Patients with cognitive decline are frequently comorbid with sleep disorders which may in turn aggravate cognitive decline. Sedative dose dexmedetomidine improved sleep quality but incresed bradycardia and hypotension; low dose dexmedetomidine produce less side effects, but the sleep promoting effects are relatively weak. Low dose esketamine also has sleep-promoting effects but may produce neuropsychiatric side effects. Both dexmedetomidine and esketamine are approved for intranasal administration. We suppose that intranasal administration of dexmedetomidine-esketamine combination may improve sleep quality and therefore cognitive function in older ptients with Alzheimer's disease cognitive impairment and sleep disorders.
Aged ≥ 60 years.
Meeting the clinical diagnostic criteria for Alzheimer's disease, with mild cognitive impairment (MoCA score 18-25) or moderate cognitive impairment (MoCA score 10-17) due to Alzheimer's disease.
Comorbid with sleep disorders (Pittsburgh Sleep Quality Index [PSQI] score ≥ 7).
Signed informed consent.
Cognitive impairment/dementia due to other causes (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease dementia).
Unsuitable for intranasal administration due to nasal cavity diseases (e.g., rhinitis, nasal polyps, or nasal congestion of any cause).
Inability to communicate due to visual, auditory, language, or other reasons, or Mini-Mental State Examination (MMSE) score ≤ 9 or MoCA score ≤ 9.
History of schizophrenia, epilepsy, or Parkinson's disease, or confirmed diagnosis of glaucoma, hyperthyroidism, pheochromocytoma, or myasthenia gravis.
Parallel
Dexmedetomidine-esketamine combination
DrugThe dosage will be calculated based on body weight (approximately 0.4 μg/kg of dexmedetomidine and 0.2 mg/kg of esketamine). The mixture of study drugs will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The combination will be administered twice a week for 4 consecutive weeks (8 sessions in total).
Placebo
DrugThe dosage (volume) will be calculated based on body weight in the same way as that in the intervention group. The placebo (normal saline) will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The placebo will be administered twice a week for 4 consecutive weeks (8 sessions in total).
Change in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 1 month
Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) . This is a self-report questionnaire including 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 to 3; the global score ranges from 0 to 21, with higher scores indicating worse sleep quality.
Changes in Montreal Cognitive Assessment (MoCA) score from baseline to 1, 2, and 3 months
Cognitive function will be assessed with the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better function).
Changes in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 2 and 3 months
Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) . This is a self-report questionnaire including 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 to 3; the global score ranges from 0 to 21, with higher scores indicating worse sleep quality.
Objective sleep parameters assessed by actigraphy
Objective sleep parameters, including Total Sleep Time (TST), Sleep Efficiency (SE), Sleep Latency (SL), and Wake After Sleep Onset (WASO), will be monitored continuously using a wearable wrist actigraphy device.
Subjective sleep quality assessed by Numeric Rating Scale (NRS)
Subjective sleep quality will be evaluated using an 11-point Numeric Rating Scale (NRS). The score ranges from 0 to 10, where 0 represents the "best sleep" and 10 represents the "worst sleep".
Change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 1, 2, and 3 months
Depression is assessed with the Patient Health Questionnaire-9 (PHQ-9). The PHQ-9 includes 9-item requiring responses of 0 (not at all) to 3 (nearly every day) to assess the occurrence of depressive symptoms over the last two weeks. It has 8 items on depressive symptoms and 1 focused on suicidal ideation. Total scores range from 0 to 27, with higher score indicating more severe symptoms.
Change in Activities of Daily Living (ADL) score from baseline to 1, 2, an 3 months
The Activities of Daily Living (ADL) scale evaluates basic activities of daily living (BADL) and instrumental activities of daily living (IADL). The total score ranges from 14 to 56, with higher scores indicating more severe impairment of daily living ability.
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