Geir Andre Ringstad

• Eide, Per Kristian; Lashkarivand, Aslan; Hernes, Susanne Miriam Sørensen; Ringstad, Geir Andre & Hovd, Markus (2026). Estimation of human brain fluid clearance using intrathecal imaging contrast agents. Fluids and Barriers of the CNS. 23(1). doi: 10.1186/s12987-026-00826-1. Full text in Research Archive Show summary

  Background Extra-vascular brain fluid dynamics, including exchange through glymphatic and meningeal lymphatic pathways, has been proposed essential for waste clearance and solute transport in the central nervous system. Although animal studies provide evidence for these pathways’ role in clearing neurotoxic proteins and distributing solutes delivered to cerebrospinal fluid (CSF), translation to humans is limited. Quantitative, in vivo measures of inter-individual variability in brain fluid clearance in clinical populations are largely lacking. This study investigated the feasibility of estimating brain fluid clearance indices using intrathecal imaging contrast agents. Methods In a prospective and observational study, iodixanol (Visipaque, GE Healthcare, USA, 270 mg I/mL, 3 mL) was administered intrathecally as a CSF tracer and its clearance from CSF to blood was quantified using population pharmacokinetic modeling. Intracranial tracer enrichment in CSF was assessed by its radiodensity (Hounsfield units) within predefined regions of interest (cisterna magna, Sylvian fissure and vertex) on cranial computed tomography (CT) performed 2-, 4- and 24-hours post-injection. These results were compared with brain fluid clearance indices derived from a separate population pharmacokinetic model using intrathecal gadobutrol (Gadovist, Bayer AG, GE, 1.0 mmol/mL, 0.50 mL), with its enrichment in CSF defined as gadobutrol-induced T1 signal increase from baseline within corresponding subarachnoid spaces on magnetic resonance imaging (MRI). Results The study included 52 subjects receiving intrathecal iodixanol and 45 individuals receiving intrathecal gadobutrol. Marked inter-individual variability was observed in brain fluid clearance to blood for both contrast agents, as well as their distribution in CSF as assessed by CT and MRI. Brain fluid clearance from iodixanol and gadobutrol were significantly correlated. Notably, clearance indices showed stronger correlations with intracranial distribution in CSF for gadobutrol-derived MRI metrics than for iodixanol-derived CT metrics. Conclusions These findings demonstrate the feasibility of estimating brain fluid clearance in humans using intrathecal imaging contrast agents as CSF tracers. Brain fluid clearance capacity exhibits pronounced inter-individual variability and correlates with the degree of contrast enrichment in intracranial subarachnoid spaces, particularly when assessed by MRI. The results underscore the importance of individualized assessment of brain fluid clearance, with implications for studies on pathogenetic mechanisms of neurodegeneration and optimization of intrathecal drug delivery.

• Mossige, Ingrid; Valnes, Lars Magnus; Storås, Tryggve Holck; Emblem, Kyrre Eeg; Eide, Per Kristian & Ringstad, Geir Andre (2026). Comparing Glymphatic Function Measures: Diffusion Tensor Image Analysis Along Perivascular Spaces (DTI-ALPS) versus Intrathecal Contrast-Enhanced MRI. Radiology. ISSN 0033-8419. 318(2). doi: 10.1148/radiol.252070. Full text in Research Archive Show summary

  Background Diffusion-tensor image (DTI) analysis along the perivascular space (ALPS) is a noninvasive but not well-validated method proposed to evaluate glymphatic function. Purpose To assess ALPS indexes across participant groups and compare them with measures of cerebrospinal fluid (CSF) tracer enrichment and clearance obtained by intrathecal contrast-enhanced MRI (glymphatic MRI [gMRI]). Materials and Methods This secondary analysis of a prospective observational study included participants who underwent clinical work-up for CSF disorders from September 2015 to December 2019. MRI scans were acquired before injection and 24 and 48 hours after intrathecal injection of 0.5 mmol of gadobutrol. DTI scans were preprocessed and segmented using the FMRIB Software Library. Intrathecal contrast-enhanced MRI (ie, gMRI) scans were registered to the baseline T1-weighted image, and cortex and white matter (WM) were segmented with FreeSurfer. ALPS indexes were compared with relative changes in normalized T1-weighted signal intensity at 24 and 48 hours in regions of the cortex, subcortical WM, and deep WM where the ALPS regions of interest are located by using regression analysis. Results A total of 56 participants were included (mean age, 48 years ± 20 [SD]; 36 women): 16 with idiopathic normal pressure hydrocephalus (iNPH), 10 with arachnoid cysts, 11 with idiopathic intracranial hypertension, and 19 reference participants. The ALPS index was lower in the iNPH group than in the reference group (ALPS index, 1.26 and 1.68, respectively; P < .001). Across groups, the ALPS index and degree of CSF tracer enrichment at 24 hours in deep WM were negatively associated (β = −48; P < .001). However, mean tracer enrichment in the ALPS regions of interest was low (10%), in some participants close to 0, whereas enrichment in the cortex ranged from 68% to 81%. Across groups, there was no evidence of associations between the ALPS index and measures of CSF tracer dynamics at 48 hours in any region (|β| ≤ 8; P ≥ .55). Conclusion CSF tracer enhancement in the ALPS regions of interest was sparse across groups, and the association between the ALPS index and gMRI markers of glymphatic function was limited.

