Targeted Magnetic Stimulation Slows Alzheimer’s Progression in Phase II Study

A personalized transcranial magnetic stimulation (TMS) protocol, designed to stimulate the precuneus within the default mode network, was well tolerated and significantly slowed clinical decline in patients with mild-to-moderate Alzheimer’s disease, according to data from a small phase II trial presented at the Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting in Madrid.

In this exclusive MedPage Today video, Giacomo Koch, MD, PhD, of the University of Ferrara in Italy, discusses the potential of this investigational approach to improve cognitive and functional outcomes in Alzheimer’s patients.

Following is a transcript of his remarks:

We recently presented at CTAD our latest 52-week trial in which we use personalized, repetitive, transcranial magnetic stimulation to stimulate the precuneus, which is a very important area within the default mode network. The default mode network is one of the first brain networks that is affected, of course, in Alzheimer disease and is important for memory functions. And there is strong evidence showing that a combination of beta-amyloid and tau actually starts in these specific areas of the brain.

So the idea that we developed in the past 10 years or so was to target with noninvasive brain stimulation, repetitive TMS, this network, and specifically the precuneus. And to do so, we developed a novel personalized method that combines neuro-navigation, of course, for precision targeting within the precuneus, and especially a combination of TMS with electroencephalography (EEG) that allows us to have a very clear readout of the stimulation.

So the parameters of stimulation can be adjusted in every patient, and we can have direct evidence that we are engaging the area and the network. So TMS-EEG is very helpful because it provides several [pieces of] information, not only in terms of local activity, but also in terms of oscillation and connectivity. So on the basis of these parameters, we selected in each patient the best spot and the best intensity to engage the brain activity and network activity.

After that, we started the trial, the therapeutic trial, in which the first 2 weeks TMS is applied every day from Monday to Friday, so 10 session in total, we call it a boosting phase. And then we have an intensive phase, and then we have a maintenance phase in which patients are treated every week for the following 50 weeks. So we previously, as mentioned before, investigated the effects of a 6-month trial that were promising. And in this case, we extended the duration of the study up to 1 year, 52 weeks.

And the results are promising. So we have to acknowledge this was a relatively small study in terms of patient enrollment. So we started with 48, but unfortunately we lost some due to the COVID pandemic. And at the end of the 52 weeks, we were able to analyze 32 patients.

But despite this relatively low number, we were happy to see statistical significance in terms of the primary endpoint, the CDR [Clinical Dementia Rating Scale]-Sum of Boxes, that show slowing in progression of the clinical scores there. And this was supported especially by secondary outcomes, and the autonomy of daily living was nearly unchanged after 1 year of therapy. And this is very important for quality of life, patients’ autonomy, and caregivers’ burden.

And also we found the significant effects in terms of ADAS-Cog [Alzheimer’s Disease Assessment Scale-Cognitive Subscale], which is a scale that’s important for assessing memory and cognitive function. And finally, this is also promising, we found an effect on behavioral disturbances as measured by the NPI, Neuropsychiatric Inventory.

So these clinical findings were also supported by neurophysiological evidence that patients that were treated with repetitive TMS and not placebo showed an increase in connectivity within the default mode network. And also we found that there was a correlation among this increase of connectivity and clinical gain as measured by the CDR-Sum of Boxes.