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

Not Applicable

Recruiting

• Conditions: Alzheimer Disease; Transcranial Magnetic Stimulation; Cerebellum

• Registration Number: NCT06669182
• Lead Sponsor: Xijing Hospital

Brief Summary

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.

Study Timeline

• Status Verified: 2024-10
• Study First Submitted: 2024-10-31
• Study First Submitted QC: 2024-10-31
• Study First Posted: 2024-11-01
• Study Start: 2025-01-07
• Last Update Submitted: 2025-01-07
• Last Update Posted: 2025-01-09
• Primary Completion: 2026-03-10
• Study Completion: 2026-04-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

1. Age: 50-85 years old
2. 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)
3. MMSE score ranges from 18-26 points; CDR score 0.5-1 points
4. 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
5. At least one adult caregiver
6. The patient or legal guardian voluntarily signs the informed consent form

Exclusion Criteria

1. Neurodegenerative disorders other than AD.

2. Significant intracranial focal or vascular pathology seen on brain MRI scan

3. History of seizure (with the exception of febrile seizures in childhood)

4. 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)

5. GDS score ≥ 8 points in baseline assessment

6. Cerebrovascular disease, severe infection, malignant tumor, or severe dysfunction of organs such as heart, liver, and kidney.

7. Pregnant or lactating women

8. Contraindications for TMS or MRI, metal or implanted devices in the body (such as pacemakers, deep brain stimulators).

9. Participate in AD related clinical trials within 6 months prior to research registration

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
The changes in CDR-SB（Clinical Dementia Rating-Sum of Boxes）	baseline, 12 weeks after start of the treatment	The changes in CDR-SB will constitute the major research outcome measure used to assess response to rTMS.There are two scoring methods for the CDR scale, namely Total Score Calculation (CDR-GS) and Sum of Six Content Calculation (CDR-SB). The scoring method used in this study is CDR-SB, with a total score of 18 points. The lower the score, the milder the symptoms

Secondary Outcome Measures

Name	Time	Method
The changes in MMSE（Mini Mental State Examination）	baseline, 12 weeks and 20 weeks after start of the treatment	The changes in MMSE will constitute the secondary research outcome.The full name of MMSE is mini-mental state examination. The higher the score, the better. In this study, changes in MMSE scores before and after treatment were used as secondary observations.
The changes in ADCS-ADL（Alzheimer's Disease Cooperative Study - Activities of Daily Living）	baseline, 12 weeks and 20 weeks after start of the treatment	ADCS-ADL total score is 54 points, the higher the score，the lighter the symptoms.
The changes in NPI（Neuropsychiatric Inventory）	baseline, 12 weeks and 20 weeks after treatment	The changes in NPI will constitute the secondary research outcome. The Neuropsychology Scale (NPI) evaluates 12 neuropsychiatric disorders which included 10 neuropsychiatric symptoms and 2 autonomic neurological symptoms based on the caregiver's perception of the patient's behavior and the perceived distress. The lower the score, the lighter the symptoms.
The changes in MRI（Magnetic Resonance Imaging）	baseline, 12 weeks and 20 weeks after treatment	This study mainly applied resting blood oxygen level dependent functional magnetic resonance imaging (BOLD), arterial spin labeling (ASL), and magnetic resonance diffusion tensor imaging (DTI) techniques to evaluate the changes in functional connectivity of the cerebellar dentate nucleus in healthy subjects and patients before and after 12 weeks of TMS treatment, as well as the changes in the cerebellar cortical white matter fiber bundles two month after treatment.

Trial Locations

Locations (1)

Xijing Hospital of Air Force Military Medical University; 🇨🇳 Xian, Shaanxi, China