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

NCT06597942 | Recruiting Phase 1 FDA Device

• 1 other identifier: 24-000811
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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

Conditions

Mild Alzheimer&Amp;Amp;#39;s Disease; Alzheimer&Amp;Amp;#39;s Disease; Alzheimer Disease; Dementia Alzheimer Type; Moderate Alzheimer&Amp;Amp;#39;s Disease; Alzheimer&Amp;#39;s Disease (AD); Alzheimer&Amp;#39;s Dementia

Keywords

Clinical Trial; deep repetitive transcranial magnetic stimulation (deep rTMS); precuneus; Mild-to-Moderate Probable Alzheimer's Dementia

Outcome Measures

Primary Outcomes (1)

• Completion Rate

  The percentage/fraction of participants who complete the full course of study treatment

  From enrollment to the end of treatment after 5 weeks

Secondary Outcomes (7)

• Adverse Events

  From enrollment until the end of treatment at 5 weeks

• Gray Matter Volume

  From pre-treatment baseline structural MRI to post-treatment structural MRI

• EEG

  From pre-treatment EEG to post-treatment EEG after 5 weeks

• NIH Cognitive Toolbox

  Enrollment to end of 5 weeks of treatment

• resting-state functional MRI connectivity

  from enrollment to the end of treatment at 5 weeks

Other Outcomes (8)

• Zarit Burden Index

  From enrollment to end of treatment at 5 weeks

• Neuropsychiatric Inventory (NPI)

  From enrollment to the end of treatment at 5 weeks

• ADL/IADL

  From enrollment to the end of treatment at 5 weeks

Study Arms (3)

Open-Label Active deep rTMS

EXPERIMENTAL

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).

Device: TMS

Randomized Active deep precuneus rTMS

EXPERIMENTAL

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.

Device: TMS

Randomized Sham deep precuneus rTMS

SHAM COMPARATOR

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.

Device: TMS; Device: Transcranial Magnetic Stimulation Sham

Interventions

TMS DEVICE

rTMS Stimulation Parameters Pulse count: 1600 pulses Frequency: 20Hz Pules per train: 40 pulses Inter-train interval: 28 seconds Intensity: 100% Motor Threshold (depth-corrected from MRI) Target: Precuneus using structural MRI navigation with MNI coordinates

Also known as: precuneus deep repetitive transcranial magnetic stimulation

Open-Label Active deep rTMS; Randomized Active deep precuneus rTMS; Randomized Sham deep precuneus rTMS

Transcranial Magnetic Stimulation Sham DEVICE

Sham coil placed in same location and set with same parameters as active treatment coil. However, this device will not output active treatment and scalp electrodes will mimic the sensation of rTMS for the participant.

Randomized Sham deep precuneus rTMS

Eligibility Criteria

• Age: 60 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

UCLA TMS Clinical and Research Service

Los Angeles, California, 90095, United States

RECRUITING

Related Publications (1)

• Leuchter MK, Oughli HA, Durbin KA, Jackson NJ, Elashoff D, Chang TS, Corlier J, Ngo D, Matthews C, Wong D, Fogel BL, Bitan G, Leuchter AF, Vossel K, Suthana N. Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimer's disease: A rationale and study design. Alzheimers Dement (N Y). 2025 Mar 10;11(1):e70043. doi: 10.1002/trc2.70043. eCollection 2025 Jan-Mar.

  PMID: 40065917 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Michael Leuchter, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cole Mathews

CONTACT

(310) 825-7797; TMSResearch@mednet.ucla.edu

Michael Leuchter, MD

CONTACT

(310) 794-2312; TMSResearch@mednet.ucla.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Fellow Physician

Model Details: The first stage will involve 5-10 participants receiving open-label active treatment to refine the protocol. After refinement, the second stage will consist of a 1:1 randomized, double-blind, sham controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding.

Study Record Dates

• First Submitted: September 11, 2024
• First Posted: September 19, 2024
• Study Start: October 17, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: Beginning within 12 months of publishing results and ending no sooner than 3 years after publication of results.
• Access Criteria: After completion of the study, de-identified data may be made available to other institutions or secure online databases on reasonable request (such as Clinical Study Data Request, https://www.clinicalstudydatarequest.com). All other data will be handled the same way it is handled during the study.

Locations

US (1)