• Eide, Per Kristian; Hovd, Markus; Valnes, Lars Magnus; Pripp, Are Hugo & Ringstad, Geir Andre (2026). When blood hits the brain: altered glymphatic and dural lymphatic function after surface bleeds. Acta Neurochirurgica. ISSN 0001-6268. 168. doi: 10.1007/s00701-025-06760-9. Full text in Research Archive Show summary

  Background The impact of acute subdural hematoma (aSDH) on measures of glymphatic–meningeal lymphatic function has not previously been reported. We present a descriptive observational study including a small case series—one patient following unilateral aSDH, three following unilateral subarachnoid hemorrhage (SAH), and three control subjects—providing new insights into the differential effects of surface intracranial bleeds. Methods The magnetic resonance imaging (MRI) contrast agent gadobutrol (0.5 mmol), administered intrathecally, was used as a cerebrospinal fluid (CSF) tracer. Multiphase contrast-enhanced MRI was performed to assess glymphatic tracer enrichment. CSF tracer clearance to blood, serving as a proxy for dural lymphatic function, was estimated using population pharmacokinetic modeling. All hemorrhagic cases involved unilateral bleeds, allowing within-subject comparison between affected and unaffected hemispheres. Results The series included one patient with aSDH (2.8 months post-event), three patients with unilateral SAH (mean 5.8 months post-event), and three age-matched, near-healthy reference subjects. Compared with controls, glymphatic tracer enrichment 24 h post-injection was slightly increased on the affected hemisphere in the aSDH case, whereas SAH patients showed markedly reduced enrichment on the affected side. Tracer distribution in controls was symmetrical. CSF clearance to blood was notably reduced in the aSDH case compared with references, suggesting impaired dural lymphatic function. Conclusion This small descriptive series suggests that aSDH and SAH may differentially affect glymphatic and dural lymphatic functions. While glymphatic enrichment appeared only modestly altered after aSDH, it was severely impaired following SAH. In contrast, CSF clearance to blood was markedly reduced in the aSDH case, potentially reflecting compromised dural lymphatic drainage. The limited number of cases prevent broad generalization, but these findings offer novel hypothesis-generating observations that may inform future studies on the effects of surface intracranial hemorrhages on brain clearance pathways.

• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Valnes, Lars Magnus & Mardal, Kent-Andre (2026). The impact of human brain geometry on the transport of an intrathecal tracer. Fluids and Barriers of the CNS. 23. doi: 10.1186/s12987-026-00764-y. Full text in Research Archive Show summary

  Intrathecal contrast-enhanced magnetic resonance imaging (MRI), utilizing the contrast agent gadobutrol as cerebrospinal fluid (CSF) tracer is emerging as a useful method to study glymphatic function in the human brain. A consistent finding with this technique is large inter-individual variability regarding tracer propagation. In this study, we outline an approach which predicts the distribution of tracer in the parenchyma based only on geometric information from brain tissue as captured by MRI, addressing one possible explanation for this variability. Registrations are computed from pre-injection MRI, and used to map images at $$24$$ hours after tracer injection to perform predictions of tracer enrichment in the parenchyma in other patients. We apply the method to a dataset of human brain MRI of $$134$$ patients examined for different tentative diagnoses including idiopathic normal pressure hydrocephalus, spontaneous intracranial hypotension and idiopathic intracranial hypertension, as well as a group of reference patients. Tracer enrichment mapped between patients by image registration correlate strongly with actual observed enrichment. For patients in the reference group, the relative root mean squared error on our predictions is on average $$26\%$$ in the gray matter, and $$15\%$$ or less in other brain regions. Predictions are generally less reliable in the gray matter, and for patients with identified CSF leaks. We show that predictions made from purely geometrical considerations correlate strongly with actual MRI tracer enrichment for patients with similar diagnoses, thus quantifying the role of geometry in tracer enrichment.

• Rieff, Melanie; Lapina, Oksana; Ringstad, Geir; Valnes, Lars; Warsza, Bogna & Eide, Per-Kristian [Show all 8 contributors for this article] (2025). U‐Net‐Based Prediction of Cerebrospinal Fluid Distribution and Ventricular Reflux Grading. NMR in Biomedicine. ISSN 0952-3480. Full text in Research Archive
• Skattør, Thor Håkon; Bjørnerud, Atle; Nome, Terje; Bakke, Kine Mari; Enriquez, Brian Anthony & Digernes, Ingrid [Show all 10 contributors for this article] (2025). Predicting lesion reversal in acute cerebral ischaemia via apparent diffusion coefficient threshold on diffusion-weighted MRI. European Radiology. ISSN 0938-7994. p. 1–11. doi: 10.1007/s00330-025-12014-0. Full text in Research Archive Show summary

