Overview
The goal of this clinical trial is to learn if a wearable ultrasound device, called ATTN201, is safe and easy to use. The study is for adults ages 65 and older who have mild cognitive impairment (MCI) and a buildup of a protein called amyloid in the brain. Amyloid buildup is an early sign of Alzheimer's disease. The ATTN201 device sends low-intensity sound waves to a deep area of the brain that helps control sleep. The aim is to boost deep-sleep brain waves. These brain waves may help the brain clear away waste, including amyloid.
The main questions it aims to answer are:
- What, if any, issues do participants have when using the ATTN201 device?
- Can participants complete the full study schedule?
Researchers will compare focused ultrasound to unfocused ultrasound. Unfocused ultrasound is a look-alike treatment. It feels and sounds the same but is not aimed at the brain target. The comparison will show if the focused treatment changes sleep brain waves, blood markers of Alzheimer's disease, or memory and thinking.
Participants will:
- Visit the study site for memory and thinking tests, blood draws, a health check, and MRI scans of the brain
- Record their sleep at home for at least 5 days with a sleep diary, a watch-like sensor, and a headband that measures brain waves
- Be assigned by chance to focused or unfocused ultrasound
- Take part in 10 nap sessions over 2 weeks while wearing the device, at the study site or at home
- Return for a final visit to repeat the first tests, and may return for an optional visit 3 months later
Description
This pilot study is a randomized, double-blind, parallel-group trial of repeated low-intensity focused ultrasound (LIFU) stimulation of the centromedian nucleus of the thalamus (CMN) in amyloid-positive older adults with mild cognitive impairment (MCI).
Background and rationale: Poor sleep both predicts and accelerates Alzheimer's disease (AD) pathology, in part by impairing glymphatic clearance of metabolites including soluble amyloid-beta and tau. Slow waves during sleep generate metabolic signals that alter neurovascular tone and cerebrospinal fluid (CSF) volume, creating pulsatile fluid flow thought to support clearance. Slow waves can be entrained by stimulating seed regions of the brain at a slow rate, but existing approaches (transcranial magnetic stimulation, optogenetic or electrical stimulation of the CMN) are too invasive, cumbersome, or costly for regular home use in a broad aging population. Low-Intensity focused ultrasound can both elicit neural activity in the CMN and directly produce fluid flow, non-invasively and with lightweight hardware. In a prior single-session study targeting the CMN in 10 patients with chronic pain, sonication improved subjective sleep for several days. This study extends that preliminary work to a clinical population for which the effects are likely to be therapeutically relevant.
Investigational device: ATTN201 is a head-worn LIFU system that delivers MRI-guided stimulation offline, without real-time imaging or clinician aid. Bilateral 64-element sparse ultrasound arrays operating at 500 kHz are positioned over the temporal windows and deliver cross-beam focused stimulation to deep brain targets. Targeting is participant-specific: before first use, each participant undergoes a 3.0T MRI for personalized targeting. Automated brain segmentation, transducer spatial mapping, and acoustic simulation are used to compute the per-element phase delays required to focus energy at the target. All stimulation remains within International Transcranial Ultrasonic Stimulation Safety and Standards (ITRUSST) consortium recommendations, with sessions lasting up to 60 minutes.
Control condition: Unfocused ultrasound is used as the comparator to maintain participant and study-administrator blinding. It mimics the auditory and peripheral sensations of focused stimulation without creating substantive pressure at the focal target relative to surrounding tissue.
Study conduct: Because the study enrolls people with MCI, capacity to consent is assessed before enrollment using a teach-back method, and only individuals who can demonstrate adequate understanding of the study are enrolled. After screening and informed consent, participants complete screening and baseline visits that include a blood draw for plasma biomarkers, cognitive and functional assessment, safety assessments, and an MRI. Participants then complete at least 5 days of at-home baseline sleep recording using actigraphy, sleep diaries, and wearable EEG. They are subsequently randomized to CMN-focused or unfocused stimulation, delivered during 10 nap opportunities over 2 weeks at the study site or the participant's home, per participant preference. Treatment visits include continuous EEG monitoring, adverse event assessment, and visual analog scales for memory and related psychiatric symptoms; home sleep monitoring continues throughout the treatment period. A post-treatment visit repeats the baseline measures, including cognitive testing, neurological exam, blood draw, and an MRI. An optional follow-up visit 3 months later repeats the same measures to assess durability of effects. The study is conducted in conformance with Good Clinical Practice (GCP).
Eligibility
Inclusion Criteria:
- 65+ years old, male or female
- Amyloid positivity as assessed by either PET, CSF, or plasma.
- Qualify for an MCI Diagnosis.
- Study partner available for informant measures.
- Willing and able to undergo a brain MRI.
- If currently on AD or sleep medications, must be at the same stable dose(s) for at least 3 weeks prior to screening and throughout the course of the study, and must continue to be under the care of their treating neurologist through the duration of the study.
- Be able and willing to wear an Attune device during treatments
- Able to sign informed consent in accordance with local regulations.
- Be able to speak, read, and understand the language of the trial staff and the informed consent form.
- Possess the ability to respond verbally to questions, follow instructions, and complete study assessments.
- Be able to adhere to the stimulation protocol and visit schedules.
- Be medically stable at baseline/randomization as assessed by medical history and non-significant clinical results of safety labs and vital signs examination.
Exclusion Criteria:
- Early-onset Alzheimer's disease, as defined by a diagnosis occurring prior to age 65.
- Clinically significant depression, as defined by a score of \>10 on the Geriatric Depression Scale
- Moderate to severe untreated obstructive sleep apnea, as defined by an Apnea-Hypopnea Index (AHI) ≥ 15.
- Has other medical or psychiatric symptoms or conditions that, in the opinion of the investigator, will interfere with study activities or confound interpretation of study results.
- Is on medication which, in the opinion of the investigator, will confound study results.
- Has a history of deep brain stimulation or ablative surgery
- Has a history of substance abuse including alcohol use disorder in the past 6 months
- Has a history of traumatic brain injury
- Has any contraindications for completing a brain MRI scan.
- The subject's head must fit within the head coil.
- Has an uncontrolled medical condition which may impact study results.
- Is or has an immediate family member of staff directly involved with this trial.
