TMS for Alzheimer's Disease

(PROMIS-AD Trial)

Overseen By Cole Mathews

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, Los Angeles

Must be taking: Cholinesterase inhibitors

Must not be taking: Anticholinergics, Sedating antihistamines

Disqualifiers: Severe dementia, Stroke, Seizure disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 5 weeks

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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

Do I need to stop my current medications to join the trial?

You may need to stop certain medications to join the trial. Specifically, you cannot be taking anticholinergic drugs, sedating antihistamines, or medications with significant anticholinergic or antihistaminic side effects. Benzodiazepines, antiepileptic, and antipsychotic agents will be considered on a case-by-case basis.

Is repetitive transcranial magnetic stimulation (rTMS) safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) has been used safely in both healthy individuals and those with various brain-related conditions since the 1990s. Safety guidelines have been established and updated over the years, with few adverse reactions reported, making it generally considered safe for human use. ^{1 2 3 4 5}

How is the treatment Deep Repetitive Transcranial Magnetic Stimulation (rTMS) for Alzheimer's disease different from other treatments?

Deep Repetitive Transcranial Magnetic Stimulation (rTMS) is unique because it is a non-invasive treatment that targets the precuneus, a key brain area affected in Alzheimer's disease, to potentially slow down cognitive decline. Unlike traditional medications, it uses magnetic fields to stimulate specific brain regions, offering a novel approach to managing Alzheimer's symptoms. ^{1 3 6 7 8}

What data supports the effectiveness of the treatment Deep Repetitive Transcranial Magnetic Stimulation (rTMS) for Alzheimer's Disease?

Research shows that targeting the precuneus area of the brain with repetitive transcranial magnetic stimulation (rTMS) can help slow down cognitive and functional decline in Alzheimer's patients. In a study, patients receiving this treatment maintained stable cognitive scores, while those receiving a fake treatment showed worsening scores. ^{1 3 6 9 10}

Who Is on the Research Team?

Michael Leuchter, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

This trial is for individuals with mild-to-moderate probable Alzheimer's Dementia. Participants will undergo memory testing, brain scans, and bloodwork. They must be able to visit the clinic for multiple rTMS sessions.

Inclusion Criteria

I agree to join the study and can complete the consent process.

I am between 60 and 100 years old.

Have a caregiver/study partner who can accompany them to all study visits

Exclusion Criteria

Currently pregnant or potentially pregnant

I am unable or unwilling to give consent for treatment.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 16 rTMS sessions over 5 weeks, including an induction phase with 4 sessions per day for 3 days and a maintenance phase with 1 session per week for 4 weeks.

5 weeks

3 visits for induction, 4 weekly visits for maintenance

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neuropsychological testing and caregiver assessments.

4 weeks

Open-label extension

Participants in the placebo group are offered a full course of active rTMS treatment after completing the randomized phase.

What Are the Treatments Tested in This Trial?

Interventions

• Deep Repetitive Transcranial Magnetic Stimulation (rTMS) of the Precuneus

Trial Overview The study tests if deep repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus can improve memory in Alzheimer's patients. It compares active stimulation with placebo while monitoring brain changes through various assessments.

How Is the Trial Designed?

Group I: Randomized Active deep precuneus rTMS Experimental Treatment 1 Intervention

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.

Group II: Open-Label Active deep rTMS Experimental Treatment 1 Intervention

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).

Group III: Randomized Sham deep precuneus rTMS Placebo Group 2 Interventions

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.

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Published Research Related to This Trial

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

In a study involving 19 participants, both a simple rTMS protocol targeting the left dorsolateral prefrontal cortex (lDLPFC) and a complex protocol involving six brain regions showed similar improvements in cognitive function, behavior, and functionality after 3 weeks of treatment.

The benefits of rTMS were maintained for an additional 4 weeks without further treatment, suggesting that targeting the lDLPFC alone may be sufficient for clinical improvement in Alzheimer's disease symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar clinical improvement and maintenance after rTMS at 5 Hz using a simple vs. complex protocol in Alzheimer's disease. Alcalá-Lozano, R., Morelos-Santana, E., Cortés-Sotres, JF., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) showed significant cognitive improvement in Alzheimer's disease patients compared to sham stimulation, as indicated by a reduction in ADAS-cog scores, but did not show improvement in MMSE scores.

rTMS was well tolerated with only a few mild adverse events reported, suggesting it is a safe intervention with potential benefits for cognitive function in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for the treatment of Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. Dong, X., Yan, L., Huang, L., et al.[2019]

In a study involving 42 Japanese patients with Alzheimer's dementia, 4 weeks of repetitive transcranial magnetic stimulation (rTMS) at 120% resting motor threshold showed significant efficacy in improving cognitive function for patients with MMSE scores ≥ 15, with 41.7% of participants experiencing a notable improvement compared to 0% in the Sham group.

