Experiences of Active Everyday Life Among Persons with Prodromal Alzheimer's Disease: A Qualitative Study.

Introduction: Identifying strategies to prevent or delay cognitive decline among the rising numbers of elderly is acknowledged as a global public health priority. Research suggests that an active lifestyle in terms of participation in activities has the potential to reduce the risk of later-life cognitive decline. The concept of "active everyday life", however, needs to be further explored. Aim: The study aimed to explore and describe the active everyday lives of persons with prodromal Alzheimer's disease (AD) in terms of quality of participation in activities and perceived restrictions. Methods: This qualitative study was part of a larger project, the MIND-ADMINI trial. Nine in-depth interviews were conducted with seven participants (2 males, 5 females; mean age of 72.3) at baseline before the intervention. The data were collected from January to October 2018 and analyzed using the grounded theory approach. Results: Four categories emerged from the analysis: (i) active body and mind; (ii) doing desired meaningful activities to feel engaged, contented, and satisfied; (iii) doing in the context of being connected to others; (iv) ability in making decisions and taking actions. From these categories, which presented the key elements of an active everyday life, a core category was identified: Living a complete life in flow. Conclusion: The findings suggest key elements of participation quality that contribute to an active life. The identified elements are important to be considered in rehabilitation to provide opportunities and possibilities for participation to enable and improve the quality of participation among persons with cognitive impairments.

Experiences of Participation in a Multimodal Preventive Trial MIND-ADMINI Among Persons with Prodromal Alzheimer's Disease: A Qualitative Study.

INTRODUCTION: Alzheimer's disease (AD) is one of the world's leading public health challenges. One-third of AD cases are attributable to modifiable vascular and lifestyle-related risk factors. The Multimodal Preventive Trial for Alzheimer's Disease, MIND-ADMINI a 6-month multinational parallel-group randomized controlled trial (RCT), targeted persons with prodromal AD and built on the positive outcomes from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial. The intervention consisted of four main components of (i) physical exercise training program, (ii) nutrition guidance, (iii) cognitive training, and (iv) social stimulation, as well as (iv) monitoring of metabolic/vascular risk factors. AIM: The study aimed to explore and describe the experiences of participation in MIND-ADMINI among persons with prodromal AD. METHODS: This qualitative study was part of the larger MIND-ADMINI project. Eight participants were interviewed twice, before and after the intervention. The data was analyzed using qualitative content analysis. RESULTS: The results are presented as categories of (i) knowledge of AD and prevention, (ii) motives for study participation, (iii) experiences of the received information about the study, (iv) taking the decision to participate, (v) expectations on study participation, (vi) experiences of study participation and (vii) internal and external factors influencing study participation. CONCLUSION: The MIND-ADMINI was well-tolerated by the participants. At the beginning of the study, the number of tasks and visits was perceived as burdensome but was later well-tolerated. The participant' knowledge about AD and prevention increased during the trial. Their motives for participating in MIND-ADMINI were described as both altruistic and self-beneficial. Health benefits from the study components, access to specialized medical care were identified as benefits. Managing the intensive flow of information was described a major challenge. The participants' needs for personalized support during the trial stress the importance of applying a person-centered approach providing the preventive trials.

Serum proBDNF Is Associated With Changes in the Ketone Body ß-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF: Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults.

Background: ß-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC). Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65-75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0-2 h to changes in BDNF at 0-4 h). ICC estimates were calculated from baseline levels from the three study days. Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: ß = 0.25, 95% CI 0.07-0.44; p = 0.007). Individual change in BHB 0-2 h, predicted change in proBDNF 0-4 h, (ß = 0.40, CI 0.12-0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0-2 h (ß = -0.88, CI -1.37 to -0.40; p < 0.001) and cumulatively 0-4 h (ß = -1.01, CI -1.75 to -0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92-0.99) for proBDNF, and 0.72 (CI 0.47-0.89) for mBDNF. Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health. Clinical Trial Registration:ClinicalTrials.gov, NCT03904433.

Attitudes of at-risk older adults about prevention of cardiovascular disease and dementia using eHealth: a qualitative study in a European context.