  Objectives Diffusion-weighted imaging (DWI) quickly detects early ischaemic changes, but does not necessarily signify irreversible tissue damage, as DWI lesion reversal (DWI-R) can occur. Apparent diffusion coefficient (ADC) thresholds have been proposed to distinguish salvageable from irreversibly damaged tissue. This study aimed to evaluate the predictive value of a single ADC threshold for DWI-R following rapid and successful recanalization with voxel-level methodology. Materials and methods In this cohort study, we retrospectively analysed consecutive patients examined with DWI before and the day after endovascular therapy, with successful recanalization within 120 min of baseline MRI. DWI-R was assessed voxel-wise for ADC values between 200 mm2/s and 760 × 10−6 mm2/s. Predictive accuracy of ADC thresholds was evaluated using receiver operating characteristic (ROC) analyses. Results Seventy-one patients with a mean baseline DWI lesion volume of 18.13 mL (IQR: 6.15, 26.25) were included. Median time from MRI to recanalization was 84.0 min (IQR: 72.0, 95.5). On average, 37.5% of voxels demonstrated reversal. The area under the curve for predicting reversal based on ADC was 0.708, and the optimal threshold was 555 × 10–6 mm2/s (sensitivity 73.8%, specificity 58.6%). The voxel-wise probability of reversal declined with lower ADC, but even low ADC values exhibited some degree of reversal. Conclusion This study reinforces existing concerns about using fixed ADC thresholds to define irreversible injury. A single ADC cut-off showed only modest sensitivity and poor specificity for predicting DWI-R. No definitive lower ADC boundary was identified across clinically relevant ranges below which the likelihood of DWI-R became negligible.

• Cengija, Vanja; Eide, Per Kristian & Ringstad, Geir Andre (2025). Do enlarged white matter perivascular spaces reflect brain clearance dysfunction? Insights from intrathecal contrast-enhanced MRI. Neuroradiology. ISSN 0028-3940. doi: 10.1007/s00234-025-03877-7. Full text in Research Archive Show summary

  Purpose Visible perivascular spaces of cerebral white matter at magnetic resonance imaging (MRI) were in several studies proposed to be an integral part of brain-wide perivascular clearance pathways, and their enlargement could therefore serve as markers of perivascular clearance dysfunction. We studied whether MRI-visible perivascular spaces in subcortical white matter communicate with subarachnoid cerebrospinal fluid (CSF). Methods MRI-visible perivascular spaces of the basal ganglia served as controls. Intrathecal 0.5 mmol gadobutrol was utilized as CSF tracer, and T1-weighted MRI was performed before, and at multiple time points after (3, 6, 24 and 48 h) injection. Perivascular spaces with diameter ≥ 2 mm were included in the analysis, and a circular region of interest was placed manually within one perivascular space and in adjacent brain parenchyma of each region. Results The study included 27 symptomatic individuals undergoing clinical work-up of various CSF circulation disorders, but in whom no treatable condition was found. Perivascular spaces of both white matter and basal ganglia enhanced with intrathecal gadobutrol, confirming CSF exchange with perivascular spaces. While perivascular spaces of basal ganglia enhanced most with peak at 6 h (233.2% [34.9 to 431.5%]) (p < 0.01), coinciding with peak enhancement in subarachnoid CSF, perivascular spaces of white matter enhanced less and more slowly with peak at 48 h (159.1% [37.9 to 280.3%]) (p < 0.01). Conclusions The various degrees of CSF exchange with MRI-visible subcortical perivascular spaces suggest these may be dilated for different reasons, therefore questioning their validity as markers of perivascular clearance function.

• Emblem, Kyrre E; Ringstad, Geir; Svensson, Siri Fløgstad; Vatnehol, Svein Are Sirirud; Storås, Tryggve Holck & Vik-Mo, Einar Osland [Show all 9 contributors for this article] (2025). Intrathecal contrast-enhanced MRI reveals an alternative route for drug delivery and brain tumor visualization. Cancer Letters. ISSN 0304-3835. 638. doi: 10.1016/j.canlet.2025.218152. Full text in Research Archive
• Pripp, Are Hugo; Ringstad, Geir; Valnes, Lars Magnus & Eide, Per Kristian (2025). A method for measuring first glymphatic influx of a cerebrospinal fluid tracer in the human brain. Frontiers in Neuroscience. ISSN 1662-4548. 19. doi: 10.3389/fnins.2025.1703748. Full text in Research Archive Show summary

  Introduction: The glymphatic system is a brain-wide perivascular transport route for fluids and solutes in which cerebrospinal fluid (CSF) serves as a conduit for solute transport and clearance of brain waste. Intrathecal contrast-enhanced magnetic resonance imaging (MRI), where the intrathecal contrast agent serves as a CSF tracer, has been developed to measure glymphatic function in humans. The normalized MRI T1 signal is a semiquantitative measure of CSF flow and exchange with the brain. Objective: To estimate first-time tracer appearance within brain tissue after intrathecal tracer injection. Methods: This study implemented segmented regression analysis to estimate the first-time tracer appearance of an intrathecal tracer within brain tissues. An increase (breakpoint) in the normalized MRI T1 signal was defined to represent first glymphatic influx of the tracer. The study included 30 reference (REF) subjects with no identified CSF disturbance and 15 patients with a diagnosis of idiopathic intracranial hypertension (IIH). We developed and evaluated the method in REF subjects and further compared it between the two study groups. Results: The time to initial glymphatic tracer enrichment in the REF cohort was approximately 1 h in the frontal, temporal, parietal, and occipital cerebral cortex and ranged from two to 4 h in the corresponding white matter regions. In subcortical limbic structures and basal ganglia structures, it was 0.6 and 2.2 h, respectively. Compared with REF subjects, IIH patients presented a non-significant mean difference in the first appearance of ±0.5 h in the cerebral cortex and white matter regions, with somewhat longer estimated delays in the parietal and insular white matter regions. The results are presented as time series plots and estimates with 95% confidence intervals. Additionally, we provide supplementary R code, which can be adapted for use in future studies, and outline a basic assessment of true versus estimated breakpoints using simulated data. Conclusion: Segmented regression was found feasible to quantify the time to first glymphatic enrichment, i.e., increase in the normalized MRI T1 signal. Moreover, the method seems reasonable to differentiate first glymphatic influx between the cohorts.

