Advantage of Cerebellar Transcranial Magnetic Stimulation in Alzheimer's Diseases （ACT-AD）

Official title

Effects of Cerebellar Transcranial Magnetic Stimulation on Patients With Alzheimer's Disease：A Multicenter Randomized Controlled Trial

Overview

Alzheimer's Disease (AD) is the primary cause of dementia, with its prominent feature being cognitive decline. The cerebellum plays a crucial role in cognitive processing, making it a potential target for therapeutic intervention. This study will be conducted to evaluate the efficacy and safety of cerebellar Intermittent theta-burst stimulation (CRB-iTBS) in participants with mild Alzheimer's disease on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 3 months of treatment in the Core Study. This project aims to provide a valid treatment to improve the cognitive function and quality of life for those with Alzheimer's disease.

Detailed description

Background:

Alzheimer's disease (AD) is a progressive neurodegenerative disease that poses substantial challenges for both families and society. The primary pathological hallmarks of AD are β-amyloid plaque (Aβ) deposition and neurofibrillary tangles. Notably, the cerebellum seems to be resilient to these pathological developments in the initial phases of AD. This early resistance of the cerebellum suggests it might contribute to compensating for the cognitive impairments associated with AD. Enhancing cerebellar reserve is a potential therapeutic approach. Repetitive transcranial magnetic stimulation (rTMS) has been explored as a means to achieve this, attributed to synaptic plasticity in the cerebellar cortex.

Hypothesis:

The cerebellar dentate nucleus (CDN), a crucial node for information transmission between the cerebellum and cerebral cortex, shows abnormal functional connectivity with cortex in AD patients. Preclinical studies demonstrated that stimulating lateral cerebellar nucleus, the rodent homologue of the human CDN, enhanced cognitive rehabilitation and improved cortical plasticity in animals after brain injury, suggesting CDN as a neuromodulation target for cognitive networks. We speculate that intermittent θ-burst stimulation (iTBS) based TMS targeting the cerebellar dentate nucleus may improve cognitive function, brain function, and lymphatic drainage in AD patients.

Specific aims:

In this study, we will conduct a randomized, double-blind, sham-controlled clinical trial focusing on the cerebellum with iTBS to assess its efficacy, safety and potential mechanisms in the treatment of AD patients. The findings yielded by the present project will have a potential strong impact on clinical practice of AD patients. Since rTMS is well tolerated and relatively low-priced, a positive result could lead to a fast application of the present proposal to the clinical experience. If successful, the proposed project will provide support for a novel treatment for cognitive dysfunction in AD patients.

Interventions

• Device Intermittent Theta-Burst Transcranial Magnetic Stimulation
  50Hz, stimulation intensity of 100% RMT, duration of 40s as a group of stimulation, 600 stimulation pulses, repeated stimulation of bilateral cerebellar dentate nuclei, with a 5-minute interval between each group, 1200 stimulation pulses per site, 5 times a week, treatment for 4 weeks, then treat once a week for 8 weeks.

Primary outcome measures

• The changes in CDR-SB（Clinical Dementia Rating-Sum of Boxes） [Time frame: baseline, 12 weeks after start of the treatment]

Secondary outcome measures (5)

• The changes in MMSE（Mini Mental State Examination） [Time frame: baseline, 12 weeks ,24 weeks and 36 weeks after start of the treatment]
• The changes in ADCS-ADL（Alzheimer's Disease Cooperative Study - Activities of Daily Living） [Time frame: baseline, 12 weeks, 24 weeks and 36 weeks after start of the treatment]
• The changes in NPI（Neuropsychiatric Inventory） [Time frame: baseline, 12 weeks, 24 weeks and 36 weeks after treatment]
• The changes in MRI（Magnetic Resonance Imaging） [Time frame: baseline and 12 weeks after treatment]
• The changes in CDR-SB（Clinical Dementia Rating-Sum of Boxes） [Time frame: 24 weeks and 36 weeks after start of the treatment]

Eligibility criteria

Inclusion criteria

• Age: 50-85 years old
• Meet the core clinical criteria of NIA-AA for possible Alzheimer's disease dementia, and PET or cerebrospinal fluid markers show elevated p-tau and decreased A β (1-42)
• MMSE score ranges from 18-26 points; CDR score 0.5-1 points
• The patient has received treatment with acetylcholinesterase inhibitors (AChEI), NMDA receptor antagonists, or mannequine therapy, and the current dosing regimen has remained stable for the 12 weeks prior to baseline assessment
• At least one adult caregiver
• The patient or legal guardian voluntarily signs the informed consent form

