Non-pharmacological treatments for sleep disturbance in mild cognitive impairment and dementia: A systematic review and meta-analysis.

No disease-modifying treatments for dementia are available. Sleep disturbance is strongly associated with cognitive impairment. Non-pharmacological treatments targeting sleep may offer an alternative therapeutic approach. We searched PubMed, CINAHL, EMBASE and the Cochrane library for non-pharmacological treatments for sleep disturbance in mild cognitive impairment (MCI) and dementia, published in English from October 1965 to 2018, including all designs, excluding studies of drug therapies. In all, 53 papers representing 48 studies were included. Participant age ranged from 67.3 to 89.4 years. Most studies (79%) had small samples (<50 participants, range 1-173) and were conducted in long-term/residential care (62%). The majority (85%) recruited participants with moderate-severe dementia; mean MMSE scores ranged from 0 to 28.3/30. Four studies examined MCI. Light therapy delivered over 1-10 weeks was the most studied stand-alone intervention (n = 27), and the majority (81.5%) of these studies found improvements on objective or subjective sleep measures, though the evidence was inconclusive with significant clinical and methodological heterogeneity. Seven multi-modal intervention studies were identified, all incorporating light exposure, and six of these reported improved sleep. Other interventions included electrotherapy stimulation (n = 4), physical exercises/activities (n = 4), acupressure/acupuncture (n = 3) and mindfulness/cognitive behavioural therapy (n = 3). Those examining MCI utilised different mono-modal approaches. A meta-analysis of data from randomised controlled trials showed a statistically significant (mean difference = 3.44, 95% CI: 0.89-5.99, I2=0%; p = 0.008) improvement in sleep efficiency between interventions and controls, favouring the pooled interventions (bright light, multi-domain and other therapies). No other significant differences in sleep or non-sleep outcomes were found. While evidence is available for non-pharmacological sleep interventions, particularly multi-domain approaches, studies were diverse and had small samples. More research examining multi-modal interventions, community-dwellers and those with MCI is required.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.