• Valnes, Lars Magnus; Storås, Tryggve Holck; Vatnehol, Svein Are Sirirud; Ringstad, Geir Andre; Emblem, Kyrre Eeg & Eide, Per Kristian (2025). Optimized Magnetic Resonance T1 Mapping for Estimation of Intrathecal Contrast Concentrations in Human Brain and Ventricular Cerebrospinal Fluid. Magnetic Resonance in Medicine. ISSN 0740-3194. doi: 10.1002/mrm.70203. Full text in Research Archive
• Storås, Tryggve Holck; Lian, Sofie Lysholm; Mossige, Ingrid; Riseth, Jørgen Nilsen; Svensson, Siri Fløgstad & Løvland, Grethe [Show all 10 contributors for this article] (2025). T2-Weighted T1 Mapping and Automated Segmentation of CSF: Assessment of Solute Gradients in the Healthy Brain. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. 0, p. 1–10. doi: 10.1002/jmri.70169. Full text in Research Archive Show summary

  Background Cerebrospinal fluid (CSF) serves as a medium for nutrient delivery and waste clearance. The T1 relaxation rate, R1, can be used to measure the concentration of intrinsic solutes and extrinsic contrast agents. Purpose To implement a method for R1 mapping and segmentation of CSF and to use this method to explore how R1 of CSF relates to protein content and gadobutrol after intrathecal administration. Study Type Prospective cohort study, complemented by phantom analysis. Population Ten healthy control subjects (mean age 65.5 ± 4.4 years, range 57–72 years; five males and five females) and protein‐ and gadobutrol‐gradient phantom. Field Strength/Sequence 3 T Philips Ingenia scanner; 3D T2W mixed inversion recovery spin‐echo (T2W‐mixed IRSE) sequence and 3D T1W turbo field echo (3D T1W‐TFE). Assessment R1 maps were calculated by combining IR and SE data. An automated segmentation method derived from FreeSurfer employed SE data for CSF segmentation and T1W‐TFE for anatomical reference. CSF was collected by lumbar puncture for protein measurements, and 0.25 mmol gadobutrol was injected intrathecally. Post‐contrast assessments were performed at 3, 24, 48, and 72 h. Statistical Tests One‐way ANOVA, followed by a post hoc Tukey HSD test, and simple and multiple linear regression analysis; significance level of 0.05. Results R1 of ventricular CSF 0.216 ± 0.001 s −1 was significantly lower than that surrounding the cerebellum 0.225 ± 0.001 and cerebrum 0.228 ± 0.002 and correlated with lumbar protein concentration ( R 2  = 0.56). Peak gadobutrol concentrations were 101 ± 84 μM in ventricles, 185 ± 89 μM in cerebellar SAS and 166 ± 91 μM in cerebral SAS. Corresponding concentrations were 6 ± 4, 17 ± 8, and 37 ± 18 μM at 72 h. Data Conclusion Intrinsic R1 of CSF in the subarachnoid space correlated with protein content. Intracranial CSF enrichment after intrathecal administration of gadobutrol showed a large variation among healthy volunteers. Evidence Level 2. Technical Efficacy 3.

• Eide, Paulina; Melin, Erik; Ringstad, Geir; Eide, Per Kristian & Sorteberg, Angelika (2025). Volume of parasagittal dura is associated with blood markers of systemic inflammation | Acta Neurochirurgica. Acta Neurochirurgica. ISSN 0001-6268. 167, p. 1–10. doi: 10.1007/s00701-025-06682-6. Full text in Research Archive Show summary

  The parasagittal dura (PSD) has been hypothesized to act as a neuro-immunological hub, though evidence in favor of the hypothesis is limited. The present study explored whether there is any association between volume and function of PSD and blood markers that may be indicative of systemic inflammation. The patient material included 76 subjects examined with intrathecal contrast-enhanced magnetic resonance imaging (MRI) where the contrast served as a cerebrospinal fluid (CSF) tracer. They were dichotomized into a control- (Ctrl) and a CSF-group. We investigated the correlations between blood markers indicative of systemic inflammation and the volume of PSD, enrichment of tracer in the PSD, and blood-measures of CSF clearance. The blood markers included C-reactive protein (CRP), erythrocyte volume fraction (EVF), hemoglobin (Hb), platelet count, neutrophiles, lymphocytes, and the neutrophil-to-lymphocyte ratio as well as the platelet-to-lymphocyte ratio. Assessment of subjective sleep quality also was included in the analysis. The main finding was that higher CRP indicative of systemic inflammation was correlated with lower volume of PSD. There was an association between lower EVF and Hb levels and lower volume of PSD, but this finding could be explained by confounders such as age, sex and disease. Confounders also explained a correlation between EVF and CSF clearance variables. Impaired subjective sleep quality was associated with markers of systemic inflammation, but not with PSD volume. Higher CRP was correlated with lower volume of PSD suggesting that the size of this anatomical structure associates with systemic inflammation. Further studies are needed to determine whether PSD volume could serve as an imaging marker of systemic inflammation.

