New Findings on Transcranial Magnetic Stimulation for Alzheimer’s

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Current approaches to treatment include cholinesterase inhibitors such as donepezil and the NMDA receptor antagonist memantine, exercise, blood pressure regulation, and psychosocial interventions. Several research teams currently are exploring the development of antibodies that attack beta-amyloid or influence the level of tau. These two brain chemicals are involved in AD pathophysiology.

A very different approach to treating AD is described in a provocative paper by Giacomo Koch and colleagues in the journal Brain. They examined the effect of repetitive transcranial magnetic stimulation (rTMS) targeting a specific brain area, the precuneus, on the progression of AD symptoms. Repetitive TMS can be helpful in treating depression; the current study suggests that rTMS also may be effective in delaying cognitive and functional deterioration in individuals with very mild dementia.

The study was a 24-week randomized, double-blind, sham-controlled study conducted in Italy. Patients were eligible for the study if they had an established diagnosis of Alzheimer’s disease, scored in a predetermined range on several common dementia rating scales, and had evidence of Alzheimer pathology in their cerebrospinal fluid (CSF). All had been taking cholinesterase inhibitor medications for at least 6 months, and they maintained this treatment during the rTMS protocol. Patients were excluded if they had a history of stroke or seizures, other neurodegenerative disorder, psychotic disorder, or other contraindication for use of TMS.

Half the patients (25) received a course of rTMS, and half received sham rTMS, meaning that an identical protocol was followed except that current was not passed through the TMS coil. The investigators stimulated an area of the skull that is nearest to a specific brain region called the precuneus. This region is an essential part of a functional brain system known as the default mode network. The precuneus is known to be involved in the earliest pathological changes associated with AD. Three individuals in the rTMS group and two individuals in the sham treatment group discontinued the treatment. Both treatment arms were well tolerated with a few patients experiencing mild side effects that rapidly resolved.

The rTMS protocol used in this study was based on earlier work. Participants received 20-minute treatments 5 days a week for the first two weeks followed by weekly treatments for the remaining 22 weeks. The primary outcome measure was the change in the Clinical Dementia Rating Scale (CDR)-Sum of Boxes score from baseline (week 0) to week 24. The six areas evaluated by this scale are memory; orientation; judgment and problem-solving; community activities; home and hobbies; and personal care. In addition, cognitive changes were measured by a commonly used test known as the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) as well as the Mini-Mental Status Examination (MMSE). Everyday activities were measured by a common battery of questions known as the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale. Evaluators were unaware of patients’ treatment group assignments.

The results of the study were encouraging. The CDR-Sum of Boxes score remained stable in the rTMS group while dropping a mean of 1.4 points in those receiving sham TMS. This is a clinically relevant difference. Similarly, the two other cognitive test scores (ADAS-Cog and MMSE) remained stable in the rTMS group while dropping significantly in the sham treatment group. The effect of rTMS on Activities of Daily Living (ADL) scores also was impressive. ADL scores were stable or slightly improved in the rTMS group, but dropped significantly (over 7 points) in the sham rTMS group.

This is an important, albeit early, study in a small sample of patients over a relatively short period (24 weeks). These results need to be replicated by other investigators in larger, multi-site, randomized, double-blind, placebo-controlled studies. Issues regarding dosing frequency of rTMS, stimulus parameters, and length of treatment also need to be addressed. Would symptoms remain stable beyond 24 weeks without further treatment? Would continued treatments be helpful? If so, for how long?

If these results can be replicated and extended in large, well-designed trials, approaches involving rTMS may represent an important advance in treating symptoms of Alzheimer’s disease. If successful, issues concerning the availability and scalability of the TMS approach will need to be addressed. Time and further studies will tell.

Eugene Rubin, MD, Ph.D. and Charles Zorumski, MD co-wrote this post.