Deep brain stimulation for the treatment of moderateto-severe Alzheimer’s disease: study protocol for a prospective self-controlled trial

Department of Neurosurgery, the 101st Hospital of PLA, Wuxi, Jiangsu Province, China

INTRODUCTION

Research background

Alzheimer’s disease (AD) is a degenerative disorder of the central nervous system with unclear origins,1which is the cause of most cases of senile dementia. AD is pathologically characterized by fibril deposition in the cerebral cortex and other brain regions. Specifically, the accumulation of extracellular space amyloid-beta and intracellular tau protein with the pathological morphology of senile plaques and neurofibrillary tangles.2-4Patients with AD eventually suffer from dementia.5With the gradual increase in an aging population, AD is causing an increasingly serious social issue that needs to be solved.

Recently, deep brain stimulation has been reported to help patients with AD. Laxton et al.6performed deep brain stimulation of the fornix/hypothalamus in six patients with mild AD.After 6 and 12 months, these patients exhibited improved symptoms. Additionally, Lazono et al.7conducted a phase II clinical trial of deep brain stimulation in 42 patients with AD,and they found that fornix deep brain stimulation appears to

be safe and effective in patients with mild AD. Their findings revealed that deep brain stimulation is safe and effective to improve cognitive function in patients over 65 years of age,as shown inTable 1.

Features and objectives of the study

Mild AD has been well documented in previous studies.However, evidence for the use of deep brain stimulation for patients with moderate-to-severe AD has not yet been reported.This trial is intended to assess the therapeutic efficacy of deep brain stimulation in moderate-to-severe AD during a 24-month follow-up.

METHODS/DESIGN

Study design

This will be a prospective, single-center, self-controlled trial at the 101stHospital of PLA in China. The study population will comprise 20 patients with moderate-to-severe AD. All patients will have a deep brain stimulator surgically implanted into the bilateral fornix. Therapeutic assessments will be performed at 1 day, and 3, 12, and 24 months after surgery. The primary outcome measure will be the percent of patients whose scores on the Mini Mental State Examination Scale (MMSE) have improved within 24 postoperative months. The secondary outcome measures include the percent of patients whose scores on the MMSE have improved at other visits, scores on Montreal Cognitive Assessment-Basic (MoCA-B), Rey-Osterrieth Complex Figure Test (ROCF), the delayed recall of the ROCF,trail making test (TMT), Hamilton Rating Scale for Depression(HAMD), as well as functional magnetic resonance imaging(fMRI) results, functional PET imaging results at each visit point, and the incidence of adverse events.

Recruitment

Potential patients will be told about the trial through a poster at the clinic and through the admitting office of the 101stHospital.Patients or their legal guardians interested in participating will contact the principal investigator directly orviathe attending physicians. Before the commencement of the trial, all patients or their legal guardians will be clearly informed about the trial procedure and objective, as well as the fact that they have the right to withdraw from the study at any time without any consequences regarding subsequent treatment.

Study population

Twenty patients with moderate-to-severe AD will be enrolled from the 101stHospital of PLA in China.

Inclusion criteria

Patients who meet all of the following conditions will be included in this trial:

• A diagnosis of AD as determined by the diagnostic guidelines for AD recommended by the National Institute on Aging-Alzheimer’s Association workgroups8

• An MMSE score9≤ 18

• Aged 55-80 years, irrespective of sex

• Provision of written informed consent from patients or their legal guardians

Exclusion criteria

The following patients will be excluded from the trial:

• Anyone exhibiting cognitive impairment or aggravated symptoms within 3 months after stroke, or those with typical features of vascular dementia such as multiple infarctions or severe hyperintense white matter lesions

• Anyone exhibiting the core features of dementia with Lewy

Strengths and limitations

Strength

• Patients with moderate-to-severe Alzheimer’s disease will be followed up for 24 months, which will sufficiently describe the long-term outcomes of deep brain stimulation.

Limitations

• A lack of control group;

• Small sample size.bodies, such as fluctuating cognitive impairment, vivid visual hallucinations, and spontaneous parkinsonism

• Anyone exhibiting prominent features of temporal lobe dementia, such as behavioral variants and marked atrophy of the frontal lobe and/or frontal temporal lobe

• Anyone with hormones or metabolic abnormalities, hypothyroidism, or folic acid/vitamin B12 deficiency

• Anyone with latah or other mental/emotional disorders,such as schizophrenia and depression

• Anyone experiencing organ failure or in critical condition

• Anyone involved in other clinical trials

Withdrawal criteria

Patients will be withdrawn from the trial in the following situations:

• Incomplete data that insufficient for the efficacy assessment

• Complications affecting efficacy and safety adjustment, or onset of diseases affecting the outcome

• Combined use of another therapy or drugs affecting efficacy adjustment

Interventions

Each participant will be required to fast the night before surgery and undergo a preoperative MRI scan of the brain. Under local anesthesia with 2% lidocaine, a head stereotaxic frame will be mounted and cranial CT scans will be performed to calculate target parameters. Each patient will be under general anesthesia in a supine position while surgeons implant the electrodes. The target location will be positioned in the front of the fornical column, as determined by microelectroderecording (Figure 1).