• Falkenberg-Jensen, Benedicte; Pripp, Are Hugo; Ringstad, Geir & Eide, Per Kristian (2025). Cranial nerves as pathways for human cerebrospinal fluid efflux: In vivo evidence. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. p. 1–11. doi: 10.1177/0271678x251386232. Full text in Research Archive Show summary

  In vivo evidence for cerebrospinal fluid (CSF) efflux along cranial nerves in humans is scarce. This study investigated whether the trigeminal, facial, and vestibulocochlear nerves serve as efflux routes for CSF in humans. A magnetic resonance imaging (MRI) contrast agent, used as a CSF tracer, was administered intrathecally at the lumbar level, and consecutive MRI acquisitions measured tracer enrichment along the trigeminal, facial, and vestibulocochlear nerves. The study included 27 patients undergoing evaluation for potential CSF disturbances, but none of whom exhibited evidence of CSF pathology or other neurological diseases. After intrathecal tracer injection, the tracer enriched the prepontine subarachnoid space. Subsequently tracer enrichment was observed within the trigeminal nerve within the subarachnoid space, Meckel’s cave, within the mandibular branch at the foramen ovale and the inferior alveolar nerve in the mandibular bone. The facial nerve was enriched within the subarachnoid space, as well as within the tympanic segment and mastoid segment nearby the stylomastoid foramen. The vestibulocochlear nerve was enriched with tracer within the subarachnoid space. These findings demonstrate that a CSF tracer penetrates the trigeminal, facial, and vestibulocochlear nerves in a peripheral direction, providing evidence that efflux of CSF occurs along cranial nerves in humans.

• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2025). Geometry Reduced Order Modeling (GROM) with application to modeling of glymphatic function. Brain Research Bulletin. ISSN 0361-9230. 231. doi: 10.1016/j.brainresbull.2025.111558. Full text in Research Archive Show summary

  Computational modeling of the brain has become a key part of understanding how the brain clears metabolic waste, but patient-specific modeling on a significant scale is still out of reach with current methods. We introduce a novel approach for leveraging model order reduction techniques in computational models of brain geometries to alleviate computational costs involved in numerical simulations. Using image registration methods based on magnetic resonance imaging, we compute inter-brain mappings which allow previously computed solutions on other geometries to be mapped on to a new geometry. We investigate this approach on two example problems typical of modeling of glymphatic function, applied to a dataset of 101 MRI of human patients. We discuss the applicability of the method when applied to a patient with no known neurological disease, as well as a patient diagnosed with idiopathic Normal Pressure Hydrocephalus displaying significantly enlarged ventricles. In each of our two example problems, we achieve a speedup of more 750 times compared to the full order problem, while introducing a comparably small additional system assembly overhead. The reduced solutions recover the full order solution with an error of less than 10% in most cases. Statement of significance: In many fields, model order reduction is a key technique in enabling high-throughput numerical simulations, but remains largely unexploited for biomedical modeling of the brain. In this work, we introduce a novel technique for building reduced representations integrating simulations performed on other brain geometries derived from MRI. Using this technique, we may leverage a dataset of previous solutions to accelerate simulations on new geometries, making patient-specific modeling more feasible.

• Rieff, Melanie; Holzberger, Fabian; Lapina, Oksana; Ringstad, Geir; Valnes, Lars Magnus & Warsza, Bogna [Show all 9 contributors for this article] (2025). U-Net-Based Prediction of Cerebrospinal Fluid Distribution and Ventricular Reflux Grading. NMR in Biomedicine. ISSN 0952-3480. 38(5). doi: 10.1002/nbm.70029. Full text in Research Archive Show summary

  Previous work indicates evidence that cerebrospinal fluid (CSF) plays a crucial role in brain waste clearance processes and that altered flow patterns are associated with various diseases of the central nervous system. In this study, we investigate the potential of deep learning to predict the distribution in human brain of a gadolinium-based CSF contrast agent (tracer) administered intrathecal. For this, T1-weighted magnetic resonance imaging (MRI) scans taken at multiple time points before and after injection were utilized. We propose a U-net-based supervised learning model to predict pixel-wise signal increase at its peak after 24 h. Performance is evaluated based on different tracer distribution stages provided during training, including predictions from baseline scans taken before injection. Our findings show that training with imaging data from only the first 2-h postinjection yields tracer flow predictions comparable to models trained with additional later-stage scans. Validation against ventricular reflux gradings from neuroradiologists confirmed alignment with expert evaluations. These results demonstrate that deep learning-based methods for CSF flow prediction deserve more attention, as minimizing MR imaging without compromising clinical analysis could enhance efficiency, improve patient well-being and lower healthcare costs.

