By Marc Dubin, MD
Department of Psychiatry, Weill Cornell Medicine
Transcranial magnetic stimulation, targeted at the precuneus in an effort to maintain a normal default mode network, shows some promise in slowing cognitive decline and maintaining normal electrophysiology in patients with mild to moderate Alzheimer’s disease.
Koch G, Casula EP, Bonni S, et al. Precuneus magnetic stimulation for Alzheimer’s disease: A randomized sham-controlled trial. Brain 2022:145;3776-3786.
Alzheimer’s disease is a significant cause of late-life morbidity and mortality currently treatable with only four acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. These medications offer modest benefits, and there is dire need for additional, well-tolerated treatment options targeting both cognitive symptoms and functional disability.
To this end, there has been significant interest in noninvasive brain stimulation. Although repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) has been successful in the treatment of depression, it has been a disappointment in early trials for cognitive symptoms of Alzheimer’s disease. This may be the result of a poor choice of stimulation target. Early pathology in Alzheimer’s disease affects posterior cortical networks, including medial and lateral posterior cortices and retrosplenial cortex, comprising the default mode network (DMN), whose central hub is the precuneus. Precuneus activation correlates with episodic memory retrieval and precuneus disconnection on functional magnetic resonance imaging (fMRI), and atrophy of the precuneus has correlated with Alzheimer’s disease onset and progression.
Using this network rationale, the current study by Koch et al targeted the precuneus with rTMS with the goal of preserving DMN function and, in turn, cognitive and functional status in Alzheimer’s disease patients. The trial was Phase II, double-blinded, and sham-controlled, consisting of a two-week acute treatment period followed by a 22-week maintenance treatment period and included cognitive and functional status endpoints as well as neurophysiological biomarkers. It is an extension of an earlier study of the acute course of treatment published by the same group in 2018.
Patients 50 to 85 years of age with mild to moderate Alzheimer’s disease (Mini-Mental State Examination [MMSE] 18 to 26, cerebrospinal fluid [CSF] containing amyloid and tau markers) were randomized to active or sham rTMS targeting the precuneus, localized by structural MRI. All subjects were taking acetylcholinesterase inhibitors for at least six months prior to, as well as during, the trial. The primary outcome measure was the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), and there were several secondary outcome measures, including the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Evoked potentials triggered by single-pulse TMS were used as a test of cortical excitability prior to the start of, as well as upon completion of, the rTMS or sham treatment course. rTMS treatment was for two weeks, five days/week in the acute phase, followed by one day/week for 22 weeks in the maintenance phase. All treatment sessions consisted of 40 runs of two seconds of 20 Hz rTMS targeting the precuneus, with runs separated by 28 seconds or an equivalent sham.
A total of 45 patients completed the protocol. rTMS was well tolerated. Sixty-eight percent of the subjects in the active rTMS group responded, defined as a ≤ 1 point decline in the CDR-SB score, while only 35% of the sham-treated subjects responded. Equivalent CDR-SB scores were stabilized in the active rTMS group, while those in the sham group declined. ADCS-ADL scores actually improved slightly in the active rTMS group, while those in the sham group declined.
On a neurophysiological level, cortical excitability evoked by a single-pulse TMS test assay was maintained at pre-treatment levels in the active rTMS group but declined in the sham group. Further, the extent of decline of cortical excitability directly correlated with the decline in CDR-SB score. Additionally, gamma (40 Hz) oscillatory activity, known to be disrupted in patients with Alzheimer’s disease as well as in animal models of Alzheimer’s, was enhanced after active rTMS but not after sham.
Koch et al proposed that these clinical and neurophysiological effects may be mediated by enhanced cortical plasticity induced by rTMS. They cited previous findings of increased dopamine DR4 gene expression and brain-derived neurotrophic factor (BDNF) in both the cerebral cortex and the hippocampus. They also suggested that rTMS could inhibit tau and beta-amyloid protein production by interrupting apoptosis.
COMMENTARY
Although this study marks a significant step forward in Alzheimer’s disease research and promises to augment the current treatment armamentarium, there are limitations and areas for additional study: confirmation in a multisite study; extension of the period of maintenance treatment; precise targeting of the precuneus using electric field modeling coupled with neuro-navigation; longitudinal measurement of CSF biomarkers, including tau and beta-amyloid; and combination with cognitive training strategies, which may benefit from enhanced synaptic plasticity.
In summary, Koch et al reported a compelling effect in staving off the cognitive and functional decline of Alzheimer’s disease over a six-month period in a rigorous Phase II clinical trial of rTMS targeting the precuneus. Their clinical outcomes are supported by robust neurophysiological markers of cortical excitability and enhancement of gamma band oscillatory activity. rTMS targeting the precuneus awaits replication in multisite trials, but promises to add to the set of available treatments for mild to moderate Alzheimer’s disease and to open avenues to novel companion treatments by modulating synaptic plasticity.
