This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Objectives: Brain health is an important focus for coming decades due to population ageing. Although the term ‘brain health’ is increasingly used in lay and professional settings, a clear definition of the term is lacking. We conducted an analysis of the concept of brain health to inform policy, practice, and research.Methods: We applied a hybrid concept analysis method involving three stages: (1) a review of the extant literature for definitions of brain health; (2) field work, involving an international survey of ‘brain health’ researchers and practitioners; and (3) a final analysis, integrating the findings into a working definition and model.Results: Our review of the literature identified 13 articles defining brain health, six of which proposed their own definition. Our survey revealed that the term ‘brain health’ was used in diverse ways based on different theoretical frameworks. From the review and survey, we extracted attributes, antecedents, and consequences of brain health. These were synthesized into a definition of brain health as a life‐long, multidimensional, dynamic state consisting of cognitive, emotional and motor domains underpinned by physiological processes and can be objectively measured and subjectively experienced. It is influenced by eco‐biopsychosocial determinants.Conclusion: This working definition of brain health is a foundation for developing policy, practice, research and advocacy. The definition needs to be operationalised through further development of empirical referents, including cross‐cultural understanding, adaptation and validation.

Background: Public health restrictions due to the COVID‐19 (SARS CoV‐2) pandemic have disproportionately affected informal caregivers of people living with long term health conditions. We aimed to explore levels of care burden, loneliness, and social isolation among caregivers of people with enduring physical and brain health conditions in English‐speaking regions worldwide, by investigating outcomes before and during the COVID‐19 pandemic.Methods: A cross‐sectional anonymous online survey data from 2287 English‐speaking caregivers of people with long term health conditions from four English‐speaking regions (UK, Ireland, USA, New Zealand) included measures of care burden, loneliness, and social isolation, reported before and during the COVID‐19 pandemic. Analyses were descriptive, followed by an ordinal regression model for predictors of burden.Results: Compared to pre‐pandemic levels, all caregivers experienced a significant increase in burden, loneliness, and isolation. Caregivers of people with both brain health and physical conditions were the most burdened and had the highest levels of loneliness and isolation compared to caregivers of people with either a brain health or physical condition only. The increase in care burden among caregivers of people with brain health challenges was associated with caregiver's gender, moderate and severe emotional loneliness, magnitude and frequency of isolation during the pandemic, and care circumstances (cohabitation with the care recipient, restrictions on the ability to provide care).Conclusions: Health and social care interventions should target caregivers' care circumstances and psychological outcomes, particularly in women, accounting for the significant additional burden of care, loneliness, and isolation resulting from pandemic‐related restrictions.

Introduction This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. Methods and analysis Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. Ethics and dissemination The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. Trial registration number EUDRACT Reference Number: 2012-002764-27.

Exercise interventions to prevent dementia and delay cognitive decline have gained considerable attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to determine the effects of an extensive exercise programme on the progression of MCI. This randomised controlled clinical intervention study will take place across three European sites. Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise (3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise intervention programme. The results will add new insights into the prevailing notion that exercise may slow the rate of cognitive decline in MCI. ClinicalTrials.gov NCT02913053