OBJECTIVES: Prevention of cardiovascular disease (CVD) and dementia is a key health priority among older adults. Understanding individuals' attitudes to, the prevention of these conditions, particularly when delivered through novel eHealth tools, could help in designing effective prevention programmes. The aim of the study was to explore the attitudes of older adults at increased risk of CVD and dementia regarding engagement in eHealth self-management prevention programmes, and to describe the facilitators and barriers. DESIGN: A qualitative research approach was used. Data were collected through eight focus groups in Finland, France and the Netherlands. Data were analysed following the principles of grounded theory. SETTING AND PARTICIPANTS: Forty-four community-dwellers aged 65+ at risk of CVD were recruited from a previous trial cohort in Finland, and through general practices in France and the Netherlands. RESULTS: The study identified three categories: access to reliable information, trust in the healthcare providers and burden and stigma of dementia. A core category was also identified: the interactive process of the three categories influencing engagement in self-management prevention programme. The categories were interconnected through an interactive process and influenced by the local healthcare culture and context which shaped them differently, becoming either facilitators or barriers to engage in eHealth self-management prevention programmes. CONCLUSIONS: The study emphasises the importance of considering the interactions between the identified categories in this study, grounded in the local healthcare culture and context in further developments of eHealth self-management interventions that aim to prevent CVD and dementia. TRIAL REGISTRATION NUMBER: ISRCTN48151589.

Ketosis After Intake of Coconut Oil and Caprylic Acid-With and Without Glucose: A Cross-Over Study in Healthy Older Adults.

Introduction: Medium-chain-triglycerides (MCT), formed by fatty acids with a length of 6-12 carbon atoms (C6-C12), constitute about two thirds of coconut oil (Coc). MCT have specific metabolic properties which has led them to be described as ketogenic even in the absence of carbohydrate restriction. This effect has mainly been demonstrated for caprylic acid (C8), which constitutes about 6-8% of coconut oil. Our aim was to quantify ketosis and blood glucose after intake of Coc and C8, with and without glucose intake. Sunflower oil (Suf) was used as control, expected to not break fasting ketosis, nor induce supply-driven ketosis. Method: In a 6-arm cross-over design, 15 healthy volunteers-age 65-73, 53% women-were tested once a week. After a 12-h fast, ketones were measured during 4 h after intake of coffee with cream, in combination with each of the intervention arms in a randomized order: 1. Suf (30 g); 2. C8 (20 g) + Suf (10 g); 3. C8 (20 g) + Suf (10 g) + Glucose (50 g); 4. Coc (30 g); 5. Coc (30 g) + Glucose (50 g); 6. C8 (20 g) + Coc (30 g). The primary outcome was absolute blood levels of the ketone ß-hydroxybutyrate, area under the curve (AUC). ANOVA for repeated measures was performed to compare arms. Results: ß-hydroxybutyrate, AUC/time (mean ± SD), for arms were 1: 0.18 ± 0.11; 2: 0.45 ± 0.19; 3: 0.28 ± 0.12; 4: 0.22 ± 0.12; 5: 0.08 ± 0.04; 6: 0.45 ± 0.20 (mmol/L). Differences were significant (all p ≤ 0.02), except for arm 2 vs. 6, and 4 vs. 1 & 3. Blood glucose was stable in arm 1, 2, 4, & 6, at levels slightly below baseline (p ≤ 0.05) at all timepoints hours 1-4 after intake. Conclusions: C8 had a higher ketogenic effect than the other components. Coc was not significantly different from Suf, or C8 with glucose. In addition, we report that a 16-h non-carbohydrate window contributed to a mild ketosis, while blood glucose remained stable. Our results suggest that time-restricted feeding regarding carbohydrates may optimize ketosis from intake of MCT. Clinical Trial Registration: The study was registered as a clinical trial on ClinicalTrials.gov, NCT03904433.

Effects of daily L-dopa administration on learning and brain structure in older adults undergoing cognitive training: a randomised clinical trial.

Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signalling in plasticity. We investigated whether supplementation with the dopamine-precursor L-dopa improves effects of cognitive training on performance. Sixty-three participants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25 mg L-dopa/benserazide (n = 32) or placebo (n = 31) prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were blinded to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0.267 SDs; 95%CI [-0.498, -0.036]; p = 0.024). Change in verbal intelligence did not significantly differ between the groups (-0.081 SDs, 95%CI [-0.242, 0.080]; p = 0.323). Subjects receiving L-dopa also progressed slower through the training and the groups displayed differential volumetric changes in the midbrain. No statistically significant differences were found for the secondary cognitive outcomes. Adverse events occurred for 10 (31%) and 7 (23%) participants in the active and control groups, correspondingly. The results speak against early pharmacological interventions in older healthy adults to improve broader cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements in the healthy elderly. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54 (2016-10-05).

Evaluation of a Novel Psychological Intervention Tailored for Patients With Early Cognitive Impairment (PIPCI): Study Protocol of a Randomized Controlled Trial.

BACKGROUND: Individuals with early phase cognitive impairment are frequently affected by existential distress, social avoidance and associated health issues (including symptoms of stress, anxiety, and depression). The demand for efficient psychological support is crucial from both an individual and a societal perspective. We have developed a novel psychological intervention (Psychological Intervention tailored for Patients with Cognitive Impairment, PIPCI) manual for providing a non-medical path to enhanced psychological health in the cognitively impaired population. The current article provides specific information on the randomized controlled trial (RCT)-design and methods. The main hypothesis is that participants receiving PIPCI will increase their psychological flexibility (the ability to notice and accept interfering thoughts, emotions, and bodily sensations without acting on them, when this serves action in line with personal values) compared to participants in the active control (cognitive training) group and the waiting list control group. The secondary hypotheses are that participants receiving PIPCI will improve psychological health (stress measures, quality of life, depression, and general health) compared to participants in the active control group and the waiting list control group. MATERIALS AND METHODS: This three-arm RCT will recruit participants from the cognitive centers at Karolinska University Hospital in Stockholm and randomize approximately 120 individuals in the early phase of cognitive impairment to either an experimental group (psychological intervention once a week for 10 weeks), an active control group (cognitive training once a week for 10 weeks) or a waiting list control group. Intervention outcome will be evaluated with self-report questionnaires on physical and psychological aspects of health, cognitive assessment, biological markers (obtained from blood and saliva) and health care costs. Assessments will be performed at pre- (1 week before the interventions) and post-intervention (1 week after the interventions), as well as at a 6-month follow-up. DISCUSSION: The development of a potentially feasible and effective psychological intervention tailored for early phase cognitive impairment (PIPCI) has the potential to advance the non-pharmacological intervention field. This is especially important given the extensive burden for many affected individuals and their families and the current lack of effective treatments. If the psychological intervention discussed here shows feasibility and efficacy, there is potential for far-reaching healthcare implications for patients with early cognitive impairment at risk of developing dementia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04356924. Date of registration: April 22, 2020. URL: https://clinicaltrials.gov/ct2/show/NCT04356924.

Capillary blood tests may overestimate ketosis: triangulation between three different measures of ß-hydroxybutyrate.

The ketone body ß-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.

Integrating nurses' experiences with supporting behaviour change for cardiovascular prevention into a self-management internet platform in Finland and the Netherlands: a qualitative study.

