Exploring quantitative group-wise differentiation of Alzheimer's disease and behavioural variant frontotemporal dementia using tract-specific microstructural white matter and functional connectivity measures at multiple time points

Objectives This study explored group-wise quantitative measures of tract-specific white matter (WM) microstructure and functional default mode network (DMN) connectivity to establish an initial indication of their clinical applicability for early-stage and follow-up differential diagnosis of Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD). Methods Eleven AD and 12 bvFTD early-stage patients and 18 controls underwent diffusion tensor imaging and resting state functional magnetic resonance imaging at 3 T. All AD and 6 bvFTD patients underwent the same protocol at 1-year follow-up. Functional connectivity measures of DMN and WM tract-specific diffusivity measures were determined for all groups. Exploratory analyses were performed to compare all measures between the three groups at baseline and between patients at follow-up. Additionally, the difference between baseline and follow-up diffusivity measures in AD and bvFTD patients was compared. Results Functional connectivity of the DMN was not different between groups at baseline and at follow-up. Diffusion abnormalities were observed widely in bvFTD and regionally in the hippocampal cingulum in AD. The extent of the differences between bvFTD and AD was diminished at follow-up, yet abnormalities were still more pronounced in bvFTD. The rate of change was similar in bvFTD and AD. Conclusions This study provides a tentative indication that quantitative tract-specific microstructural WM abnormalities, but not quantitative functional connectivity of the DMN, may aid early-stage and follow-up differential diagnosis of bvFTD and AD. Specifically, pronounced microstructural changes in anterior WM tracts may characterise bvFTD, whereas microstructural abnormalities of the hippocampal cingulum may characterise AD

Analyzing the effect of APOE on Alzheimer's disease progression using an event-based model for stratified populations

Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. In the ε4 carrier group, the model predicted with high confidence that CSF Amyloidβ42 and the cognitive score of Alzheimer's Disease Assessment Scale (ADAS) are early biomarkers. Hippocampus was the earliest volumetric biomarker to become abnormal, closely followed by the CSF Phosphorylated Tau181 (PTAU) biomarker. In the homozygous ε3 carrier group, the model predicted a similar ordering among CSF biomarkers. However, the volume of the fusiform gyrus was identified as one of the earliest volumetric biomarker. While the findings in the ε4 carrier and the homozygous ε3 carrier groups fit the current understanding of progression of AD, the finding in the ε2 carrier group did not. The model predicted, with relatively low confidence, CSF Neurogranin as one of the earliest biomarkers along with cognitive score of Mini-Mental State Examination (MMSE). Amyloid β42 was found to become abnormal after PTAU. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials

A review of barriers to using psychiatric advance directives in clinical practice.

Despite advocacy and demand for psychiatric advance directives (PADs), uptake and implementation in clinical practice is low. We examine why PAD implementation has been difficult globally by reviewing barriers in existing evidence. The review includes 30 studies, and identified 13 barriers, clustered into system level barriers, health professional level barriers, and service user level barriers. The considerable barriers to uptake and implementation hamper PAD use. We propose several potential strategies for overcoming some of the barriers. In order to realise these strategies, additional research is needed, particularly more field-based and operational research to understand processes and difficulties experienced in clinical practice

Facilitators and Barriers to Service user Involvement in Mental Health Guidelines: Lessons from The Netherlands.

This study is the first in-depth qualitative study of service user involvement in the development of multidisciplinary mental health guidelines in the Netherlands. The study comprised a desk study of guidelines (n = 12) and case studies of service user involvement in five guidelines using document analysis, interviews (n = 24) and observations. The desk study shows that all multidisciplinary mental health guidelines have taken service user perspectives into account to some extent. The five guideline case studies led to the identification of ten main themes. Findings will assist guideline developers in making early, informed decisions on involving service users effectively