Intracranial inflammation and meningeal fibrosis are associated with perivascular changes, altered CSF tracer dynamics, and cognitive decline in a rat model of communicating hydrocephalus

Normal pressure hydrocephalus (NPH), a chronic communicating hydrocephalus characterized by ventriculomegaly and progressive cognitive decline, is increasingly prevalent in today’s rapidly expanding aging population. Although cerebrospinal fluid (CSF) diversion ameliorates symptoms, early diagnosis and effective intervention remain challenging due to incomplete understanding of the underlying pathophysiology. Disturbances in CSF circulation and perivascular transport have been implicated in NPH; however, their relationships to meningeal alterations and neurodegenerative changes remain to be clarified. Chronic communicating hydrocephalus was induced in adult rats with parietal subarachnoid kaolin injection. Intracranial inflammation, meningeal alterations, perivascular changes, CSF tracer elimination dynamics, ventriculomegaly, and cognitive behaviors were examined two weeks, one month, and three months following kaolin treatment. Ventriculomegaly appeared late, three months following parietal subarachnoid kaolin injection, consistent with the characteristic of chronic communicating hydrocephalus. Interestingly, a series of intracranial pathological changes occurred as early as two weeks after kaolin induction, including meningeal thickening with increased collagen deposition, elevated interleukin-6 and CD163 expressions, astrocyte activation, expansion of perivascular spaces, downregulation of occludin, and increased and mislocalized aquaporin 4 expression. By one month, CSF tracer elimination was significantly reduced, accompanied by decreased expression of collagen IV, a key basal lamina component, and excitatory postsynaptic proteins postsynaptic density protein 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 was retained up to three months following kaolin injection, spatial memory declined progressively from one to three months post-treatment. This study demonstrates that in adult rats, parietal subarachnoid kaolin injection induces meningeal inflammation, cerebral pathological changes, altered CSF dynamics and ultimately communicating hydrocephalus with selective spatial memory impairment. This temporal sequence of events may provide insight into the pathological processes relevant to human NPH and inform future studies on CSF–perivascular transport alterations.