The Coarse-Grained Plaque: A Divergent Aβ Plaque-Type in Early-Onset Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies

Theory- and evidence-based best practices for physical activity counseling for adults with spinal cord injury

This project used a systematic and integrated knowledge translation (IKT) approach to co-create theory- and evidence-based best practices for physical activity counseling for adults with spinal cord injury (SCI). Guided by the IKT Guiding Principles, we meaningfully engaged research users throughout this project. A systematic approach was used. An international, multidisciplinary expert panel (n = 15), including SCI researchers, counselors, and people with SCI, was established. Panel members participated in two online meetings to discuss the best practices by drawing upon new knowledge regarding counselor-client interactions, current evidence, and members’ own experiences. We used concepts from key literature on SCI-specific physical activity counseling and health behavior change theories. An external group of experts completed an online survey to test the clarity, usability and appropriateness of the best practices. The best practices document includes an introduction, the best practices, things to keep in mind, and a glossary. Best practices focused on how to deliver a conversation and what to discuss during a conversation. Examples include: build rapport, use a client-centred approach following the spirit of motivational interviewing, understand your client’s physical activity barriers, and share the SCI physical activity guidelines. External experts (n = 25) rated the best practices on average as clear, useful, and appropriate. We present the first systematically co-developed theory- and evidence-based best practices for SCI physical activity counseling. The implementation of the best practices will be supported by developing training modules. These new best practices can contribute to optimizing SCI physical activity counseling services across settings.</p

The co-development and evaluation of an e-learning course on spinal cord injury physical activity counselling:a randomized controlled trial

Background: Health, fitness and lifestyle professionals can play important roles in promoting physical activity in groups at risk of developing an inactive lifestyle, such as people with spinal cord injury (SCI). Tailored counselling is a promising tool to promote and improve physical activity levels. To support professionals to effectively have a conversation about physical activity with clients with SCI, evidence-based training and resources are needed. This project aimed to (1) co-develop an e-learning course on best practices for SCI physical activity counselling and, (2) examine the effectiveness and usability of this course. Methods: Guided by the technology-enhanced learning (TEL) evaluation framework, we used a systematic, multistep approach to co-develop and evaluate an e-learning course. The development process was informed by input and feedback from a diverse group of end-users and experts (n &gt; 160) via online surveys and (think-aloud) interviews. A randomized controlled trial was used to compare learning outcomes (post-knowledge and self-efficacy) between participants who completed the course (intervention group) and the wait-listed control group. Usability, learning experiences, and satisfaction were assessed among all participants. Results: Forty-one participants (21 intervention-group; 20 control-group) with various backgrounds (e.g., lifestyle counsellors, physiotherapists, occupational therapists, recreation therapists, fitness trainers) enrolled in the randomized controlled trial. After completing the course, participants in the intervention group showed significantly improved knowledge on the best practices for SCI physical activity counselling and higher self-efficacy for using these best practices in conversations with clients with SCI compared to the control group (p &lt;.001). Participants reported above average usability scores, positive learning experiences, and high levels of satisfaction when completing the course. Conclusion: We used a systematic, multi-step, theory-informed approach to co-develop and evaluate an evidence-based e-learning course on SCI physical activity counselling to support professionals to promote physical activity in their daily practices. The overall positive findings demonstrate that the e-learning course is feasible and ready for further implementation in various health and community settings. Implementation of the e-learning course can help professionals improve the physical activity support they provide to their clients, and subsequently increase physical activity participation in people with SCI.</p

Excitability of the Motor Cortex Ipsilateral to the Moving Body Side Depends on Spatio-Temporal Task Complexity and Hemispheric Specialization

Unilateral movements are mainly controlled by the contralateral hemisphere, even though the primary motor cortex ipsilateral (M1ipsi) to the moving body side can undergo task-related changes of activity as well. Here we used transcranial magnetic stimulation (TMS) to investigate whether representations of the wrist flexor (FCR) and extensor (ECR) in M1ipsi would be modulated when unilateral rhythmical wrist movements were executed in isolation or in the context of a simple or difficult hand-foot coordination pattern, and whether this modulation would differ for the left versus right hemisphere. We found that M1ipsi facilitation of the resting ECR and FCR mirrored the activation of the moving wrist such that facilitation was higher when the homologous muscle was activated during the cyclical movement. We showed that this ipsilateral facilitation increased significantly when the wrist movements were performed in the context of demanding hand-foot coordination tasks whereas foot movements alone influenced the hand representation of M1ipsi only slightly. Our data revealed a clear hemispheric asymmetry such that MEP responses were significantly larger when elicited in the left M1ipsi than in the right. In experiment 2, we tested whether the modulations of M1ipsi facilitation, caused by performing different coordination tasks with the left versus right body sides, could be explained by changes in short intracortical inhibition (SICI). We found that SICI was increasingly reduced for a complex coordination pattern as compared to rest, but only in the right M1ipsi. We argue that our results might reflect the stronger involvement of the left versus right hemisphere in performing demanding motor tasks

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk : a case-control study

Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels

Walk it off! The effectiveness of walk and talk coaching in nature for individuals with burnout- and stress-related complaints

Mental health problems are considered to represent the most frequent noncommunicable diseases in modern times. A growing field is now investigating the implementation of nature exposure in mental health care interventions. The present study investigated a walk and talk coaching program of approximately 12–18 weeks, in which coach and client go outside in a natural setting. Forty participants (31 females) with burnout- and stress-related complaints entered the study, half of them followed the walk and talk program and the other half were in the (passive) control group. Stress and burnout related symptoms and health and wellbeing were measured at baseline, mid-term, and post-intervention. Evaluative questions were added to measure participants’ experiences with the program as well as their experiences with the natural setting. Results show that participants in the walk and talk group improved more on burnout, stress symptoms, general mental health, and wellbeing than those in the control group. These improvements were most pronounced at the post-intervention measurement, but some effects were already visible at mid-term. Participants also evaluated the program positively. The majority of participants indicated to have experienced added benefits of the natural setting