Pharmacological and non‐pharmacological interventions to enhance sleep in mild cognitive impairment and mild Alzheimer's disease: A systematic review

Abstract

Suboptimal sleep causes cognitive decline and probably accelerates Alzheimer's Disease (AD) progression. Several sleep interventions have been tested in established AD dementia cases. However early intervention is needed in the course of AD at Mild Cognitive Impairment (MCI) or mild dementia stages to help prevent decline and maintain good quality of life. This systematic review aims to summarize evidence on sleep interventions in MCI and mild AD dementia. Seven databases were systematically searched for interventional studies where ≥ 75% of participants met diagnostic criteria for MCI/mild AD dementia, with a control group and validated sleep outcome measures. Studies with a majority of participants diagnosed with Moderate to Severe AD were excluded. After removal of duplicates, 22,133 references were returned in two separate searches (August 2019 and September 2020). 325 full papers were reviewed with 18 retained. Included papers reported 16 separate studies, total sample (n = 1,056), mean age 73.5 years. 13 interventions were represented: Cognitive Behavioural Therapy – Insomnia (CBT‐I), A Multi‐Component Group Based Therapy, A Structured Limbs Exercise Programme, Aromatherapy, Phase Locked Loop Acoustic Stimulation, Transcranial Stimulation, Suvorexant, Melatonin, Donepezil, Galantamine, Rivastigmine, Tetrahydroaminoacridine and Continuous Positive Airway Pressure (CPAP). Psychotherapeutic approaches utilising adapted CBT‐I and a Structured Limbs Exercise Programme each achieved statistically significant improvements in the Pittsburgh Sleep Quality Index with one study reporting co‐existent improved actigraphy variables. Suvorexant significantly increased Total Sleep Time and Sleep Efficiency whilst reducing Wake After Sleep Onset time. Transcranial Stimulation enhanced cortical slow oscillations and spindle power during daytime naps. Melatonin significantly reduced sleep latency in two small studies and sleep to wakefulness transitions in a small sample. CPAP demonstrated efficacy in participants with Obstructive Sleep Apnoea. Evidence to support other interventions was limited. Whilst new evidence is emerging, there remains a paucity of evidence for sleep interventions in MCI and mild AD highlighting a pressing need for high quality experimental studies exploring alternative sleep interventions.

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders

“…Neurodegeneration is accompanied by sleep difficulties due to reduction of amplitude and phase changes of circadian rhythms such as that of melatonin secretion, as well as the disturbing influences of neurodegenerative processes on sleep. The relation between sleep and neurodegenerative diseases is bidirectional and several studies have shown that sleep disruption is a major contributor to neuropathology ( 30 , 73 – 76 ). Alzheimer disease (AD) patients with disturbed sleep-wake rhythms did not only exhibit reduced amounts of melatonin secretions, but also a higher degree of irregularities in the melatonin pattern, such as variations in phasing of the peak.…”

“…An emerging symptom of this circadian disruption is “sundowning,” a chronobiological phenomenon observed in patients with AD along with sleep and wakefulness disorder. “Sundowning” is characterized by symptoms appearing in the late afternoon or early evening, which include reduced ability to maintain attention to external stimuli, disorganized speech, and thinking, a variety of motor disturbances including agitation, wandering, and repetitious physical behaviors with emotional disturbances ( 30 , 73 – 76 ).…”

Sleep-Based Interventions in Alzheimer’s Disease: Promising Approaches from Prevention to Treatment along the Disease Trajectory

“…Beyond pharmacological treatments, several non-invasive techniques have recently demonstrated their ability to modulate the human EEG oscillations during sleep with beneficial effects on memory [173,174]. Therefore, the interest in their possible application in healthy and pathological aging is progressively growing [175][176][177], and several encouraging results are available (Table 2). This approach fits with the general notion that monitoring and managing sleep EEG features may support brain plasticity-dependent process during rehabilitative paradigms in different pathological conditions [178].…”

Current Alzheimer disease research highlights: evidence for novel risk factors

“…One recent review summarized the effects of several sleep interventions that have been studied in patients with MCI or mild dementia, including Cognitive Behavioral Therapy-Insomnia (CBT-I), a structured limbs exercise program, aromatherapy, phase locked loop acoustic stimulation, transcranial stimulation, suvorexant, melatonin, donepezil, galantamine, rivastigmine, tetrahydroaminoacridine, and Continuous Positive Airway Pressure (CPAP) and concluded that CBT-I, melatonin, suvorexant, and CPAP for OSA hold the most promises. [ 25 ] Since medications might further impair cognition, non-pharmacological interventions are of particular interest for older adults who are at high risk for dementia. Cordone et al [ 26 ] highlighted several promising techniques to enhance NREM sleep oscillations that have solid scientific basis for preventing or slowing down AD pathology but remain to be tested in clinical settings.…”