In Vivo Evidence for Impaired Glymphatic Function in the Visual Pathway of Patients With Normal Pressure Hydrocephalus

Abstract

Purpose: Impaired ability to remove toxic metabolites from central nervous system may be an important link between cerebral and ophthalmic degenerative diseases. The aim of the present study was to compare the glymphatic function in the visual pathway in patients with idiopathic normal pressure hydrocephalus (iNPH), a neurodegenerative dementia subtype, with a reference group.

Methods: We compared 31 subjects with Definite iNPH (i.e., shunt-responsive) with 13 references in a prospective and observational study. After intrathecal injection of the magnetic contrast agent gadobutrol (Gadovist, 0.5 mL, 1.0 mmol/mL, Bayer Pharma AG), serving as a tracer, consecutive magnetic resonance imaging (MRI) scans were obtained (next 24-48 hours). The normalized MRI T1 signal recorded in the cerebrospinal fluid (CSF) and along the visual pathway served as a semi-quantitative measure of tracer enrichment. Gadobutrol does not penetrate the blood-brain barrier and is thus confined to the extravascular space. Overnight measurements of pulsatile intracranial pressure were used as a surrogate marker for the intracranial compliance.

Results: The tracer enriched the prechiasmatic cistern similarly in both groups, but clearance was delayed in the iNPH group. Moreover, both delayed enrichment and clearance of the tracer were observed in the visual pathway in the iNPH subjects. The enrichment in the visual pathway and the CSF correlated. Individuals with elevated pulsatile intracranial pressure showed reduced enrichment within the visual pathway.

Conclusions: There was delayed enrichment and clearance of a tracer in the visual pathway of iNPH patients, which suggests impaired glymphatic function in the visual pathway in this disease.

Figure 1.

Anatomic location for placement of ROIs in the intraorbital segment of the visual pathway in iNPH using T1-MRI. The figure demonstrates the approximate intraorbital location along the visual pathway used for placement of the ROI. The left image provides an anatomical overview in the axial plane where the letters a–d correspond with the magnified coronal slices A–D, shown in the images to the right. The following locations are shown and indicated by arrows: Vitreous body (a/A), retrobulbar part of optic nerve (b/B), mid part of optic nerve (c/C), and posterior part of optic nerve (d/D).

Figure 2.

Anatomic location for placement of ROIs in the intracranial segment of the visual pathway in iNPH using T1-MRI. The figure demonstrates the approximate intracranial location along the visual pathway used for placement of the ROI. An anatomic overview is shown in the axial and sagittal planes where the letters a–d correspond with the magnified coronal slices (A–D). The following locations are shown and indicated by arrows: prechiasmatic part of optic nerve (arrow) (a/A), optic chiasma (b/B), optic tract (arrow) (c/C), and primary visual cortex and superior sagittal sinus (arrow) (d/D).

Figure 3.

Trend plots of time-dependent enrichment of tracer in cerebrospinal fluid. The figure shows the percentage changes in tracer enrichment (i.e., normalized T1 signal units) within cerebrospinal fluid (CFS) space of prechiasmatic cistern in references (blue lines) and iNPH patients (red lines). There were no significant difference between the groups during the enrichment phase, whereas during the clearance phase, tracer enrichment were higher after 24 and 48 hours in iNPH, indicative of delayed clearance of tracer from the CSF space in iNPH subjects. Error bars refer to standard error (SE). Significant differences between the groups was assessed by the independent t-test; *P < 0.05, **P < 0.01.

Figure 4.

Trend plots of time-dependent tracer enrichment in orbital visual pathway structures. The figure shows the percentage changes in tracer enrichment (i.e., normalized T1 signal units) within the orbital compartment, including (a) ocular bulb, (b) retrobulbar optic nerve, (c) mid part of optic nerve, and (d) posterior part of optic nerve in references (blue line), and iNPH patients (red line). In iNPH cases the tracer enrichment was delayed in the retrobulbar part of the optic nerve shown as significantly lower tracer enrichment at four to six hours (Table 2). A delay in clearance of tracer was seen in the mid and posterior parts, as shown by higher tracer enrichment in the clearance phase at 48 hours (Table 2). Error bars refer to 95% CI. Significant differences between the groups at specific time points were assessed by independent t-test; *P < 0.05, **P < 0.01.

Figure 5.

Trend plots of time-dependent tracer enrichment in intracranial visual pathway. The figure shows the percentage changes in tracer enrichment (i.e., normalized T1 signal units) within the intracranial compartment, including (a) prechiasmatic optic nerve, (b) optic chiasm, (c) optic tract, and (d) primary visual cortex (gray matter) in references (blue line) and iNPH patients (red line). In iNPH cases the tracer enrichment was delayed in the optic chiasm and the optic tract, as shown by significantly lower tracer enrichment at four to six hours (Table 2). The clearance of tracer was delayed at 48 hours for the prechiasmatic optic nerve and the primary visual cortex, as shown by more pronounced tracer enrichment in the clearance phase at 48 hours (Table 2). Error bars refer to 95% CI. Significant differences between the groups at specific time points were assessed by independent t-test; *P < 0.05, **P < 0.01.