. Self-experience practices may offer caregivers an opportunity to acquire knowledge, empathy, and skills related to person-centred care, especially through recreating experiences similar to dementia. Given the need to enhance the understanding of self-experience practices in dementia care, a more comprehensive investigation of these training interventions for (future) caregivers is needed. METHODS: We conducted a scoping review to map the evidence on the use of self-experience practices in dementia training. We systematically searched Cochrane Library, MEDLINE via PubMed, CINAHL, and Web of Science. We also searched for grey literature, as well as registry entries, and conducted backward citation tracking of included reviews. We analysed data on intervention characteristics, factors influencing the implementation, and learning outcomes based on Kirkpatrick's model. RESULTS: We included 44 reports across 30 intervention programmes. The majority of reports (91%) were published from 2016 onwards, with 32% originating from the USA and 25% from the UK. We identified passive, interactive, immersive, and multicomponent self-experience interventions in dementia education and training. Learning outcomes based on Kirkpatrick's model were fairly distributed across all identified modalities. Both consumers and providers emphasised aspects related to the development and implementation of practices, particularly organisational-related considerations such as temporal and spatial planning of trainings. CONCLUSIONS: Our review highlights diverse interventions incorporating self-experience practices, with an increasing role for technological tools. While self-experience interventions engage participants, the impact on individuals with dementia and organisational levels remain largely unreported. Our overview, informed by current literature, underscores unique considerations and challenges associated with dementia-related self-experience practices. Implementing and evaluating complex training interventions using self-experience practices should consider ethical aspects. TRIAL REGISTRATION: Registry: Registered within the Open Science Framework (available at https://osf.io/fycxa/).

Facing the Next "Geriatric Giant"-A Systematic Literature Review and Meta-Analysis of Interventions Tackling Loneliness and Social Isolation Among Older Adults.

OBJECTIVES: Loneliness and social isolation are associated with adverse health outcomes, especially within the older adult population, underlining the need for effective interventions. This systematic review and meta-analysis aims to summarize all available evidence regarding the effectiveness of interventions for loneliness and social isolation, to map out their working mechanisms, and to give implications for policy and practice. DESIGN: Systematic literature review and meta-analysis. SETTING AND PARTICIPANTS: Older adults (≥65 years). METHODS: A systematic search was conducted in MEDLINE, PsycINFO, and CINAHL for studies quantitively or qualitatively assessing effects of interventions for loneliness and social isolation in older adults, following predefined selection criteria. Risk of bias as well as small study effects were assessed and, wherever appropriate, information about effect sizes of individual studies pooled using random-effects meta-analyses. Sources for between-study heterogeneity were explored using meta-regression. RESULTS: Of n = 2223 identified articles, n = 67 were eventually included for narrative synthesis. Significant intervention effects were reported for a proportion of studies (55.9% and 50.0% for loneliness and social isolation, respectively) and 57.6% of studies including a follow-up measure (n = 29) reported sustained intervention effects. Meta-analysis of n = 27 studies, representing n = 1756 participants, suggested a medium overall effect of loneliness interventions (d = -0.47; 95% CI, -0.62 to -0.32). Between-study heterogeneity was substantial and could not be explained by differences in study design, year of publication, outcome measures, intervention length, participant demographics, setting, baseline level of loneliness, or geographic location. However, non-technology-based interventions reported larger effect sizes on average (Δd = -0.35; 95% CI, -0.66 to -0.04; P = .029) and were more often significant. Qualitative assessment of potential intervention mechanisms resulted in 3 clusters of effective components: "promoting social contact," "transferring knowledge and skills," and "addressing social cognition". CONCLUSIONS AND IMPLICATIONS: Interventions for loneliness and social isolation can generally be effective, although some unexplained between-study heterogeneity remains. Further research is needed regarding the applicability of interventions across different settings and countries, also considering their cost-effectiveness.

Heterogeneity of morphometric similarity networks in health and schizophrenia.

Introduction: Morphometric similarity is a recently developed neuroimaging phenotype of inter-regional connectivity by quantifying the similarity of a region to other regions based on multiple MRI parameters. Altered average morphometric similarity has been reported in psychotic disorders at the group level, with considerable heterogeneity across individuals. We used normative modeling to address cross-sectional and longitudinal inter-individual heterogeneity of morphometric similarity in health and schizophrenia. Methods: Morphometric similarity for 62 cortical regions was obtained from baseline and follow-up T1-weighted scans of healthy individuals and patients with chronic schizophrenia. Cortical regions were classified into seven predefined brain functional networks. Using Bayesian Linear Regression and taking into account age, sex, image quality and scanner, we trained and validated normative models in healthy controls from eleven datasets (n = 4310). Individual deviations from the norm (z-scores) in morphometric similarity were computed for each participant for each network and region at both timepoints. A z-score ≧ than 1.96 was considered supra-normal and a z-score ≦ -1.96 infra-normal. As a longitudinal metric, we calculated the change over time of the total number of infra- or supra-normal regions per participant. Results: At baseline, patients with schizophrenia had decreased morphometric similarity of the default mode network and increased morphometric similarity of the somatomotor network when compared with healthy controls. The percentage of patients with infra- or supra-normal values for any region at baseline and follow-up was low (<6%) and did not differ from healthy controls. Mean intra-group changes over time in the total number of infra- or supra-normal regions were small in schizophrenia and healthy control groups (<1) and there were no significant between-group differences. Conclusions: In a case-control setting, a decrease of morphometric similarity within the default mode network may be a robust finding implicated in schizophrenia. However, normative modeling suggests that significant reductions and changes over time of regional morphometric similarity are evident only in a minority of patients.

