Deep Repetitive Transcranial Magnetic Stimulation (rTMS) of the Precuneus for Alzheimer Disease (AD)

Phase 1

Recruiting

• Conditions: Alzheimer's Disease; Alzheimer Disease; Dementia Alzheimer Type; Mild Alzheimer's Disease; Moderate Alzheimer's Disease; Alzheimer's Disease (AD); Alzheimer's Dementia
• Interventions: Device: TMS; Device: Transcranial Magnetic Stimulation Sham

• Registration Number: NCT06597942
• Lead Sponsor: University of California, Los Angeles

Brief Summary

The goal of this clinical trial is to learn if using deep repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus is feasible, tolerable, and potentially efficacious for memory in Probable Alzheimer's Dementia. Previous work studying rTMS in Alzheimer's is mixed, but recent work studying rTMS of the precuneus is encouraging for both its short-term and long-term effects. The main questions this study aims to answer are:

* Is deep rTMS of the precuneus feasible and tolerable in Alzheimer's?

* Are there signs of positive brain changes in response to deep rTMS?

* Is deep rTMS potentially efficacious for memory in Alzheimer's? Researchers will compare active stimulation to placebo stimulation while obtaining memory testing and measurements of the brain (imaging, scalp electrode measurements, bloodwork) to see if active treatment works to treat mild-to-moderate probable Alzheimer's Dementia.

Participants will:

* Engage with memory testing, brain scans, and bloodwork during a comprehensive assessment

* Visit the clinic 3 times for 12 consolidated rTMS sessions, followed by 4 once weekly maintenance sessions

* Be offered a full open-label active treatment course after completing their treatment course if they are initially in the placebo group

Detailed Description

This study is designed to examine whether non-invasive electromagnetic stimulation of a specific brain region can help improve memory in the short-term in Alzheimer's Disease (AD). AD is a progressive neurodegenerative disease that affects multiple domains, including cognitive (e.g. memory, executive function), behavioral (e.g. wandering, difficulty controlling impulses, irritability), emotional (e.g. anxiety, depression), and functional (e.g. ability to live independently and complete activities of daily living) domains. It is also associated with increased caregiver burden, which can adversely affect caregivers' health.

One increasingly apparent contributor to disease progression in AD is brain network dysregulation, particularly within the default mode network. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive therapeutic modality that can be used to stimulate the precuneus, a key node in the default mode network, and maintain signaling function within the default mode network. Previous studies have shown that targeting the precuneus with rTMS may enhance memory in the short term and delay disease progression and functional decline in AD over longer periods. rTMS protocols that have demonstrated promise for treatment delay have first shown short-term impacts on memory, particularly memory of recent and past events.

We will conduct a two-phase trial of rTMS targeting the precuneus in patients with mild to moderate probable AD focused primarily on determining safety and feasibility and secondarily focused on determining short-term efficacy for memory. Participants will be recruited through fliers, social media, print, and web advertising, as well as referrals from other UCLA studies, UCLA clinics, and known community clinics. The first phase will be a handful of subjects (5-10) receiving active treatment only to refine the protocol. After refinement, the second phase will consist of a randomized, double-blind, sham controlled clinical trial with post-blinding crossover examining both safety and short-term efficacy for memory. Participants will be randomized on a 1:1 ratio to either receive precuneus or sham rTMS.

Participants will undergo 16 total rTMS brain stimulation sessions (each session being about 20 minutes) over the course of 5 weeks. The initial induction 3-day intensive course in which rTMS (or sham) will be applied four times daily with 1-hour breaks between treatments will be followed by a 4-week maintenance course in which stimulation will be applied once weekly.

Participants will undergo a range of assessments including brain imaging and oxygenation, genotyping, eye reactivity to light testing, and brain electrical activity measurements to identify changes that occur in the precuneus and its connected regions over time. Participants will also undergo comprehensive neuropsychological (memory and behavioral) testing at baseline and during follow up. Additionally, participants and their caregivers will complete brief weekly check-ins at each treatment during the study.