• Eide, Per Kristian; Undseth, Ragnhild Marie; Pripp, Are Hugo; Lashkarivand, Aslan; Nedregaard, Bård & Sletteberg, Ruth [Show all 10 contributors for this article] (2025). Impact of Subarachnoid Hemorrhage on Human Glymphatic Function: A Time-Evolution Magnetic Resonance Imaging Study. Stroke. ISSN 0039-2499. 56(3), p. 678–691. doi: 10.1161/STROKEAHA.124.047739. Full text in Research Archive Show summary

  BACKGROUND: Subarachnoid hemorrhage (SAH) is associated with significant mortality and morbidity. The impact of SAH on human glymphatic function remains unknown. METHODS: This prospective, controlled study investigated whether human glymphatic function is altered after SAH, how it differs over time, and possible underlying mechanisms. Glymphatic enrichment was examined by intrathecal contrastenhanced magnetic resonance imaging (MRI, glymphatic MRI), utilizing the MRI contrast agent gadobutrol (Gadovist, Bayer AG, GE; 0.50 mmol) as a cerebrospinal fluid (CSF) tracer. The distribution of the tracer in the brain and the subarachnoid and ventricular CSF spaces was assessed using standardized multi-phase MRI T1 sequences, and between-group differences in percentage change of standardized T1 signal unit ratios over time were analyzed by linear mixed models. RESULTS: The study comprised 27 patients with SAH (19 female/8 male; 59.3±10.2 years) who were examined <3 months (n=5), 3 to 6 months (n=10), 6 to 12 months (n=5), or >12 months (n=7) after bleed. A sex- and age-matched control group of 22 individuals (15 female/7 male; 55.5±10.5 years) underwent the same glymphatic MRI protocol but had no neurological or CSF disease. The patients with SAH showed a marked impairment of glymphatic enrichment throughout the brain (particularly addressing the cerebral cortex and subcortical white matter), especially after 24 hours. The glymphatic impairment was accompanied by redistribution of CSF tracer from subarachnoid spaces toward ventricles. These alterations were most pronounced after 3 to 6 months and less after 12 months, though with interindividual variation. CSF tracer transport within perivascular subarachnoid spaces was impaired and coincided with impaired glymphatic enrichment. CONCLUSIONS: Human glymphatic function is severely impaired by SAH, particularly shortly after the event. Glymphatic failure is associated with redistribution of CSF from subarachnoid spaces toward ventricles. SAH-related impairment of fluid transport within perivascular subarachnoid spaces may contribute to reduced glymphatic influx. Since patient groups are small, care should be made when concluding about the impact of time on glymphatic function.

• Ringstad, Geir; Eide, Per Kristian; Naganawa, Shinji & Agarwal, Nivedita (2025). Gadolinium-Based Imaging and the Study of Neurofluid Dynamics. Neuroimaging clinics of North America. ISSN 1052-5149. 35(2), p. 191–209. doi: 10.1016/j.nic.2024.12.008. Full text in Research Archive
• Eide, Per Kristian; Hovd, Markus; Pripp, Are Hugo; Gjertsen, Øivind; Løvland, Grethe & Lashkarivand, Aslan [Show all 9 contributors for this article] (2025). Altered brain fluid dynamics in spontaneous intracranial hypotension. Fluids and Barriers of the CNS. 22. doi: 10.1186/s12987-025-00679-0. Full text in Research Archive Show summary

  Background This prospective observational study explored alterations in brain fluid dynamics in patients with spontaneous intracranial hypotension (SIH) and confirmed spinal cerebrospinal fluid (CSF) leakage, specifically addressing CSF clearance to blood, glymphatic influx and measures of CSF flow. Methods A cohort of SIH patients with verified spinal CSF leaks was compared with an age- and sex-matched reference group having no CSF disturbance or neurological disorders. Prior to repair of CSF leakage, CSF clearance was quantified using population pharmacokinetics, glymphatic influx was assessed by intrathecal contrast-enhanced magnetic resonance imaging (MRI), and CSF flow patterns were measured using either phase-contrast MRI or multiphase analysis of CSF tracer transport within the subarachnoid spaces. Results The study included eight SIH cases and nine reference subjects. SIH was accompanied with a greater CSF clearance, severely reduced tracer enrichment in the subarachnoid spaces and impaired glymphatic influx throughout the brain, after the patients had been upright. However, with patients in the supine position during MRI scanning, times to first enrichment of tracer in cisterna magna or perivascular subarachnoid spaces were not affected, with no changes in CSF flow through the Sylvian aqueduct, indicating that ventricular CSF production remained unaffected. Conclusions SIH caused by spinal CSF leakage is accompanied with altered brain fluid dynamics, here illustrated by accelerated CSF clearance to blood and reduced glymphatic influx, likely due to reduced CSF volume load to the intracranial compartment in the upright position.

