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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
100
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.
Xijing Hospital of Air Force Military Medical University
Xi'an, Shaanxi, China
RECRUITINGTangdu Hospital of Air Force Military Medical University
Xi'an, Shannxi, China
RECRUITINGThe First Affiliated Hospital of Xi'an Medical University
Xi'an, Shannxi, China
RECRUITINGThe Third Hospital of Xi'an
Xi'an, Shannxi, China
RECRUITINGThe changes in CDR-SB（Clinical Dementia Rating-Sum of Boxes）
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
Time frame: baseline, 12 weeks after start of the treatment
The changes in MMSE（Mini Mental State Examination）
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.
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）
ADCS-ADL total score is 54 points, the higher the score，the lighter the symptoms.
Time frame: baseline, 12 weeks, 24 weeks and 36 weeks after start of the treatment
The changes in NPI（Neuropsychiatric Inventory）
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.
Time frame: baseline, 12 weeks, 24 weeks and 36 weeks after treatment
The changes in MRI（Magnetic Resonance Imaging）
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.
Time frame: baseline and 12 weeks after treatment
The changes in CDR-SB（Clinical Dementia Rating-Sum of Boxes）
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
Time frame: 24 weeks and 36 weeks after start of the treatment
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