The treatment was found to be safe, with no serious adverse events reported, suggesting that rTMS could be a promising intervention for patients with moderate to mild Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan. Saitoh, Y., Hosomi, K., Mano, T., et al.[2023]

This meta-analysis of seven studies involving 94 patients with mild to moderate Alzheimer's disease found that high-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improves cognitive function, with a standardized mean difference of 1.00, indicating a strong effect.

The effectiveness of rTMS was found to be dependent on the stimulation frequency and the targeted brain hemisphere, with significant improvements observed when stimulating the right or bilateral dorsolateral prefrontal cortex, but not the left.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation as an Alternative Therapy for Cognitive Impairment in Alzheimer's Disease: A Meta-Analysis. Liao, X., Li, G., Wang, A., et al.[2015]

In a study involving 12 Alzheimer's disease patients, four sessions of high-frequency repetitive transcranial magnetic stimulation (rTMS) over two weeks led to significant improvements in language skills, which were sustained for at least four weeks after treatment.

Functional MRI results indicated increased brain activation during cognitive tasks following rTMS, supporting the idea that rTMS may enhance cognitive function in Alzheimer's patients, consistent with findings from other studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, short-term, repetitive transcranial magnetic stimulation in patients with Alzheimer's disease with functional imaging correlates and literature review. Devi, G., Voss, HU., Levine, D., et al.[2014]

Repetitive transcranial magnetic stimulation (rTMS) can effectively improve cognitive function and behavioral symptoms in dementia patients, as demonstrated in a case where a patient showed significant improvement after switching from 1 Hz to 10 Hz rTMS.

While rTMS is generally beneficial, it can lead to adverse reactions such as seizures; however, adjusting the treatment parameters (like reducing the frequency) can help mitigate these risks and continue to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The repetitive transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia: a case report. Yang, Z., Zhou, Y.[2023]

A 24-week randomized, double-blind trial with 50 Alzheimer's patients showed that targeting the precuneus with repetitive transcranial magnetic stimulation (rTMS) helped maintain cognitive function, as indicated by stable scores on the Clinical Dementia Rating Scale, while the sham group experienced a decline.

Patients receiving precuneus rTMS also demonstrated significant improvements in secondary cognitive assessments and maintained cortical excitability, suggesting that this non-invasive treatment could slow cognitive decline in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial. Koch, G., Casula, EP., Bonnì, S., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) significantly improved action naming accuracy in 15 patients with Alzheimer's disease during picture-naming tasks.

These results suggest that rTMS could be a promising new treatment approach for language dysfunction in Alzheimer's patients, although the exact mechanisms behind this improvement are still unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Cotelli, M., Manenti, R., Cappa, SF., et al.[2006]

In a pilot study involving 30 Alzheimer's disease patients, focal repetitive transcranial magnetic stimulation (rTMS) using the H2-coil showed a trend toward improved cognitive function, with a mean decrease of -1.01 points on the ADAS-Cog scale after treatment, although this effect was not sustained two months post-treatment.

The study indicates that rTMS with the H2-coil is safe and feasible for Alzheimer's patients, suggesting potential cognitive benefits that warrant further investigation in larger trials, especially when combined with cognitive rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study. Leocani, L., Dalla Costa, G., Coppi, E., et al.[2021]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. [2006]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Open-label, short-term, repetitive transcranial magnetic stimulation in patients with Alzheimer's disease with functional imaging correlates and literature review. [2014]

5. United States pubmed.ncbi.nlm.nih.gov

Similar clinical improvement and maintenance after rTMS at 5 Hz using a simple vs. complex protocol in Alzheimer's disease. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The repetitive transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia: a case report. [2023]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation as an Alternative Therapy for Cognitive Impairment in Alzheimer's Disease: A Meta-Analysis. [2015]

10. United States pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation for the treatment of Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. [2019]