Plasma biomarkers of neurodegeneration and neuroinflammation in intracranial atherosclerotic disease

Abstract Intracranial atherosclerotic stenosis is a leading cause of stroke and an increasingly recognized contributor to cognitive impairment and dementia. The mechanisms underlying cognitive dysfunction in Intracranial atherosclerotic stenosis remain poorly understood, particularly whether they involve direct vascular brain injury or accelerate neurodegeneration and neuroinflammation. Ultrasensitive plasma biomarkers, including the amyloid-β 42/40 ratio, phosphorylated tau at threonine 217, glial fibrillary acidic protein, and neurofilament light chain, offer insights into these processes, but their role in intracranial atherosclerotic stenosis has not been elucidated. We recruited 403 patients with intracranial atherosclerotic stenosis (84 with 50% asymptomatic stenosis, 154 with ≥50% asymptomatic stenosis, and 165 with ≥50% symptomatic stenosis) and 98 intracranial atherosclerotic stenosis-free controls across nine centers. Plasma biomarkers were quantified using single-molecule array technology. Cognitive function was assessed with a standardized neuropsychological battery, and multimodal MRI was performed to evaluate infarcts and cerebral small vessel disease burden. Multivariable models examined associations among intracranial atherosclerotic stenosis severity, biomarkers levels, and cognitive impairment. Plasma biomarker levels in patients with asymptomatic stenosis 50% were comparable to those in controls. Glial fibrillary acidic protein was elevated in asymptomatic stenosis ≥50%, while both glial fibrillary acidic protein and neurofilament light chain were increased in symptomatic stenosis. The amyloid-β 42/40 ratio was reduced in symptomatic stenosis ≥50%, whereas phosphorylated tau at threonine 217 was unchanged across groups. In multivariable analyses, none of the plasma biomarkers were significantly associated with cognitive impairment. In contrast, intracranial atherosclerotic stenosis itself was independently associated with cognitive impairment in a graded manner (asymptomatic stenosis 50%: OR = 2.48; asymptomatic stenosis ≥50%: OR = 2.65; symptomatic stenosis: OR = 4.14). These findings indicate that although plasma biomarkers of neurodegeneration and neuroinflammation are altered in advanced intracranial atherosclerotic stenosis, they do not explain the associated cognitive impairment. Instead, cognitive deficits appear to be driven primarily through vascular mechanisms. Our results support reconceptualizing intracranial atherosclerotic stenosis not only as a stroke-prone vascular disorder but also as a covert threat to brain health and cognition. Early identification and aggressive management of intracranial atherosclerotic stenosis, even before conventionally “significant” stenosis or symptoms, are warranted.