New research supports the therapeutic
potential of repetitive transcranial magnetic stimulation (rTMS) for
Alzheimer’s disease (AD).
In a 52-week phase 2 trial, personalized
rTMS applied over the precuneus, a core component of the default mode
network (DMN), slowed the progression of cognitive and functional
decline in patients with mild to moderate AD.
As reported previously by Medscape Medical News, the 52-week results align with the results seen at 24 weeks.
“These
latest results provide new additional evidence...supporting the
potential for neuromodulation of the DMN to slow the impairment of
cognitive functions, preserve activities of daily living, and reduce
behavioral disturbances in Alzheimer’s patients, with no significant
side effects,” Giacomo Koch, MD, PhD, professor of physiology,
University of Ferrara, Ferrara, Italy, and director of the Brain
Stimulation Laboratory, Santa Lucia Foundation, said in a statement.
The results were presented at the 17th Clinical Trials on Alzheimer’s Disease (CTAD) Conference.
Personalized Neuromodulation
The
DMN is responsible for memory and shows preferential accumulation of
amyloid beta and tau vs other brain regions. The precuneus is the key
hub in the DMN, and patients with AD show alterations of this key
functional area, Koch explained.
The
phase 2 trial enrolled 48 patients (mean age, 72 years; 56% women) with
mild to moderate AD on acetylcholinesterase inhibitor therapy for at
least 6 months.
They received an initial 2-week intensive course
of rTMS or sham rTMS applied over the precuneus five times per week for 2
weeks (10 sessions, 1600 pulses, 20 Hz), followed by a 50-week
maintenance phase, in which the same stimulation was applied once
weekly.
Personalization of the rTMS treatment was established
using single-pulse TMS concurrently in combination with
electroencephalography (TMS-EEG) based on the recording, processing, and
proprietary analysis of transcranial evoked potentials and patient MRI
data.
A total of 32 patients (68%) completed the study.
The
study showed that personalized rTMS of the precuneus had a significant
effect on the primary outcome of change from baseline to week 52 of the
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).
The estimated mean change in CDR-SB after 52 weeks was 1.36 in the rTMS group vs 2.45 in the sham rTMS group (P = .038) — representing a 44% slowing of AD’s progression over 12 months.
There
were also statistically significant effects of rTMS on key secondary
outcome measures of the AD Assessment Scale-Cognitive Subscale (P = .02), AD Cooperative Study-Activities of Daily Living scale (P < .001), Mini Mental State Examination (P = .05), and Neuropsychiatric Inventory (P = .048) scores.
The study also showed an increase in functional connectivity within the DMN in the active rTMS group but not in the sham group.
rTMS
was safe and well tolerated with only a few minor adverse events
reported, including mild headache, skin or scalp discomfort, and neck
pain.
Limitations of the study included the small sample size,
single-center design, and lack of cerebrospinal fluid or blood-based
biomarkers that would provide evidence for the biological effects of
rTMS.
Koch said personalized noninvasive brain stimulation of the DMN “could represent a novel therapeutic approach in AD patients.”
He
noted that “personalization is a key factor,” and his group is working
on algorithms that may “automatize the selection of individual
parameters.”
The technology has received breakthrough device
designation by the US Food and Drug Administration. The researchers plan
to launch a pivotal randomized controlled clinical trial in 2025.
‘Exciting Frontier’
Reached
for comment, Shaheen Lakhan, MD, PhD, neurologist and researcher based
in Miami, noted that the “personalized nature of the rTMS intervention
in this Alzheimer’s study is a particularly exciting aspect.”
“By
using TMS-EEG to optimize the stimulation parameters for each individual
patient, the researchers were able to potentially maximize the benefits
of this noninvasive neuromodulation technique,” said Lakhan, who wasn’t
involved in the research.
“This
approach aligns well with the growing recognition that Alzheimer’s
disease is not a single, monolithic condition, but rather an amalgam of
different, smaller diseases based on genetics, protein signatures,
structural and functional neuroanatomy, behavioral profiles, and other
phenomic factors,” Lakhan told Medscape Medical News.
He
said the field is increasingly understanding that so-called “common”
diseases like AD are highly heterogeneous, with diverse underlying
mechanisms driving the observed clinical presentation.
“This
heterogeneity necessitates a move away from one-size-fits-all treatments
towards more personalized, precision-based interventions. If these
findings continue to demonstrate the promise of personalized,
biomarker-guided neuromodulation, it could pave the way for the
development of digital therapeutics that can achieve similar levels of
individualization,” Lakhan predicted.
“The
ability to precisely modulate brain networks based on each patient’s
unique neurophysiology represents an exciting frontier in the search for
more effective, patient-centered approaches to managing these complex
neurodegenerative disorders,” he added.
Funding for the study
was provided in part by the BrightFocus Foundation, the Italian Ministry
of Health, European Commission, Alzheimer’s Drug Discovery Foundation,
and Sinaptica Therapeutics. Koch is a scientific co-founder and holds
stocks of Sinaptica Therapeutics; received payment or honoraria for
lectures, presentations, speakers bureaus, manuscript writing, or
educational events from Epitech, Roche, and Novo Nordisk; and holds a
patent on the use of rotigotine in combination with cholinesterase
inhibitors in patients with AD and another on systems and methods for
providing personalized targeted noninvasive stimulation to a brain
network. Lakhan had no relevant disclosures.
Peer-Reviewed