Table 1: Clinical trials on deep brain stimulation for Alzheimer’s disease (AD)

Figure 1: Schematic diagram of deep brain stimulation.

Outcome measures

Primary outcome measure

The primary outcome measure is the percent of patients whose scores on the MMSE have improved (MMSE score ＞ 18) at 24 months after surgery. The MMSE scale is a 30-point questionnaire with 20 questions that has been extensively used to measure cognitive impairment. Lower scores indicate more severe cognitive impairment,10and all participants will initially have scores below 18 (see inclusion criterion #2 above).

Secondary outcome measures

• MMSE score on 1 day and at 3 and 12 months after surgery.

• The MoCA-B is a 30-point test for rapidly screening cognitive impairments that comprises 11 items in 8 cognitive domains, including attention, executive function, memory,language, visuospatial skills, abstraction, calculation, and orientation. Lower scores indicate poorer cognitive function.11MoCA-B score will be determined on 1 day and at 3, 12, and 24 months after surgery.11

• ROCF scores will be determined on 1 day and at 3, 12,and 24 months after surgery. The ROCF will be broken down into 18 components, and 0-2 points will be awarded for each component. Total scores range from 0-36, with higher scores indicating better visuospatial ability.12Copy and recall ability will be scored in the same way.

• Scores on the delayed recall of the ROCF will be determined on 1 day and at 3, 12, and 24 months after surgery. The time interval for delayed recall will be set to 20-25 minutes, and during this period, each patient will be required to complete a series of tests such as speech fluency and abstract reasoning, but none will involve visuospatial copy or memory.Higher scores indicate better non-verbal memory ability.13

• TMT scores will be determined on 1 day and at 3, 12, and 24 months after surgery. The TMT is a frequently used neuropsychological test of visual attention and executive function that has high reliability and validity. It consists of two parts: in part A, the patient will be required to connect a set of 25 numbers in sequential order; in part B, the 25 numbers will be enclosed in 13 circles (from 1 to 13) and 12 squares (from 1 to 12), and the patient will be required to draw a line alternating between circles and squares while connecting the numbers in sequential order. The time taken to complete each part of the task will be recorded,with higher durations indicating poorer attention/executive function.14

• HAMD scores will be determined on 1 day and at 3, 12,and 24 months after surgery. The HAMD is the most commonly used scale for clinical assessment of depression. It has 24 domains, with higher scores indicating more severe depression.15

• fMRI examinations will be performed on 1 day and at 3,12, and 24 months after surgery. 3T MRI scanners (GE,Boston, MA, USA) will be used for fMRI detection. Patients will be asked to keep quiet and lie flat on their backs, and then T1, T2, DTI, and resting state functional sequences will be collected.

• Functional PET detection will be performed on 1 day and at 3, 12, and 24 months after surgery. Functional PET machines (GE, Boston, MA, USA) will be used for detecting brain metabolism. During the detection, patients will keep quiet 60 minutes before scanning.

• Adverse events seldom occur during deep brain stimulation.If limb numbness or uncoordinated movement occurs, they can be gradually adapted to or disappear after parameter adjustment. Researchers will judge and deal with adverse events based on symptoms, signs, and/or other clinical data. All adverse events and corresponding treatments will be recorded in the patient’s case report form. To protect the patient’s rights and interests, proper judgments and measures will be taken if a severe adverse event occurs.The ethics committee has the right to immediately terminate the clinical trial if necessary. When the clinical trial is discontinued, the patients, sponsors, and ethics committee will be informed of the causes and will be given explanations. At the same time, detailed description of the causes and explanations will be truthfully reported to the Jiangsu Food and Drug Administration and the State Food and Drug Administration of China.

Trial procedure

Flow chart of this trial is shown inFigure 2, and timing of outcome assessment is shown inTable 2.

Sample size

In accordance with previous findings,16we hypothesized that the improvement rate of the MMSE score at 24 months after surgery would be 90%. Assumingβ= 0.1, power = 90%, and two-sidedα= 0.05, a final sample size ofn= 158 cases was calculated using the PASS 11.0 software (PASS, Kaysville, UT,USA). Considering a loss rate of 20%, at least 190 patients should be included. However, only 20 cases will be included in the phase I trial because of time and financial restrictions.

