A possible role for meningeal inflammation in the early pathogenesis of idiopathic normal pressure hydrocephalus

The pathogenesis of idiopathic Normal Pressure Hydrocephalus (iNPH) is not clearly understood. Some studies have implicated neuroinflammation and glymphatic dysfunction as part of the pathogenesis but the role of microglia activation in the early stages of iNPH has not been investigated in vivo. Here, we present a case with imaging evidence of meningeal neuroinflammation seven years prior to iNPH diagnosis. We re-analyzed Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) images of a patient enrolled in a longitudinal assessment of isolated Rapid-Eye-Movement sleep Behavior Disorder (iRBD) who later developed comorbid iNPH. As part of the iRBD study, the patient had received serial 11C(R)-PK11195 PET to assess inflammation and high-resolution structural MRI at baseline in 2015 and at 3-year follow-up. The patient was diagnosed with iNPH in 2022. Both baseline and follow-up 11C(R)-PK11195 PET images showed evidence of abnormally increased meningeal inflammation several years before the iNPH diagnosis, compared to both age matched healthy controls and the other iRBD patients in the cohort. Over the three-year follow-up, the inflammation worsened while key imaging features of iNPH began to develop on the MRI. No structural abnormalities were observed in the meninges. Our findings suggest that progressive meningeal inflammation could have been an early event in the development of iNPH in this patient. They also provide the rationale for further studies to investigate the role of neuroinflammation and meningeal involvement in iNPH and the possible therapeutic implications.