Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in idiopathic normal pressure hydrocephalus

Abstract

Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0-4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans' index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten's medial temporal atrophy scores, Fazeka's scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3-4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration.

Keywords: ICP; MRI biomarkers; cerebrospinal fluid; glymphatic system; idiopathic normal pressure hydrocephalus.

Graphical Abstract

Figure 1

Grading of ventricular reflux. We categorized ventricular reflux in five categories: (A) Grade 0: No supra-aqueductal reflux. (B) Grade 1: Sign of supra-aqueductal reflux. (C) Grade 2: Transient enrichment of lateral ventricles Day 1. (D) Grade 3: Lasting enrichment of lateral ventricles Day 2 (not isointense with CSF subarachnoid). (E) Grade 4: Lasting enrichment of lateral ventricles Day 2 (isointense with CSF subarachnoid). This illustration shows the gMRI for one individual for each of the ventricular reflux grades. The ventricular reflux grades 3–4 are typical features of iNPH

Figure 2

Molecular clearance from CSF and brain parenchyma and association with ventricular reflux. Comparison of time course of CSF tracer level within (A) CSF of cisterna magna and (B) parenchyma of ERC in iNPH (n = 34) and REF (n = 17) subjects. The CSF tracer level is expressed as mean (standard error) percentage change of normalized signal unit ratio (*P = 0.013, ** P < 0.001; independent samples t-test). Comparisons of (C) one-night clearance (n = 50) and (D) two-night clearance (n = 27) of CSF tracer from cisterna magna in individuals with ventricular reflux grades 0–2 (n = 18) and 3–4 (n = 33). Both one- and two-night clearances were impaired in the individuals with ventricular reflux grades 3–4. Comparisons of (E) one-night clearance (n = 50) and (F) two-night clearance (n = 27) of CSF tracer from parenchyma of ERC in individuals with ventricular reflux grades 0–2 (n = 18) and 3–4 (n = 33) showed significantly impaired one-night clearance in individuals with ventricular reflux grades 3–4. Statistical differences are indicated, and were determined by independent samples t-test. Error bars 95% CI

Figure 3

Association between pulsatile ICP and MRI biomarkers of CSF tracer dynamics, CSF space anatomy, and neurodegeneration. The MWA, which is indicative of the intracranial compliance, associate significantly with the MRI biomarkers of CSF tracer dynamics (A–C), CSF space anatomy (D–F) and neurodegeneration (G–I). CSF tracer dynamics: (A) Comparison of overnight average MWA scores in individuals with ventricular reflux grades 0–2 (n = 18) and 3–4 (n = 33) shows significantly increased average levels of MWA in the individuals with ventricular reflux grades 3–4. The MWA level in this latter group was above established thresholds (Eide and Sorteberg, 2010). Moreover, individuals with overnight MWA above established thresholds (n = 33), indicative of impaired intracranial compliance, presented with significantly (B) reduced one-night clearance from CSF, and (C) reduced one-night clearance of CSF tracer from ERC. CSF space anatomy: There was (A) a significant positive correlation between overnight average MWA and Evans’ index (n = 38), (B) a significant negative correlation between callosal angle and average MWA (m = 38), and (C) the overnight MWA was significantly higher in individuals with positive DESH signs (n = 38). Neurodegeneration: The overnight MWA was (D) significantly higher in individuals with MTA grades 2–3 (n = 33) as compared with 0–1 (n = 17), (E) significantly higher in individuals with Fazeka’s grades 2–3 (n = 21) versus 0–1 (n = 30). (F) Moreover, there is significant correlation between overnight average MWA and ERC thickness (n = 37). Significance levels were determined by independent samples t-test. For scatter plots are shown the fit lines and Pearson correlation coefficients with significance levels. Error bars 95% CI

Figure 4

Rationale for utility of established and proposed MRI biomarkers for iNPH disease. The diagram provides an overview of our rational for the previously established and presently proposed MRI biomarkers of iNPH disease. Possible etiological factors in iNPH are indicated (red boxes). We propose that failure of glymphatic and meningeal lymphatic function may be key features of iNPH (green boxes). The possible consequences of impaired glymphatic and meningeal lymphatic function are indicated (blue boxes), as well as the MRI biomarkers that may be suggestive of iNPH pathogenesis (yellow boxes)