Study on the Effect of Transcranial Magnetic Stimulation in Mild to Moderate Alzheimer's Disease

Study Overview
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Brief Summary
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The investigators will compare cognitition, mood (depression), ADL, and brain structural and functional MRI before and after 4-week transcranial magnetic stimulation in patients with mild to moderate Alzheimer's disease. The investigators also compare the change of cognitition, mood (depression), ADL, and brain structural and functional MRI between TMS group and sham coil group.

Detailed Description
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Each 16 patients will be allocated to TMS group and sham coil group. Before TMS/sham coil stimulation, the investigators will take fMRI of each patient, and figure out which focus has strongest connectivity to hippocampus among lateral parietal regions of the brain. The investigators will fix the TSM transduced and apply accurate TMS stimulation to the focus using personalized frames. The investigators will make the frame using 3D printing technology. After 4 week- TMS stimulation, the investigators will compare cognitition, mood (depression), ADL, and brain structural and functional MRI beween baseline and after intervention. The investigators also compare the change of cognitition, mood (depression), ADL, and brain structural and functional MRI between TMS group and sham coil group.

Official Title
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Prospective, Randomized, Evaluator-blind, Single Center Study on the Effect of Transcranial Magnetic Stimulation in Mild to Moderate Alzheimer's Disease

Conditions
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Mild to Moderate Alzheimer Disease

Intervention / Treatment
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* Device: TMS
* Device: sham coil stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients who visited memory clinic of Samsung Medical Center aged 55   90 diagnosed as probable Alzheimer dementia according to NIA-AA guideline 2011, or MCI patiens with amyloid PET positivity below -1SD in SVLTdelayed recall test and RCFT delayed recall test K-MMSE >=18 no epileptic discharge in EEG no history of epilepsy no arrhythmia or MI in ECG can read and write Korean (literate) volunteer and agree to the registration Exclusion Criteria: no other neurologic deficit which can cause dementia except for Alzheimer's disease paitient who has severe cerebral white matter hyperintensities. (deep white matter >=2.5cm and caps or band >=1.0 cm) patients with severe medical disease including caner and ishemic heart disease claustrophobia or allergic to contrast of MRI medical deviced which is not removable (e.g pacemaker, cochlear implantation, dental prosthesis) history of brain surgery, and intervension or surgery of intra/extracranial artery(e.g. carotid artery stent insertion, CEA) patient with dyspnea during resting history of loss of consciousness for more than 1 hour except for general anesthesia patients who cannot read written material because of poor visual acuity patients who cannot communicate because of severe hearing difficulty history of ototoxicity medication or exposure severe noises determined as inapropriate to participate clinical trial

