Brain Barriers in Normal Pressure Hydrocephalus: Mechanisms and Therapeutic Perspectives

Normal pressure hydrocephalus (NPH), which is characterized by gait disturbances, cognitive impairment, and urinary incontinence, is a distinct subtype of hydrocephalus that predominantly affects older adults. Unlike other subtypes of hydrocephalus, NPH presents with ventricular enlargement despite normal intracranial pressure, underscoring its distinct and complex pathogenesis. Recent evidence has implicated impaired cerebrospinal fluid (CSF) dynamics together with dysfunction of central nervous system (CNS) barriers, particularly the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), as key contributors to the pathomechanism of NPH. Brain-barrier dysfunction may contribute to neuroinflammation, alterations in CSF dynamics and composition, and susceptibility to infection, thereby promoting neuronal damage in NPH.

This review focused on the structural and functional alterations of endothelial and epithelial cells that constitute the BBB and BCSFB, with an emphasis on mitochondrial dysfunction as a contributor to impaired barrier integrity in NPH.

We discuss the current and emerging therapeutic strategies aimed at enhancing barrier function, including interventions targeting mitochondrial function, oxidative stress, and inflammation. By moving beyond the traditional focus on CSF circulation abnormalities, this review highlights brain-barrier dysfunction to expand the understanding of the pathophysiology of NPH and encourage a barrier-oriented approach for future studies and therapeutic development.