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?

This trial explores whether a brain stimulation technique called deep repetitive transcranial magnetic stimulation (rTMS) can improve memory in individuals with probable Alzheimer's Dementia. Researchers aim to determine if this treatment is easy to use, well-tolerated, and shows potential for boosting brain function. Participants will receive either active rTMS or a placebo (inactive) version, with an option for real treatment later if they begin in the placebo group. This trial suits individuals with mild-to-moderate Alzheimer's Dementia who are already taking or have tried memory-enhancing medication. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking Alzheimer's research.

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.

What prior data suggests that deep rTMS of the precuneus is safe for Alzheimer's patients?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) is generally safe for people with Alzheimer's disease. In various studies, participants have tolerated this treatment well, experiencing few serious side effects. Some mild side effects, such as headaches or scalp discomfort, have occurred but typically do not last long.

Trials targeting a specific area of the brain called the precuneus have demonstrated promising immediate and long-term effects of rTMS. This suggests it might be a helpful approach for Alzheimer's, offering potential benefits while maintaining safety. However, the current trial is in the early stages, so while initial findings are positive, further research is needed to confirm these results. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for Alzheimer's?

Researchers are excited about using deep repetitive transcranial magnetic stimulation (rTMS) for Alzheimer's disease because it offers a novel way to target brain activity. Unlike current treatments that primarily use medications to manage symptoms, rTMS directly stimulates the brain's precuneus region, which is involved in memory and attention. This method uses MRI-guided neuronavigation to deliver precise magnetic pulses, potentially leading to more targeted and effective treatment outcomes. Additionally, the use of a sham comparator group allows researchers to rigorously assess the true effectiveness of this intervention. This approach could pave the way for a more direct and potentially faster-acting therapy for Alzheimer's disease.

What evidence suggests that deep rTMS of the precuneus might be an effective treatment for Alzheimer's?

This trial will evaluate the effects of deep repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus in individuals with Alzheimer's disease. Studies have shown that rTMS can improve memory and thinking skills in people with Alzheimer's. Recent research on the precuneus, a brain region involved in memory, suggests that rTMS targeting this area may have positive effects both in the short and long term. Evidence indicates that rTMS is a safe and potentially effective treatment for Alzheimer's symptoms, with some trials showing improvement in clinical outcomes. These findings offer hope that deep rTMS could be a helpful approach for those with Alzheimer's. Participants in this trial will join either an active deep rTMS group or a sham comparator group to assess the treatment's effectiveness. ^{2 4 5 6 7}

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]

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