INTRACRANIAL INFLAMMATION CAUSES MENINGEAL FIBROSIS AND GLYMPHATIC STRUCTURAL CHANGES, RESULTING IN COMPROMISED BRAIN FLUID CLEARANCE AND COGNITIVE DECLINE IN A RAT COMMUNICATING HYDROCEPHALUS MODEL

Normal pressure hydrocephalus (NPH), a chronic form of communicating hydrocephalus characterized by ventriculomegaly and progressive cognitive decline, is becoming increasingly prevalent. Although cerebrospinal fluid (CSF) diversion can ameliorate symptoms, early diagnosis and effective intervention remain challenging due to an incomplete understanding of its underlying pathophysiology.
To explore this, we induced NPH in adult rats with parietal subarachnoid kaolin injection. Consistent with the characteristics of NPH, ventriculomegaly appeared late, beginning three months post-induction. However, intracranial pathological changes occurred as early as two weeks, including meningeal thickening with increased collagen deposition, elevated expressions of interleukin-6 and CD163, astrocyte activation, expansion of perivascular spaces, downregulation of occludin, and increased/mislocalized expression of aquaporin-4. By one month, brain fluid clearance function was markedly impaired, accompanied by decreased expression of collagen IV (a key basal lamina component) and the excitatory postsynaptic protein PSD-95 and spinophilin. At three months, myelin basic protein expression was reduced, while α‑synuclein—an indicator of neurodegeneration—accumulated within cortical pyramidal neurons. Although recognition memory remained intact up to three months, spatial memory declined progressively from one to three months post-treatment.
In summary, we demonstrate that parietal subarachnoid kaolin injection in adult rats, induced meningeal inflammation and cerebral pathological changes that alter brain fluid dynamics. These events ultimately result in communicating hydrocephalus with selective spatial memory impairment. This temporal sequence of events may reflect the etiology of human NPH, and serves as a valuable model for exploring diagnostic and therapeutic strategies targeting the glymphatic and CSF clearance pathways.