Precuneus magnetic stimulation for Alzheimer’s disease: a randomized, sham-controlled trial

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer’s disease. Alzheimer’s disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer’s disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer’s disease. Fifty Alzheimer’s disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale–Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale–Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer’s disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer’s disease patients.

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients

“…Along the same lines, we have recently demonstrated that a 2‐week course of 20‐Hz rTMS over the PC improves long‐term memory in patients with AD, providing key preliminary evidence that PC stimulation is a viable strategy to improve cognitive dysfunction in AD 18 . This result has been recently confirmed by the first long‐term 24 weeks, phase II, randomized‐controlled trial in which we reported safety and efficacy of rTMS over the PC in reducing functional and cognitive decline in a sample of 50 patients with AD (NCT03778151) 47 . Hence, the current findings may be important for future studies to consider, as they can better stratify patients with AD and evaluate potential responses to therapy in the context of clinical applications based on neurostimulation.…”

Connectivity between default mode and frontoparietal networks mediates the association between global amyloid‐β and episodic memory

“…This has clear implications for clinical trials that aim to enroll individuals with elevated amyloid, who have the highest likelihood of suffering cognitive decline during the trial. Future research should examine if connectivity of this circuit may facilitate interventions (Koch et al, 2022 ) and provide a biomarker for outcomes in cognitive remediation trials (Rajji et al, 2020 ).…”

Band-specific features of EEG connectome in patients with early-stage Parkinson's disease

“…Finally, EEG-based band-specific connectivity analysis could be more useful than fMRI in identifying innovative targets for transcranial electrical and magnetic neuromodulation or focused ultrasound techniques (Stefani et al, 2022), which are increasingly showing value as symptomatic or also disease-modifying therapies in other neurodegenerative neurological diseases (Koch et al, 2022).…”