This study aims to evaluate whether digital cognitive training and/or PCSK9 inhibitor-enhanced lipid-lowering therapy on top of moderate-intensity statin 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 440 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, parallel-group design:
No cognitive training + moderate-intensity statin therapy
Cognitive training + moderate-intensity statin therapy
No cognitive training + moderate-intensity statin plus PCSK9 inhibitor
Cognitive training + moderate-intensity statin plus PCSK9 inhibitor
Cognitive training consists of 30 minutes of tablet-based exercises, 5 days per week for 24 weeks (first 12 weeks as the intensive phase, followed by 12 weeks continuation phase). The PCSK9 inhibitor (Recaticimab) is administered subcutaneously according to the product label, on top of moderate-intensity statin.
The main outcome is change in a composite cognitive score from baseline to 24 weeks. Secondary outcomes include changes in specific cognitive domains, serum LDL-C, 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 cervical artery 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 10mg or Atorvastatin 20mg orally once daily, at the moderate-intensity 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 according to the product label, on top of moderate-intensity 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 24 weeks (first 12 weeks as the intensive phase, followed by 12 weeks continuation phase). The system adjusts difficulty based on performance.
Active Control
BehavioralParticipants receive science popularization and health education push notifications. Used to control for non-specific effects of study participation 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. The MoCA scale ranges from 0 to 30, with higher scores indicating better cognitive function. 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, 3, 4) across 11 intracranial arterial segments (range 0-44, higher indicates greater burden). Outcome is change from baseline to week 24.
Change from baseline in vascular stenosis severity at week 24
Intracranial arterial stenosis severity assessed by TOF-MRA. Outcome is change from baseline to week 24.
Change from baseline in brain structure and function at week 24
Brain structure (DTI, 3D T1WI) and function (resting-state fMRI) changes. Outcome is change from baseline to week 24.
Change from baseline in other lipid parameters at week 24
Other lipid parameters including TC, non-HDL-C, Lp(a), TG, and HDL-C. Outcome is change from baseline to week 24.
Change from baseline in plasma biomarkers at week 24
Plasma biomarkers including Aβ42/Aβ40, p-tau217, NfL, and GFAP. Outcome is change from baseline to week 24.
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