Statistical analysis

Statistical analyses will be performed using SPSS 23.0 (IBM,Armonk, NY, USA) according to the intention-to-treat principle. Categorical variables will be expressed as percentages,and compared using chi-square tests at each visit point. Continuous variables will be expressed as the mean ± SD or a rate,and analyzed using pairedt-test or Wilcoxon rank sum test. A value ofP＜ 0.05 will be considered statistically significant.

Data collection and management

Figure 2: Trial flow chart.

Table 2: Time of outcome measurements

Collected data will be recorded in the CRF by clinical researchers, and input into a self-developed electronic data acquisition system by the 101stHospital of PLA. Data that cannot be input immediately will be collected in a paper form. Any data related to patient privacy, such as clinical trial observation forms and informed consent forms, must be stored alone as confidential files. Only researchers, sponsors, inspectors, ethics committees, and drug regulatory agencies have the right to inspect all research records if necessary. Every effort will be made to protect the privacy of patients’ medical data, to the extent permitted by law. All data will be encrypted and preserved for at least 5 years after the termination of clinical trials.

Audits

During the trial, regular audits by inspectors responsible for quality control will be performed to ensure that the trial is conducted in strict accordance with the study protocol, as well as that the information is recorded correctly. All physicians involved in clinical trials will have extensive clinical experience in ophthalmic treatment, and all evaluators will receive professional training and have rich experience in clinical evaluation. During the trial, inspectors responsible for quality control, assigned by the principal investigator, will audit the trial records for the correctness and completeness of the CRF data. Clinical researchers will be responsible for the accurate,full, and timely completion of case report forms. Data analyses will be completed by statisticians. Patients included in this trial will receive a transportation allowance and have their appointment and follow-up examination fees waived during the follow-up period. The researchers will provide insurance coverage for all subjects, cover the costs of treatment, and provide financial compensation for subjects suffering damage or death associated with the trial.

Ethics and dissemination

This study was approved by the Institution Review Board of the 101stHospital of PLA of China (approval No. L2017002;Additional file 1). This trial will follow the relevant laws and regulations of theDeclaration of Helsinki, formulated by the World Medical Association. All participants or their legal guardians will be informed of the trial protocol and procedure,and written informed consent will be provided with premise of fully understanding the treatment plan. The whole process will be supervised by the Institution Review Board of the 101stHospital of PLA. This manuscript was prepared and modified according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 2). The results of the trial will be disseminated by publication in a peer-reviewed journal or through presentation in a scientific conference, and anonymized trial data will be published at www.figshare.com.

DISCUSSION

Past findings and existing problems

Application of deep brain stimulation for AD has been gradually increasing in clinical trials because adverse events are relatively mild. Previous studies have shown that deep brain stimulation is safe and effective for improving the clinical symptoms of patients with mild AD.6,7

Study novelty

Previous studies have only demonstrated the efficacy of deep brain stimulation in patients with mild AD, and studies on patients with moderate-to-severe AD are lacking. This study intends to include a 24-month follow-up visit, which will allow a full description of the long-term effects of deep brain stimulation in patients with moderate-to-severe AD.

Study limitations

The trial will be a self-controlled study with a small sample size. Therefore, subsequent investigations on large-scale samples will be warranted.

Study significance

This trial will provide objective and quantitative data for the clinical use of deep brain stimulation in patients with moderateto-severe AD.

TRIAL STATUS

The trial was designed in October 2015, and the study protocol was proved by the Institution Review Board of the 101stHospital of PLA in December 2016. Participant recruitment was started at October 2017, and was expected to be finished within 12 months. Data analysis will be completed until October 2020. Patient recruitment is ongoing at the time of submission.

Additional files

Additional file 1: Ethical approval document.

Additional file 2: SPIRIT checklist.

Author contributions

Study investigator: WL. Implementation of surgery: YHW, LKY, JRD,and TCS. Cognitive assessment: DW, XMX, and SBS. Perioperative patient management: JZ. Perioperative management: LZ.

Conflicts of interest

The authors declare that the research will be conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest.

Financial support

None.

Institutional review board statement

All protocols will be performed in accordance with the ethical principles of theDeclaration of Helsinki. This trial has been approved by the Institution Review Board of the 101stHospital of PLA in China(approval number: L2017002).

Declaration of patient consent

The authors certify that they will obtain all appropriate patient or their legal guardian consent forms. In the form the patients or their legal guardians will give their consent for patients’ images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the 101stHospital of PLA, China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be in particular shared. Study protocol and informed consent form will be available within 6 months after completion of the trial. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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