A new approach to TMS may slow cognitive decline in Alzheimer’s disease

A new approach to repetitive transcranial magnetic stimulation (rTMS) that targets the precuneus appears to slow the progression of cognitive and functional decline in patients with Alzheimer’s disease (AD), according to new research.

Results from a 6-month phase 2 double-blind randomized trial show that patients with Alzheimer’s disease who received rTMS during the 24-week trial maintained stable scores on the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), while the scores of those who received sham treatment declined over the 24 weeks.


Dr Emiliano Santarnecchi

“Our electromagnetic therapeutic approach is unique in that it primarily intervenes in the electrical rather than chemical side of the brain to treat AD,” said researcher Emiliano Santarnecchi, PhD. Medscape Medical News..

“This allows for a non-invasive, safe and precision-based therapeutic approach, and it has the ability to adapt to each patient through an innovative approach,” he added.

Santarnecchi is director of the precision neuroscience and neuromodulation program at Massachusetts General Hospital in Boston, Massachusetts, and co-founder of Sinaptica Therapeutics, which is currently developing an AD treatment system called the SinaptiStim-AD System in which TMS is used to treat patients with UN D.

The study was published online October 25 in Brain.

Preserved cognition

Several small randomized controlled trials have compared rTMS to a dummy treatment for patients with AD. In 2018, a meta-analysis of these studies found that rTMS significantly improved cognition in people with AD, but showed no difference between the two groups in terms of functional performance.

The current Phase 2 trial, with lead investigator Giacomo Koch, MD, PhD, enrolled 50 patients with AD from the Santa Lucia Foundation Hospital in Rome, Italy, between February 2018 and April 2020. Koch is also co-founder of SinaptiStim and director of the non-invasive brain stimulation laboratory of the Santa Lucia Foundation in Rome.

Patients were eligible for the study if they had an established diagnosis of mild to moderate AD, met specific score criteria on the Clinical Dementia Rating Scale and Mini-Mental State Examination, and had evidence of CSF biomarkers for amyloid disease and tau for Alzheimer’s disease.

Participants were randomly assigned to receive either rTMS or simulation on the precuneus area of ​​the brain five times per week for 2 weeks, followed by a 22-week maintenance phase during which TMS was applied once a week to all patients.

Investigators administered rTMS (or simulation) as an adjunct to standard treatment with acetylcholinesterase inhibitors and measured brain cortical activity with EEG at each treatment.

Investigators who were blinded to the study group assessed patients with several cognitive and functional scales at baseline, 12 weeks, and 24 weeks.

At 24 weeks, those who received the rTMS maintained a stable score on the CDR-SB, a global measure used to assess cognition and to stage the severity of dementia, while those who received the sham TMS experienced a drop in scores.

“TMS treatment slowed cognitive decline by 82% during the trial compared to those who received the sham treatment. This represented a treatment difference in CDR-SB of 1.3 points (P = 0.009), which is considered clinically significant,” the researchers note.

Those who received TMS also had better functional outcomes compared to those who received sham treatment. On the ADCS-ADL (Alzheimer’s Disease Cooperative Study–Activities of Daily Living) scale, those treated with TMS showed improved cognitive function compared to those who received sham treatment, with an estimated mean change in scores ADCS-ADL of -0.7 for the treatment group and 7.5 for the sham group, demonstrating a difference of 108% between the treatment and sham groups at 6 months.

Patients who received the TMS also performed better on the Alzheimer’s Disease Rating Scale – Cognitive Subscale (ADAS-Cog) trial and the mini-exam. mental status (MMSE), demonstrating a slowing of functional decline, with an estimated mean change in ADAS-Cog score of -0.67 for the treatment group and -4.2 for the sham group. The estimated mean change in MMSE score was 0.30 for the treatment group and 1.8 for the sham group.

Eight patients reported mild adverse events, such as mild headache, scalp discomfort, and neck pain/stiffness. Most of these effects disappeared on the day of surgery.

The fact that the treatment group had minimal declines on several measures of cognition and was clinically stable during the study and improved, rather than decreased, on the primary outcome measure of functional ability (ADCS-ADL) is an impressive feat for any therapeutic in a randomized, double-blind, placebo-controlled study in AD, Santarnecchi said.

The researchers target the precuneus as the main node of the default mode network, which has been shown to be impaired in AD patients in the early stages and even in the preclinical phases of AD.

“We are impacting synaptic plasticity at the micro level and network connectivity at the macro level,” Santarnecchi said. “These electromagnetic pulses are able to fire neurons where we are targeting, inducing plasticity in that region of the brain. Essentially, you can think of this as rewiring and reconnecting around the growing damage caused by the [AD] to preserve both cognitive and functional abilities,” he noted.

The researchers hope that, pending replication of the results in a larger sample, the new app will be approved by the US Food and Drug Administration (FDA) for use in patients with Alzheimer’s disease.

No direct link to results

Commenting on the findings of Medscape Medical NewsAlvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and medical director of the Deanna and Sidney Wolk Center for Memory Health at Hebrew SeniorLife, said while he believes the study presents a number of strengths, including the recruitment of well-characterized patients with tau biomarkers for AD, and while articulating a clear and compelling hypothesis, the researchers did not link the change in gamma activity or mode network connectivity. by default directly to the results.



Dr. Alvaro Pascual-Leone

“They recognize modulation activity in the default mode network, but it would be nice to see if the clinical benefit is taken into account by this activity, because that is the hypothesis of the study,” he said. -he declares.

Pascual-Leone was not involved in the study and conducted his own research into rTMS and AD.

He pointed out that the group that received a sham treatment “decreased to a surprising degree” over the 6-month trial, as evidenced by the assessment scores, which seems to explain that the differences between the two groups seem more pronounced.

“The main clinical effect seems to be a lack of progression in the treatment group, but 6 months is a relatively short period, so it would be nice to see how these results hold up over a longer period. -he declares.

The researchers plan to conduct a larger multicenter study of TMS in patients with AD in 2023.

“We have received FDA Breakthrough Device designation after sharing our approach and supporting data and will discuss with the agency the design of a pivotal study that has the potential to replicate and hopefully , even improve those results,” said Santarnecchi.

The study was funded by the Brightfocus Foundation and the Italian Ministry of Health. Santarnecci reports having patents on noninvasive brain stimulation applications in neurodegenerative diseases.

Brain. Published online October 25, 2022. Full text

Eve Bender is a Pittsburgh-based medical journalist who has previously written for Psychiatric News, Neurology Today, and MedPage Today.

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