Study Timeline

• Study First Submitted: 2024-09-11
• Study First Submitted QC: 2024-09-13
• Study First Posted: 2024-09-19
• Status Verified: 2024-10
• Study Start: 2024-10-17
• Last Update Submitted: 2025-01-06
• Last Update Posted: 2025-01-08
• Primary Completion: 2026-10
• Study Completion: 2026-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 54

Inclusion Criteria

• Age 60-100 at the start of the study
• Established diagnosis of Alzheimer's Clinical Syndrome (which is also met through a diagnosis of Alzheimer's Dementia)
• Agreement to participate in study and able to complete informed consent process
• Have a caregiver/study partner who can accompany them to all study visits
• Have a known alternate surrogate decision-maker (in case needed) who can accompany them to the informed consent visit (this person may be the study partner mentioned above)
• Screening MMSE score of 18-26
• Screening GDS score <6
• Either 1) treated with memory-enhancing medication (cholinesterase inhibitor) for at least 2 months, 2) failed trial with no plan to re-trial, or 3) no trial planned during the course of the study for other reasons
• No change in use of psychotropic medication for the treatment of depression, anxiety, ADHD, or psychosis for 2 weeks prior to the study

Exclusion Criteria

• Participant and/or their surrogate are unwilling or unable to provide informed consent

• Currently pregnant or potentially pregnant

• Diagnosis of a dementia or cognitive disorder due to a cause other than Alzheimer's Disease

• Diagnosis of severe Dementia (CDR > 2.0) at the start of the study

• History of substance use disorder currently not in sustained remission

• Substance misuse within the past 6 months (excluding nicotine or caffeine)

• History of stroke, traumatic brain injury with loss of consciousness, or other major neurologic disorder (e.g., epilepsy, Huntington's disease, Parkinson's disease)

• History of seizure disorder or family history of seizure disorder in a first-degree relative

• Poorly-controlled hypertension, cardiovascular disease, or cerebrovascular disease

• History of any other major active medical, neurologic, or psychiatric illness affecting cognition (associated with cognitive impairment) or a participant's ability to safely and meaningfully participate in the study

• Non-fluent in English (not native or functionally-native)

• Contraindication to TMS or MRI including claustrophobia, MRI-incompatible or unknown metal in body (including facial tattoos with uknown or metallic inks), surgery within 60 days, certain implants (excluding dental fillings), or previous abnormal MRI results.

• Has previous history of TMS treatment in the past (not TMS naïve)

• Currently enrolled in a memory-enhancement study

• Alteration in cognitive-enhancement medication dose within the past 2 months or active plans for dose alteration during the course of the study (previously unplanned changes that occur during the study will be examined on a case-by-case basis)

• History of treatment with lecanemab, aducanumab, donanemab, or other monoclonal antibody treatment for Alzheimer's Disease (due to lack of knowledge surrounding the impacts of these treatments)

• Currently or within the past 2 weeks taking any of the following classes of medication:

  • Anticholinergic (e.g., tolterodine, benztropine)
  • Sedating antihistamines (e.g., diphenhydramine)
  • any drug that has significant anticholinergic or antihistaminic side effects (e.g., tricyclic antidepressant medications, mirtazapine).
  • Benzodiazepines. While not a strict rule out, this will be decided on a case-by-case basis
  • Antiepileptic agents. While not a strict rule out, this will be decided on a case-by-case basis
  • Antipsychotic agents. While not a strict rule out, this will be decided on a case-by-case basis

