Alzheimer Dementia (AD)
Conditions
Keywords
Alzheimer's Disease, Non-Invasive Brain Stimulation
Brief summary
This study aims to evaluate the efficacy and safety of non-invasive brain-computer interface (BCI) neuromodulation technique combined with 40Hz audio-visual stimulation on cognitive function in patients with Alzheimer's disease (AD). This is a single-center, randomized, double-blind, sham-controlled trial. A total of 90 participants with Aβ-PET positive AD diagnosed according to NIA-AA criteria will be enrolled and randomly assigned to three groups in a 1:1:1 ratio: (1) 40Hz stimulation group (fixed 40Hz audio-visual stimulation, 60 minutes daily for 6 months), (2) individualized stimulation group (closed-loop BCI with real-time EEG feedback to adjust stimulation parameters, 60 minutes daily for 6 months), and (3) sham stimulation group (inactive stimulation, same duration). The primary outcome is the change in MoCA-B score from baseline to 6 months. Secondary outcomes include changes in cognitive domain-specific assessments (AVLT, STT, DST), multimodal brain imaging, EEG parameters, peripheral blood AD biomarkers, safety, tolerability, and comparison of efficacy between open-loop and closed-loop stimulation.
Interventions
DEVICE40Hz Stimulation Group
Participants receive fixed 40Hz combined audio-visual stimulation (visual + auditory) for 60 minutes per day, once daily, for 6 consecutive months. The stimulation parameters are fixed and do not adjust based on EEG feedback.
DEVICEIndividualized Stimulation Group
Participants receive 40Hz combined audio-visual stimulation (visual + auditory) for 60 minutes per day, once daily, for 6 consecutive months. In addition, the device performs EEG acquisition and closed-loop feedback adjustment based on preset algorithms. This allows individualized, closed-loop neuromodulation.
DEVICESham Stimulation Group
Participants receive sham stimulation using a device identical in appearance and weight to the active device. The sham device does not output effective individualized audio-visual stimulation; only low-intensity, randomized flashes and audio cues are delivered.
Sponsors
Ruijin Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Alzheimer's disease according to the NIA-AA 2018 diagnostic criteria. 2. Age between 50 and 80 years, inclusive. 3. Positive Aβ-PET scan result. 4. Has a stable caregiver who can assist with daily stimulation intervention. 5. Chronic medical conditions stable for at least 30 days. 6. Adequate vision and hearing to perform testing (at minimum, ability to perceive light and communicate in daily conversation). 7. Good mobility (able to walk independently or with assistive devices). 8. Willing and able to provide voluntary signed informed consent.
Exclusion criteria
1. History of epilepsy or seizure disorder. 2. Inability to undergo MRI or presence of significant abnormalities on MRI screening. 3. Geriatric Depression Scale (GDS) score \> 6. 4. Current suicidal ideation or suicide attempt within the past 6 months. 5. Other major neurological disorders, including but not limited to: dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, or mixed dementia; other neurodegenerative diseases (Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, etc.); history of severe brain infection (meningitis/encephalitis) or multiple concussions; metabolic/systemic diseases causing cognitive impairment (syphilis, vitamin B12 or folate deficiency, etc.). 6. Psychiatric disorders. 7. Severe cardiac disease, chronic liver/kidney/respiratory disease, or uncontrolled diabetes mellitus or thyroid disease. 8. History of drug or alcohol abuse within the past 12 months. 9. Current exposure to anti-Aβ antibody immunotherapies. 10. Current use of memantine within 30 days prior to intervention. 11. Life expectancy \< 24 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montreal Cognitive Assessment - Basic (MoCA-B) Score | Baseline (pre-treatment) and 6 months (end of treatment) | The primary outcome is the change in MoCA-B score from baseline to 6 months. The MoCA-B is a validated cognitive screening tool for assessing global cognitive function. The score ranges from 0 to 30, with higher scores indicating better cognitive function. The change score (ΔMoCA-B) will be calculated as the 6-month score minus the baseline score. Assessments will be performed by trained neuropsychologists who are blinded to group assignment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Auditory Verbal Learning Test (AVLT) Score | Baseline, 3 months, and 6 months | The AVLT is a validated neuropsychological test assessing verbal learning and memory function. The test evaluates immediate recall, delayed recall, and recognition. Higher scores indicate better verbal memory performance. Assessments will be performed by trained neuropsychologists blinded to group assignment. |