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TMS group<br>Transcranial magnetic stimulation for four weeks | Device: TMS<br>* stimulation intensity : motor threshold 100% stimulation frequency : 1600 pulses for 20 minutes stimulation duration :for four weaks, 20 minutes/day, 5 days per week (Monday - Friday )<br>|
| Sham Comparator: Sham group<br>sham coil stimulation for four weeks (Although the sound of sham coil is the same to that of real TMS during intervension, no stimulation is applied. ) | Device: sham coil stimulation<br>* no stimulation Although the sound from device during stimulation is similar, no stimulation is applied.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the short term change of K-MMSE score in TMS group | the short term change of K-MMSE (Korean version of mini mental status exam) score in TMS group | 4 weeks | 
| the short term change of K-MoCA score in TMS group | the short term change of K-MoCA (Korean version of Montreal cognitive assessment) score in TMS group | 4 weeks | 
| the short term change of ADAS-Cog score in TMS group | the short term change of ADAS-Cog(the Alzheimer's disease assessment scale-cognitive subscale) score in TMS group | 4 weeks | 
| the short term change of COWAT score in TMS group | the short term change of COWAT(controlled oral word association) score in TMS group | 4 weeks | 
| the short term change of Stroop score in TMS group | the short term change of Stroop score in TMS group | 4 weeks | 
| the short term change of TMT score in TMS group | the short term change of TMT(trail-making test) score in TMS group | 4 weeks | 
| the short term change of RVP score in TMS group | the short term change of RVP(raid visual information processing) score in TMS group | 4 weeks | 
| the short term change of SWM score in TMS group | the short term change of SWM (spatial working memory) score in TMS group | 4 weeks | 
| the short term change of PRM score in TMS group | the short term change of PRM(pattern recognition memory) score in TMS group | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the long term change of K-MMSE score in TMS group | the long term change of K-MMSE (Korean version of mini mental status exam) score in TMS group | 8 weeks | 
| the long term change of K-MoCA score in TMS group | the long term change of K-MoCA (Korean version of Montreal cognitive assessment) score in TMS group | 8 weeks | 
| the long term change of ADAS-Cog score in TMS group | the long term change of ADAS-Cog(the Alzheimer's disease assessment scale-cognitive subscale) score in TMS group | 8 weeks | 
| the long term change of COWAT score in TMS group | the long term change of COWAT(controlled oral word association) score in TMS group | 8 weeks | 
| the long term change of Stroop score in TMS group | the long term change of Stroop score in TMS group | 8 weeks | 
| the long term change of TMT score in TMS group | the long term change of TMT(trail-making test) score in TMS group | 8 weeks | 
| the long term change of RVP score in TMS group | the long term change of RVP(raid visual information processing) score in TMS group | 8 weeks | 
| the long term change of SWM score in TMS group | the long term change of SWM (spatial working memory) score in TMS group | 8 weeks | 
| the long term change of PRM score in TMS | the long term change of PRM(pattern recognition memory) score in TMS group | 8 weeks | 
| the change of ADL(activity of daily life) in TMS group | the score change of S-IADL(Seoul-Instrumental activities of daily life) | 4 weeks | 
| the short term change of mood (depression) in TMS group | the score change of GDS(geriatric depression scale) short form | 4 weeks | 
| the long term change of mood (depression) in TMS group | the score change of GDS(geriatric depression scale) short form | 8 weeks | 
| the change of brain function in TMS group | the qualititve change of resting functional MRI | 4 weeks | 
| the change of brain structure in TMS group | the change of FA (fractional anisotropy) value in DTI (diffusion tensor imaging) analysis | 4 weeks | 
| the comparison of short term change of K-MMSE score between TMS group and sham group | the score change of K-MMSE (Korean version of mini mental status exam) | 4 weeks | 
| the comparison of short term change of K-MoCA score between TMS group and sham group | the score change of K-MoCA (Korean version of Montreal cognitive assessment) | 4 weeks | 
| the comparison of short term change of CDR-SOB between TMS group and sham group | the score change of CDR-SOB (Clinical dementia rating-sum of boxes) | 4 weeks | 
| the comparison of short term change of ADAS-Cog between TMS group and sham group | the score change of ADAS-Cog ( the Alzheimer's disease assessment scale-cognitive subscale) | 4 weeks | 
| the comparison of short term change of COWAT score between TMS group and sham group | the score change of COWAT(controlled oral word association) score | 4 weeks | 
| the comparison of short term change of Stroop test score between TMS group and sham group | the score change of Stroop test score | 4 weeks | 
| the comparison of short term change of TMT between TMS group and sham group | the score change of TMT (trail making test) | 4 weeks | 
| the comparison of short term change of RVP score between TMS group and sham group | the score change of RVP(raid visual information processing) score | 4 weeks | 
| the comparison of short term change of SWM between TMS group and sham group | the score change of SWM (spatial working memory) score | 4 weeks | 
| the comparison of short term change of PRM between TMS group and sham group | the score change of PRM(pattern recognition memory) score | 4 weeks | 
| the comparison of change of K-MMSE between TMS group and sham group | the score change of K-MMSE(Korean version of mini mental status exam) | 8 weeks | 
| the comparison of long term change of K-MoCA between TMS group and sham group | the score change of K-MoCA (Korean version of Montreal cognitive assessment) | 8 weeks | 
| the comparison of long term change of CDR-SOB between TMS group and sham group | the score change of CDR-SOB(Clinical dementia rating-sum of boxes) | 8 weeks | 
| the comparison of long term change of ADAS-Cog between TMS group and sham group | the score change of ADAS-Cog ( the Alzheimer's disease assessment scale-cognitive subscale) | 8 weeks | 
| the comparison of long term change of COWAT score between TMS group and sham group | the score change of COWAT(controlled oral word association) score | 8 weeks | 
| the comparison of long term change of stroop test score between TMS group and sham group | the score change of stroop test score | 8 weeks | 
| the comparison of long term change of TMT score between TMS group and sham group | the score change of TMT(trail making test) | 8 weeks | 
| the comparison of long term change of RVP score between TMS group and sham group | the score change of RVP(raid visual information processing) | 8 weeks | 
| the comparison of long term change of SWM score between TMS group and sham group | the score change of SWM (spatial working memory) score | 8 weeks | 
| the comparison of long term change of cognitive function between TMS group and sham group | the score change of PRM(pattern recognition memory) score | 8 weeks | 
| the comparison of short term change of mood (depression) between TMS group and sham group | the score change of GDS (geriatric depression scale) short form | 4 weeks | 
| the comparison of long term change of mood (depression) between TMS group and sham group | the score change of GDS (geriatric depression scale) short form | 8 weeks | 
| the comparison of short term change of ADL between TMS group and sham group | the score change of S-IADL(Seoul instrumental activity of daily life ) | 4 weeks | 
| the comparison of long term change of ADL between TMS group and sham group | the score change of S-IADL(Seoul instrumental activity of daily life ) | 8 weeks | 
| the comparison of change of resting fMRI between TMS group and sham group | the qualititve change of resting fMRI | 4 weeks | 
| the comparison of change of FA value between TMS group and sham group | the change of FA(fractional anisotropy) value in DTI(diffusion tensor imaging) analysis | 4 weeks |