OBJECTIVES: Global ageing is linked to an increased burden of cardiovascular disease and dementia, which calls for better prevention strategies. Self-management and eHealth applications are regarded as promising strategies to support prevention. The aim of this study was to explore nurses' best practices concerning behaviour change guidance for cardiovascular (CV) prevention in order to learn how to optimally integrate them into a coach-supported internet platform for CV self-management. DESIGN: Qualitative focus group study in Finland and the Netherlands. Discussions were audiotaped and transcribed. Data were thematically analysed following principles of grounded theory. SETTING: Dutch and Finnish primary care settings. PARTICIPANTS: Six Finnish and seven Dutch primary care nurses with experience in CV prevention. RESULTS: Similar best practices were found in both countries and comprised of (1) establishing a relationship of trust, (2) managing awareness and expectations and (3) appropriate timing and monitoring of the process of behaviour change. However, the Finnish and Dutch nurses used different approaches for accomplishment of these practices, which was reflected in their recommendations for online support. Both groups emphasised that online support should be combined with human support and integrated into regular care. Finnish nurses had more confidence in patient self-management and remote communication than Dutch nurses, who emphasised the importance of face-to-face contact and preferred to keep control of medical aspects of prevention. CONCLUSIONS: Differences in Dutch and Finnish's nurses' practices for supporting CV prevention appear to reflect their local healthcare practices, which should be taken into account when designing internet platforms for health self-management. Including cognitive health as a goal of CV prevention might stimulate motivation for health behaviour change. TRIAL REGISTRATION NUMBER: ISRCTN48151589; Pre-results.

Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's disease and elderly controls after oral administration of sembragiline.

PURPOSE: In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. METHODS: This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [11C]-L-deprenyl-D2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6-15 days. RESULTS: At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an Emax of ∼80-90 % across brain regions of interest and in an EC50 of 1-2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. CONCLUSIONS: This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.

Recognition memory for emotional faces in amnestic mild cognitive impairment: an event-related potential study.

This study examined the temporal course of emotional face recognition in amnestic mild cognitive impairment (aMCI). Patients and healthy controls (HC) performed a face recognition task, giving old/new responses to previously studied and novel faces displaying a negative or neutral expression. In aMCI patients, recognition accuracy was preserved for negative faces. Event-related potentials (ERPs) revealed disease-related changes in early perceptual components but not in ERP indices of explicit recognition. Specifically, aMCI patients showed impaired recognition effects for negative faces on the amplitudes of N170 and P2, suggesting deficient memory-related processing of negative faces at the stage of structural encoding and during an early recognition stage at which faces are individuated, respectively. Moreover, while a right-lateralized emotion effect specifically observed for correctly recognized faces on the amplitude of N170 was absent in aMCI, a similar emotion effect for successfully recognized faces on P2 was preserved in the patients, albeit with a different distribution. This suggests that in aMCI facilitated processing of successfully recognized emotional faces starts later in the processing sequence. Nonetheless, an early frontal old/new effect confined to negative faces and a parietal old/new effect unaffected by facial emotion were observed in both groups. This indicates that familiarity and conceptual priming processes may specifically contribute to recognition of negative faces in older adults and that aMCI patients can recruit the same retrieval mechanisms as controls, despite disease-related changes on early perceptual ERP components.

Practical lessons from amyloid immunotherapy trials in Alzheimer disease.

OBJECTIVES: Amyloid immunotherapy trials are central in Alzheimer disease (AD) drug development, with the potential to influence all future disease-modifying randomized controlled trials (RCTs). This study investigates practical experiences of staff and participants in immunotherapy RCTs. SETTING AND METHODS: The Clinical Trial Research Unit of the Memory Clinic at Karolinska University Hospital, Sweden is an experienced centre specialized in Alzheimer RCTs, where four active and passive phase I/II immunotherapy trials are currently ongoing. Meetings were held with staff members, who were asked to describe their experiences and suggest necessary improvements. In addition, a pilot study was conducted to investigate motivations and expectations of participants in immunotherapy RCTs. A questionnaire was sent to 20 patients, and another similar questionnaire to their caregivers. RESULTS: The main issues emphasized by staff members concerned the critical window of opportunity for recruiting RCTs participants, the much higher level of effort required of patients and caregivers in immunotherapy RCTs compared to classical cholinesterase inhibitor RCTs, problematic informed consent procedures, and confidentiality limitations in trials with different sponsors. For patients and caregivers, the main reason for participating in RCTs was the wish to help research and other people, followed by the need for information, continuity of care, safety and support. Compared to patients, caregivers' expectations of trial results were more realistic. CONCLUSIONS: More open debates of practical experiences from different trial centres and sponsors are essential for optimizing trial designs and improving conditions for participants.