| Change in Shape Trails Test (STT-A and STT-B) Score | Baseline, 3 months, and 6 months | The STT is a validated neuropsychological test assessing executive function, attention, and psychomotor speed. STT-A primarily measures processing speed, while STT-B measures executive function and task-switching ability. Lower completion time indicates better performance. Assessments will be performed by trained neuropsychologists blinded to group assignment. |
| Change in Digit Span Test (DST) Score | Baseline, 3 months, and 6 months | The DST is a validated neuropsychological test assessing working memory and attention. The test includes forward digit span (attention) and backward digit span (working memory). Higher scores indicate better working memory performance. Assessments will be performed by trained neuropsychologists blinded to group assignment. |
| Change in Structural MRI Parameters | Baseline and 6 months | Changes in structural brain imaging parameters will be assessed using 3T MRI, including gray matter volume, cortical thickness, and hippocampal volume. These parameters will be used to evaluate the neuroprotective effects of the intervention. Imaging data will be analyzed by neuroradiologists blinded to group assignment. |
| Change in Functional MRI (fMRI) Parameters | Baseline and 6 months | Changes in functional brain connectivity will be assessed using resting-state fMRI. Key parameters include functional connectivity within the default mode network (DMN) and gamma-band related networks. Imaging data will be analyzed by neuroradiologists blinded to group assignment. |
| Change in Peripheral Blood Alzheimer's Disease Biomarkers | Baseline and 6 months | Changes in peripheral blood biomarkers associated with Alzheimer's disease pathology will be assessed. Biomarkers include: (1) amyloid beta 42 (Aβ42); (2) amyloid beta 40 (Aβ40) and the Aβ42/Aβ40 ratio; (3) phosphorylated tau (p-Tau181 or p-Tau217); (4) total tau (t-Tau); (5) neurofilament light chain (NfL). |
| Change in Aβ-PET Standardized Uptake Value Ratio (SUVR) | Baseline and 6 months | Changes in brain amyloid beta burden will be assessed using Aβ-PET imaging. The primary measure is the standardized uptake value ratio (SUVR) in predefined regions of interest (including frontal, temporal, parietal, and occipital cortices, as well as the precuneus and cingulate). Higher SUVR indicates greater amyloid burden. Imaging data will be analyzed by nuclear medicine physicians blinded to group assignment. |
| Change in tau-PET Standardized Uptake Value Ratio (SUVR) | Baseline and 6 months | Changes in brain tau pathology will be assessed using tau-PET imaging. The primary measure is the standardized uptake value ratio (SUVR) in predefined regions of interest (including medial temporal lobe, temporal cortex, parietal cortex, and other Braak stage regions). Higher SUVR indicates greater tau burden. Imaging data will be analyzed by nuclear medicine physicians blinded to group assignment. |
| Incidence of Serious Adverse Events (SAEs) | Baseline through 6 months (entire study period) | The incidence, severity, and causality of all serious adverse events (SAEs) will be assessed throughout the study period. SAEs include: death, life-threatening events, persistent or significant disability or incapacity, hospitalization or prolonged hospitalization, fetal distress, fetal death, congenital anomalies or birth defects, and any other important medical events that may jeopardize the patient or require intervention to prevent one of the above outcomes. |
| Incidence of Adverse Events (AEs) | Baseline through 6 months (entire study period) | The incidence, severity, and causality of all adverse events (AEs) will be assessed throughout the study period. AEs include but are not limited to: transient dizziness, visual fatigue, headache, nausea, attention fluctuation, drowsiness, eye dryness, tinnitus, irritability, anxiety, and any other unexpected events. Severity will be graded as mild, moderate, or severe. Relationship to the intervention will be classified as: definitely related, possibly related, potentially related, possibly unrelated, or definitely unrelated. |
Countries
China
Contacts
CONTACTChao Gao
CONTACTBinyin Li, MD，Ph.D
Outcome results
None listed