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

There are few treatments that slow neurodegeneration in Alzheimer's disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood-brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aß) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). In vitro, trontinemab showed a similar binding affinity to fibrillar Aß40 and Aß plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, Macaca fascicularis), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4-18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.

Daily-Life Physical Activity of Healthy Young Adults Associates With Function and Structure of the Hippocampus.

Previous research on Physical Activity (PA) has been highly valuable in elucidating how PA affects the structure and function of the hippocampus in elderly populations that take part in structured interventions. However, how PA affects the hippocampus in younger populations that perform PA during daily-life activities remains poorly understood. In addition, this research has not examined the impact of PA on the internal structure of the hippocampus. Here, we performed a cross-sectional exploration of the way structural and functional aspects of the hippocampus are associated with habitual PA performed during work, leisure time, and sports in the daily lives of healthy young adults (n = 30; 14 female; mean age = 23.9 y.o.; SD = 7.8 y.o.). We assessed PA in these three different contexts through a validated questionnaire. The results show that PA performed during work time correlated with higher subicular volumes. In addition, we found that PA changed functional connectivity (FC) between a location in the middle/posterior hippocampus and regions of the default mode network, and between a location in the anterior hippocampus and regions of the somatomotor network. No statistical effects of PA performed during leisure time and sports were found. The results generalize the impact of PA on younger populations and show how PA performed in daily-life situations correlates with the precise internal structure and functional connectivity of the hippocampus.

Contributions of human amygdala nuclei to resting-state networks.

The amygdala is a brain region with a complex internal structure that is associated with psychiatric disease. Methodological limitations have complicated the study of the internal structure of the amygdala in humans. In the current study we examined the functional connectivity between nine amygdaloid nuclei and existing resting-state networks using a high spatial-resolution fMRI dataset. Using data-driven analysis techniques we found that there were three main clusters inside the amygdala that correlated with the somatomotor, ventral attention and default mode networks. In addition, we found that each resting-state networks depended on a specific configuration of amygdaloid nuclei. Finally, we found that co-activity in the cortical-nucleus increased with the severity of self-rated fear in participants. These results highlight the complex nature of amygdaloid connectivity that is not confined to traditional large-scale divisions, implicates specific configurations of nuclei with certain resting-state networks and highlights the potential clinical relevance of the cortical-nucleus in future studies of the human amygdala.

Medial temporal lobe contributions to resting-state networks.

The medial temporal lobe (MTL) is a set of interconnected brain regions that have been shown to play a central role in behavior as well as in neurological disease. Recent studies using resting-state functional magnetic resonance imaging (rsfMRI) have attempted to understand the MTL in terms of its functional connectivity with the rest of the brain. However, the exact characterization of the whole-brain networks that co-activate with the MTL as well as how the various sub-regions of the MTL are associated with these networks remains poorly understood. Here, we attempted to advance these issues by exploiting the high spatial resolution 7T rsfMRI dataset from the Human Connectome Project with a data-driven analysis approach that relied on independent component analysis (ICA) restricted to the MTL. We found that four different well-known resting-state networks co-activated with a unique configuration of MTL subcomponents. Specifically, we found that different sections of the parahippocampal cortex were involved in the default mode, visual and dorsal attention networks; sections of the hippocampus in the somatomotor and default mode networks; and the lateral entorhinal cortex in the dorsal attention network. We replicated this set of results in a validation sample. These results provide new insight into how the MTL and its subcomponents contribute to known resting-state networks. The participation of the MTL in an expanded range of resting-state networks is in line with recent proposals on MTL function.

Association Between Cognition, Health Related Quality of Life, and Costs in a Population at Risk for Cognitive Decline.

BACKGROUND: The association between health-related quality of life (HRQoL) and care costs in people at risk for cognitive decline is not well understood. Studying this association could reveal the potential benefits of increasing HRQoL and reducing care costs by improving cognition. OBJECTIVE: In this exploratory data analysis we investigated the association between cognition, HRQoL utilities and costs in a well-functioning population at risk for cognitive decline. METHODS: An exploratory data analysis was conducted using longitudinal 2-year data from the FINGER study (n = 1,120). A change score analysis was applied using HRQoL utilities and total medical care costs as outcome. HRQoL utilities were derived from the Short Form Health Survey-36 (SF-36). Total care costs comprised visits to a general practitioner, medical specialist, nurse, and days at hospital. Analyses were adjusted for activities of daily living (ADL) and depressive symptoms. RESULTS: Although univariable analysis showed an association between cognition and HRQoL utilities, multivariable analysis showed no association between cognition, HRQoL utilities and total care costs. A one-unit increase in ADL limitations was associated with a -0.006 (p < 0.001) decrease in HRQoL utilities and a one-unit increase in depressive symptoms was associated with a -0.004 (p < 0.001) decrease in HRQoL utilities. CONCLUSION: The level of cognition in people at-risk for cognitive decline does not seem to be associated with HRQoL utilities. Future research should examine the level at which cognitive decline starts to affect HRQoL and care costs. Ideally, this would be done by means of cross-validation in populations with various stages of cognitive functioning and decline.