This study aims to evaluate whether digital cognitive training and/or intensive lipid-lowering therapy with a PCSK9 inhibitor can improve cognitive function in patients with intracranial atherosclerosis (ICAS).
ICAS is a common cause of stroke and is also linked to thinking and memory problems. The study will enroll 420 adults aged 55-80 years who have 50-99% narrowing of an intracranial artery, subjective memory complaints, and LDL cholesterol ≥1.8 mmol/L, but who are not demented.
Participants will be randomly assigned to one of four groups in a 2×2 factorial design:
1. No cognitive training + standard statin therapy 2. Cognitive training + standard statin therapy 3. No cognitive training + intensive statin plus PCSK9 inhibitor 4. Cognitive training + intensive statin plus PCSK9 inhibitor
Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 12 weeks. The intensive lipid-lowering group receives a PCSK9 inhibitor (Recaticimab) injection at weeks 0, 4, and 12, on top of maximally tolerated statin.
The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, MRI markers of brain structure and function, and safety measures.
The study is multicenter, open-label with blinded outcome assessment, and is conducted under the approval of the ethics committee of Peking Union Medical College Hospital.
Age 55-80 years old
The number of years of education is greater than or equal to 6 years
50%-99% stenosis of the intracranial artery confirmed by MRA, CTA or DSA
Head CT or MRI confirmed that there were no infarct lesions/softening foci larger than 3 cm in the brain
Extracranial vascular stenosis ≥ 50%
Acute cerebrovascular events within 90 days
Contraindications to MRI (metal implants in the body, claustrophobia, etc.)
Visual and auditory impairments, as well as communication difficulties, that affect cognitive training
Factorial
Rosuvastatin
DrugRosuvastatin 20mg or Atorvastatin 40mg orally once daily, at the maximally tolerated dose, for 24 weeks. Dose may be adjusted for intolerance or safety.
Ezetimibe
DrugEzetimibe 10mg orally once daily, at investigator's discretion, in combination with statin therapy for 24 weeks.
Recaticimab
DrugRecaticimab (PCSK9 inhibitor) subcutaneous injection: 150mg at week 0, 300mg at week 4, 450mg at week 12, on top of maximally tolerated statin ± ezetimibe. Total treatment duration 24 weeks.
Digital Cognitive Training
BehavioralTablet-based adaptive cognitive training covering six domains: processing speed, attention, perception, memory, language, and executive function. Participants are instructed to train 30 minutes/day, 5 days/week for 12 weeks. The system adjusts difficulty based on performance.
Active Control
BehavioralParticipants receive low-difficulty standardized tasks on the same tablet platform, with similar contact time and push frequency as the intervention group. No adaptive multi-domain training is provided. Used to control for non-specific effects of device use and attention.
Change from baseline in composite cognitive Z-score at week 24
The composite cognitive Z-score is derived from five cognitive domains: memory, executive function, visuospatial ability, attention, and language. Each individual test score is first standardized to a Z-score using normative mean and SD, with direction aligned so that higher scores indicate better function (reaction times are reverse-coded). Domain Z-scores are the equally weighted average of the prespecified core tests within each domain. The overall composite Z-score is the equally weighted average of the five domain Z-scores. The outcome is the change from baseline to week 24, with positive values indicating improvement.
Change from baseline in composite cognitive score at week 12
Same composite Z-score as primary outcome, derived from memory, executive, visuospatial, attention, and language domains. Outcome is change from baseline to week 12.
Change from baseline in MoCA total score at week 12 and week 24
Montreal Cognitive Assessment (MoCA) total score . Outcome is change from baseline at week 12 and week 24.
Change from baseline in five cognitive domain Z-scores at week 12 and week 24
Domain-specific Z-scores for memory, executive function, visuospatial ability, attention, and language. Each domain Z-score is the equally weighted average of prespecified core tests within that domain. Outcome is change from baseline at week 12 and week 24.
Change from baseline in whole-brain atherosclerotic burden at week 24
Whole-brain atherosclerotic burden is assessed by TOF-MRA, summing stenosis scores (0,1,2) across 11 intracranial arterial segments (range 0-22, higher indicates greater burden). Outcome is change from baseline to week 24.
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