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Open-Label Active deep rTMS	TMS	The first stage of the study will consist of protocol refinement. In this first stage of 5-10 participants, all participants will receive open-label active treatment. Treatment will consist of 16 sessions of deep rTMS spread over 5 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 60 minutes between sessions), followed by 1 session per week for 4 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 28 second intertrain interval (roughly 20 minutes per session).
Randomized Active deep precuneus rTMS	TMS	The second stage of the study will consist of both active and sham treatment groups. Treatment will consist of 16 sessions of deep rTMS spread over 5 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 60 minutes between sessions), followed by 1 session per week for 4 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 28 second intertrain interval (roughly 20 minutes per session). The active group will receive this protocol using an active treatment coil delivering real rTMS.
Randomized Sham deep precuneus rTMS	TMS	The second stage of the study will consist of both active and sham treatment groups. Treatment will consist of 16 sessions of deep rTMS spread over 5 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 60 minutes between sessions), followed by 1 session per week for 4 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 28 second intertrain interval (roughly 20 minutes per session). The placebo group will receive this protocol using a sham TMS coil delivering inactive rTMS. Participants in the sham/placebo group will be offered a full open-label extension treatment course of active rTMS on completion of the randomized phase.
Randomized Sham deep precuneus rTMS	Transcranial Magnetic Stimulation Sham	The second stage of the study will consist of both active and sham treatment groups. Treatment will consist of 16 sessions of deep rTMS spread over 5 weeks. The induction phase of treatment will be 4 sessions per day for 3 consecutive days (with 60 minutes between sessions), followed by 1 session per week for 4 weeks. Individual sessions will consist of 1600 pulses of 20Hz rTMS delivered in 40 pulse trains to the precuneus (using MRI structural neuronavigation) at 100% of depth-corrected motor-threshold with a 28 second intertrain interval (roughly 20 minutes per session). The placebo group will receive this protocol using a sham TMS coil delivering inactive rTMS. Participants in the sham/placebo group will be offered a full open-label extension treatment course of active rTMS on completion of the randomized phase.

Primary Outcome Measures

Name	Time	Method
Completion Rate	From enrollment to the end of treatment after 5 weeks	The percentage/fraction of participants who complete the full course of study treatment

Secondary Outcome Measures

Name	Time	Method
Adverse Events	From enrollment until the end of treatment at 5 weeks	The incidence of adverse events/side effects during the course of study treatment. Known common side effects of rTMS for other indications include discomfort/pain at the site of stimulation and mild transient headaches. Known rare though serious side effects include seizure (generally 1 in 30,000)
Gray Matter Volume	From pre-treatment baseline structural MRI to post-treatment structural MRI	There are indications rTMS may preserve gray matter volume in neurodegenerative disease near the site of stimulation and connected areas. Volume of the precuneus, stimulated areas, and connected areas will be studied before and after treatment.
EEG	From pre-treatment EEG to post-treatment EEG after 5 weeks	Beta and Gamma Oscillatory power, as well as Beta/Theta periodic power ratios will be examined.
NIH Cognitive Toolbox	Enrollment to end of 5 weeks of treatment	The NIH Cognitive Toolbox consists of a battery of tests well-validated for memory testing. Participants will undergo testing with this tool before and after completing treatment.
resting-state functional MRI connectivity	from enrollment to the end of treatment at 5 weeks	Participants will undergo resting-state functional blood-oxygen-level dependent (BOLD) MRI (rs-fMRI) to examine functional connectivity between the precuneus and other areas of the brain, particularly within the default mode network
Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS Update)	From pre-treatment to post-induction pre-maintenance to end-of-treatment after 5 weeks.	The RBANS Update is a well-established neuropsychological test for memory. Participants will undergo testing with the RBANS before treatment, between induction and maintenance treatment, and after completing treatment. Scores range from 40 to 160, with higher scores indicating better performance and lower scores indicating worse performance.
Clinical Dementia Rating Scale (CDR)	From enrollment to the end of treatment at 5 weeks	CDR score and CDR-SB (sum of boxes score) are gathered from the CDR, an interview-based measure of global dementia severity. Participants and caregivers engage in interview. Global scores range from 0 to 3 with higher scores indicating greater severity of dementia. Sum of boxes scores range from 0 to 18 with higher scores indicating greater severity of dementia.

Trial Locations

Locations (1)

UCLA TMS Clinical and Research Service; 🇺🇸 Los Angeles, California, United States