Involvement of the Nigrostriatal Pathway in Patients With Idiopathic Normal Pressure Hydrocephalus and Parkinsonism

Abstract

Background and objectives: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait disturbance, cognitive decline, and urinary incontinence and may include parkinsonism. The underlying mechanism of parkinsonism in iNPH-whether neurodegenerative or mechanical-remains unclear. This study aimed to assess nigrostriatal integrity in iNPH patients with parkinsonism using dopaminergic transporter imaging (DAT-SPECT) and nigrosome MRI.

Methods: This prospective study was conducted at the Movement Disorders Clinic, Santa Chiara Hospital, Pisa University, from 2021 to 2023. Inclusion criteria for the iNPH group included the following: (1) clinical diagnosis of probable iNPH per the 2021 Japanese Society Guidelines and (2) parkinsonism per United Kingdom Parkinson's Disease Society Brain Bank criteria. An equal number of patients with Parkinson disease (PD), matched for age and sex, served as a comparison group. All participants underwent DAT-SPECT and 3T MRI within 1 month. Statistical analyses included the Student t test or Fisher-Pitman permutation tests for continuous variables and χ² tests for categorical variables. Multiple linear regression (adjusted for age and sex) compared DAT binding between groups. Pearson correlation assessed relationships between striatal DAT binding and parkinsonism in patients with iNPH evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III.

Results: A total of 20 patients with iNPH (mean age 75.4 ± 5.1 years, 65% female) and 20 patients with PD (mean age 74 ± 3.7 years, 55% female) were included. Reduced striatal DAT binding was observed in 45% of patients with iNPH, with none exhibiting nigrosome loss. Conversely, all patients with PD showed both reduced DAT binding and nigrosome loss (p < 0.001). After adjusting for age and sex, patients with iNPH exhibited significantly higher putaminal and caudate DAT binding than patients with PD (right putamen: β = -0.644, p < 0.001; left putamen: β = -0.659, p < 0.001; right caudate: β = -0.429, p = 0.006; left caudate: β = -0.391, p = 0.016), with an elevated putaminal/caudate ratio (p = 0.012). In patients with iNPH, striatal DAT binding negatively correlated with motor severity (left: r = -0.626, p = 0.004; right: r = -0.425, p = 0.07).

Discussion: Findings suggest that parkinsonism in iNPH may stem from mechanical disruption of the nigrostriatal pathway rather than neurodegeneration, as indicated by preserved nigrosome integrity despite reduced DAT binding. Limitations include the small sample size and lack of postsurgical follow-up data.