• Therkelsen, Helena Eide; Enger, Rune; Eide, Per Kristian & Ringstad, Geir (2025). Evidence for cellular and solute passage between the brain and skull bone marrow across meninges: A systematic review. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 45(4), p. 581–599. doi: 10.1177/0271678X251316392. Full text in Research Archive Show summary

  A potential two-way passage of cells and substances between the brain and skull bone marrow may open for new insights into neurological disease. The arachnoid membrane was traditionally considered to restrict cells and larger molecules in CSF from entering the dura and bone marrow directly. However, new data on exchange between brain and skull bone marrow have recently emerged. Here, we conducted a systematic literature to answer the question: What is the current evidence regarding the movement of cells and molecules between the brain and skull bone marrow, spanning CSF and meninges? We excluded studies related to head or skull trauma, cranial fractures or defects, cancer invasion, CSF leakage, spontaneous intracranial hypotension, spinal dura mater, and studies solely focusing on meningeal lymphatic vessels or the passage of substances from CSF to meningeal lymphatic vessels. The review identified 16 studies that provide evidence of communication between the brain, meninges and skull bone marrow. Cells (such as B and T cells and neutrophils), bacteria, and substances (tracers, drug compounds) have been reported to pass between the brain and skull bone. However, most studies are performed in rodents, emphasizing the need for translation to humans.

• Eide, Per Kristian & Ringstad, Geir (2024). Glymphatic-stagnated edema induced by traumatic brain injury. TIPS - Trends in Pharmacological Sciences. ISSN 0165-6147. 45(5), p. 390–390. doi: 10.1016/j.tips.2024.01.005. Full text in Research Archive Show summary

  Traumatic brain injury (TBI) outcomes are notably affected by brain edema. A recent report by Hussain et al. unveils a unique form, glymphatic-stagnated brain edema, that stems from impaired glymphatic and lymphatic drainage induced by noradrenergic activation. Consequently, pan-noradrenergic inhibition may emerge as an innovative treatment for TBI-related edema, challenging traditional therapeutic approaches.

• Atai, Shahriar; Andersen, Martin Knudtzon; Wiedmann, Markus; Dahlberg, Daniel; Øystese, Kristin Astrid Berland & Bollerslev, Jens [Show all 8 contributors for this article] (2024). Unravelling pituitary tumours in medically treated patients with acromegaly: the impact of systematic MRI reassessment. Acta Radiologica. ISSN 0284-1851. 65(7), p. 753–758. doi: 10.1177/02841851241246107. Full text in Research Archive
• Eide, Per Kristian; Undseth, Ragnhild Marie; Gjertsen, Øivind; Valnes, Lars Magnus; Ringstad, Geir Andre & Lindstrøm, Erika Kristina (2024). Significant individual variation in cardiac-cycle-linked cerebrospinal fluid production following subarachnoid hemorrhage. Fluids and Barriers of the CNS. 21(1). doi: 10.1186/s12987-024-00587-9. Full text in Research Archive Show summary

  Background Spontaneous subarachnoid hemorrhage (SAH) often results in altered cerebrospinal fluid (CSF) flow and secondary hydrocephalus, yet the mechanisms behind these phenomena remain poorly understood. This study aimed to elucidate the impact of SAH on individual CSF flow patterns and their association with secondary hydrocephalus. Methods In patients who had experienced SAH, changes in CSF flow were assessed using cardiac-gated phasecontrast magnetic resonance imaging (PC-MRI) at the Sylvian aqueduct and cranio-cervical junction (CCJ). Within these regions of interest, volumetric CSF flow was determined for every pixel and net CSF flow volume and direction calculated. The presence of acute or chronic hydrocephalus was deemed from ventriculomegaly and need of CSF diversion. For comparison, we included healthy subjects and patients examined for different CSF diseases. Results Twenty-four SAH patients were enrolled, revealing a heterogeneous array of CSF flow alterations at the Sylvian aqueduct. The cardiac-cycle-linked CSF net flow in Sylvian aqueduct differed from the traditional figures of ventricular CSF production about 0.30–0.40 mL/min. In 15 out of 24 patients (62.5%), net CSF flow was retrograde from the fourth to the third and lateral ventricles, while it was upward at the cranio-cervical junction in 2 out of 2 patients (100%). The diverse CSF flow metrics did not distinguish between individuals with acute or chronic secondary hydrocephalus. In comparison, 4/4 healthy subjects showed antegrade net CSF flow in the Sylvian aqueduct and net upward CSF flow in CCJ. These net CSF flow measures also showed interindividual variability among other patients with CSF diseases. Conclusions There is considerable inter-individual variation in net CSF flow rates following SAH. Net CSF flow in the Sylvian aqueduct differs markedly from the traditional ventricular CSF production rates of 0.30–0.40 mL/min in SAH patients, but less so in healthy subjects. Furthermore, the cardiac-cycle-linked net CSF flow rates in Sylvian aqueduct and CCJ suggest an important role of extra-ventricular CSF production.