Exclusion criteria

• Neurodegenerative disorders other than AD.
• Significant intracranial focal or vascular pathology seen on brain MRI scan
• History of seizure (with the exception of febrile seizures in childhood)
• Any of the following psychotic disorders (DSM IV-TR criteria):

• Major depressive disorder (current)
• Schizophrenia
• Other psychotic disorders, bipolar disorder, or substance related disorders (within the past 5 years)
• GDS score ≥ 8 points in baseline assessment
• Cerebrovascular disease, severe infection, malignant tumor, or severe dysfunction of organs such as heart, liver, and kidney.
• Pregnant or lactating women
• Contraindications for TMS or MRI, metal or implanted devices in the body (such as pacemakers, deep brain stimulators).
• Participate in AD related clinical trials within 6 months prior to research registration

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 4 centers

• Xijing Hospital of Air Force Military Medical University — Xi'an
• Tangdu Hospital of Air Force Military Medical University — Xi'an
• The First Affiliated Hospital of Xi'an Medical University — Xi'an
• The Third Hospital of Xi'an — Xi'an

Publications

• Cooperrider J, Furmaga H, Plow E, Park HJ, Chen Z, Kidd G, Baker KB, Gale JT, Machado AG. Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model. J Neurosci. 2014 Jul 2;34(27):9040-50. doi: 10.1523/JNEUROSCI.0953-14.2014. PMID 24990924
• Pezzetta R, Gambarota F, Tarantino V, Devita M, Cattaneo Z, Arcara G, Mapelli D, Masina F. A meta-analysis of non-invasive brain stimulation (NIBS) effects on cerebellar-associated cognitive processes. Neurosci Biobehav Rev. 2024 Feb;157:105509. doi: 10.1016/j.neubiorev.2023.105509. Epub 2023 Dec 13. PMID 38101590
• Chan HH, Hogue O, Mathews ND, Hunter JG, Kundalia R, Hermann JK, Floden DP, Machado AG, Baker KB. Deep cerebellar stimulation enhances cognitive recovery after prefrontal traumatic brain injury in rodent. Exp Neurol. 2022 Sep;355:114136. doi: 10.1016/j.expneurol.2022.114136. Epub 2022 Jun 3. PMID 35667396
• Olivito G, Serra L, Marra C, Di Domenico C, Caltagirone C, Toniolo S, Cercignani M, Leggio M, Bozzali M. Cerebellar dentate nucleus functional connectivity with cerebral cortex in Alzheimer's disease and memory: a seed-based approach. Neurobiol Aging. 2020 May;89:32-40. doi: 10.1016/j.neurobiolaging.2019.10.026. Epub 2020 Jan 15. PMID 32081466
• Tacyildiz AE, Bilgin B, Gungor A, Ucer M, Karadag A, Tanriover N. Dentate Nucleus: Connectivity-Based Anatomic Parcellation Based on Superior Cerebellar Peduncle Projections. World Neurosurg. 2021 Aug;152:e408-e428. doi: 10.1016/j.wneu.2021.05.102. Epub 2021 May 29. PMID 34062299
• Benarroch E. What Is the Role of the Dentate Nucleus in Normal and Abnormal Cerebellar Function? Neurology. 2024 Aug 13;103(3):e209636. doi: 10.1212/WNL.0000000000209636. Epub 2024 Jul 2. No abstract available. PMID 38954796
• Di Nuzzo C, Ruggiero F, Cortese F, Cova I, Priori A, Ferrucci R. Non-invasive Cerebellar Stimulation in Cerebellar Disorders. CNS Neurol Disord Drug Targets. 2018;17(3):193-198. doi: 10.2174/1871527317666180404113444. PMID 29623859
• van Dun K, Mitoma H, Manto M. Cerebellar Cortex as a Therapeutic Target for Neurostimulation. Cerebellum. 2018 Dec;17(6):777-787. doi: 10.1007/s12311-018-0976-8. PMID 30276522

Identifiers

NCT: NCT06669182 · KY20242285jiangwen

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