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NCT Number: NCT07298876

Low-intensity Hippocampal Transcranial Ultrasound Stimulation for Managing Cognitive and Sleep Dysfunction in Preclinical Alzheimer's Disease

Background: Sleep disturbances, as a common symptom, can jeopardize the brain health and cognitive function and even lead to cognitive impairments in older adults. The co-occurring sleep disturbances cognitive complaints can significantly affect brain functions, and even be implicated as a key contributing factor in the development of prodromal Alzheimer's disease (AD). At present, very few non-pharmacological therapies are developed for managing these comorbidities in older adults. Focused low-intensity transcranial ultrasound stimulation (TUS) enables to stimulation the deep brain structures, such as hippocampus, with optimized focality and specific frequency.

Objectives: 1) To investigate the safety, feasibility and efficacy of a 2-week focused low-intensity hippocampal TUS on the severity of sleep disturbances and cognitive impairments in elderly patients; 2) to determine the sample size of a full-scale randomized clinical trial of low-intensity TUS in patients with preclinical AD; 3) to evaluate the effects of low-intensity TUS on the severity of sleep quality and cognitive functions at 2, 6 and 10 weeks after the treatments.

Design: A 2-week randomized, double-blind, controlled clinical trial. Methods: Chinese right-handed preclinical AD patients with sleep disturbances (aged from 60 to 90 years) will be randomly assigned to a 2-week intervention of either low intensity TUS or sham TUS, with 10 participants per arm. Before intervention, T1-weighted magnetic resonance imaging (MRI) data is used to construct individual realistic head model. Comprehensive assessments, including sleep quality, cognitive performance and plasma p-tau217, Aß42 and Aß40 will be conducted at baseline, 2nd week, 6th week and 10th week. Program adherence and adverse effects will be monitored throughout intervention.

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Key information

Conditions

Sleep Disturbances Aging Central Nervous System Diseases Cognition Disorders Cognitive Dysfunction Cognitive Impairment, Mild Mental Disorders Nervous System Diseases Neurocognitive Disorders Parasomnias Sleep Wake Disorders

Age range

60 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Tai Po Hospital

Hong Kong, Tai Po District, 100000

About this study

Significance: This study aims to investigate the feasibility, safety and efficacy of low intensity hippocampal TUS for sleep disturbances and cognitive impairments in patients with preclinical Alzheimer's disease. It wills also test the program adherence, tolerability and adverse effects of this innovative neuromodulation. Information will be helpful for in-depth understanding the relationship of "sleep, glymphatic function and cognition" and guiding the further studies of neurodegenerative diseases and sleep medicine.

Data analysis: The primary outcomes will be the changes in sleep quality and cognition, and the comparisons of group differences across different time points. Secondary outcomes will be the changes of glymphatic function and neuropathological factors. Intention-to-treat analysis will be carried out. Changes of efficacy indicators from baseline to each follow up point will be tested with mixed effect model.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Chinese, right-handed, aged from 60 to 85 years.
  • Mild neurocognitive disorder due to Alzheimer's disease (NCD-AD) is identified with the Montreal Cognitive Assessment (MoCA) score range from 22 to 26.
  • Sleep disturbances or poor sleep quality is assessed and defined with a total score of the Pittsburgh Sleep Quality Index (PSQI) greater than 5.
  • No impairments in the activities of daily living.

Exclusion criteria

  • Previous diagnosis of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson disease.
  • History of neurological diseases including brain tumor, and stroke.
  • History of psychiatric disorders including schizophrenia and depression.
  • Presence of positive neurological diseases, such as stroke, brain tumor, dementia.
  • Physically unable to attend the sessions of intervention.
  • Currently enrolled in another intervention study.
  • Currently taking a psychiatric or other medication that may affect sleep quality and cognition.

Treatment and study plan

Low-intensity transcranial ultrasound stimulation

Device

Low-intensity TUS, as an advanced modality of transcranial brain stimulation, enables to stimulate the deep brain structures with optimized focality and specific frequency.

Sham low-intensity transcranial ultrasound stimulation

Device

Sham TUS uses the same settings as the active low-intensity TUS. During the sham treatment, the power will be off.

Primary outcomes

  1. Pittsburg Sleep Quality Index (PSQI)

    Time frame: 10 weeks

    Description: The PSQI is a 19-item questionnaire that includes seven areas of subjective sleep quality and patterns in adults over the last month including the following components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, SDs, use of sleeping medications, and daytime dysfunction. Each item in the scale is scored from 0 to 3 scale (0 = no difficulty; 3 = severe difficulty). The scores are added to yield a global score ranging from 0 to 21 (0 = no difficulty; 21 = severe difficulties in all areas). This scale has good reliability and validity psychometrics and is widely used in research: Cronbach's alpha (0.77 to 0.83), sensitivity (89.6%), specificity (86.5%). Greater score of PSQI indicates worse sleep quality.

  2. Delayed recall of the words

    Time frame: 10 weeks

    Word-list learning test (WLLT), consisting of sixteen semantically non-associated words that is presented consecutively over three free trials of immediate recall, a 20-min delayed recall (to prevent recency effects). Delayed recall of the words derived from WLLT is used as a proxy for measuring working memory function.

Secondary outcomes

  1. Objective sleep quality

    Time frame: 2 weeks

    Actigraphy records will be used to quantify sleep-wake cycle during treatment.

  2. The levels of plasma Aß

    Time frame: 10 weeks

    The levels of plasma Aß, including Aß42, Aß40 and Aß42/40 ratio, are assessed at the baseline and post-intervention time points.

  3. The levels of plasma tau

    Time frame: 10 weeks

    The levels of plasma tau, are assessed at the baseline and post-intervention time points.

Sponsors and collaborators

Lead sponsor

Chinese University of Hong Kong

Other

Collaborators

  • The Hong Kong Polytechnic University

Registry information

Official study title

Low-intensity Hippocampal Transcranial Ultrasound Stimulation for Managing Cognitive and Sleep Dysfunction in Preclinical Alzheimer's Disease Patients: A Randomized Clinical Trial

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Dec 23, 2025
Registry last updated
Dec 23, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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