• Osch, Matthias J. P. van; Wåhlin, Anders; Scheyhing, Paul; Mossige, Ingrid; Hirschler, Lydiane & Eklund, Anders [Show all 16 contributors for this article] (2024). Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood. NMR in Biomedicine. ISSN 0952-3480. 37(9). doi: 10.1002/nbm.5159. Full text in Research Archive Show summary

  Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the “EU Joint Programme – Neurodegenerative Disease Research (JPND)” consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration–time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

• Ringstad, Geir & Eide, Per Kristian (2024). Glymphatic-lymphatic coupling: assessment of the evidence from magnetic resonance imaging of humans. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 81(1). doi: 10.1007/s00018-024-05141-2. Full text in Research Archive Show summary

  solutes to meningeal lymphatic vessels have sparked a tremendous interest in translating these seminal findings from animals to humans. A potential two-way coupling between the brain extra-vascular compartment and the peripheral immune system has implications that exceed those concerning neurodegenerative diseases, but also imply that the central nervous system has pushed its immunological borders toward the periphery, where cross-talk mediated by cerebrospinal fluid may play a role in a range of neoplastic and immunological diseases. Due to its non-invasive approach, magnetic resonance imaging has typically been the preferred methodology in attempts to image the glymphatic system and meningeal lymphatics in humans. Even if flourishing, the research field is still in its cradle, and interpretations of imaging findings that topographically associate with reports from animals have yet seemed to downplay the presence of previously described anatomical constituents, particularly in the dura. In this brief review, we illuminate these challenges and assess the evidence for a glymphatic-lymphatic coupling. Finally, we provide a new perspective on how human brain and meningeal clearance function may possibly be measured in future.

• Lashkarivand, Aslan; Ringstad, Geir & Wiedmann, Markus (2024). Empowering early career vascular neurosurgeons in the endovascular Era: Managing intraoperative aneurysm rupture through a systematic algorithmic approach. Journal of clinical neuroscience. ISSN 0967-5868. 120, p. 229–231. doi: 10.1016/j.jocn.2024.01.006. Full text in Research Archive
• Eide, Per Kristian & Ringstad, Geir (2024). Functional analysis of the human perivascular subarachnoid space. Nature Communications. 15, p. 1–14. doi: 10.1038/s41467-024-46329-1. Full text in Research Archive Show summary

  The human subarachnoid space harbors the cerebrospinal fluid, which flows within a landscape of blood vessels and trabeculae. Functional implications of subarachnoid space anatomy remain far less understood. This study of 75 patients utilizes a cerebrospinal fluid tracer (gadobutrol) and consecutive magnetic resonance imaging to investigate features of early (i.e. within 2-3 h after injection) tracer propagation within the subarachnoid space. There is a time-dependent perivascular pattern of enrichment antegrade along the major cerebral artery trunks; the anterior-, middle-, and posterior cerebral arteries. The correlation between time of first enrichment around arteries and early enrichment in nearby cerebral cortex is significant. These observations suggest the existence of a compartmentalized subarachnoid space, where perivascular ensheathment of arteries facilitates antegrade tracer passage towards brain tissue. Periarterial transport is impaired in subjects with reduced intracranial pressure-volume reserve capacity and in idiopathic normal pressure hydrocephalus patients who also show increased perivascular space size.

• Janerås, Lars; Breivik, Harald Petter; LUNDELAND, BÅRD; Ringstad, Geir & Stubhaug, Audun (2024). Long-term intrathecal infusion of low-dose morphine effectively relieves symptoms of severe restless legs syndrome/Willis-Ekbom disease without inducing opioid tolerance. Pain. ISSN 0304-3959. 162(12), p. 2693–2697. doi: 10.1097/j.pain.0000000000003311. Full text in Research Archive
• Melin, Erik; Ringstad, Geir; Valnes, Lars Magnus & Eide, Per Kristian (2023). Human parasagittal dura is a potential neuroimmune interface. Communications Biology. 6(1). doi: 10.1038/s42003-023-04634-3. Full text in Research Archive Show summary

  Parasagittal dura (PSD) is located on both sides of the superior sagittal sinus and harbours arachnoid granulations and lymphatic vessels. Efflux of cerebrospinal fluid (CSF) to human PSD has recently been shown in vivo. Here we obtain PSD volumes from magnetic resonance images in 76 patients under evaluation for CSF disorders and correlate them to age, sex, intracranial volumes, disease category, sleep quality, and intracranial pressure. In two subgroups, we also analyze tracer dynamics and time to peak tracer level in PSD and blood. PSD volume is not explained by any single assessed variable, but tracer level in PSD is strongly associated with tracer in CSF and brain. Furthermore, peak tracer in PSD occurs far later than peak tracer in blood, implying that PSD is no major efflux route for CSF. These observations may indicate that PSD is more relevant as a neuroimmune interface than as a CSF efflux route.

• Vinje, Vegard; Zapf, Bastian; Ringstad, Geir; Eide, Per Kristian; Rognes, Marie Elisabeth & Mardal, Kent-Andre (2023). Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation. Fluids and Barriers of the CNS. 20. doi: 10.1186/s12987-023-00459-8. Full text in Research Archive Show summary

  Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5 $$\times $$ × that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1–9 $$\mu $$ μ m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

• Warsza, Bogna; Due-Tønnessen, Pernille; Due-Tønnessen, Paulina; Pripp, Are Hugo; Ringstad, Geir & Eide, Per Kristian (2023). Prevalence of pineal cysts in healthy individuals: Emphasis on size, morphology and pineal recess crowding. Journal of the Neurological Sciences. ISSN 0022-510X. 453. doi: 10.1016/j.jns.2023.120801. Full text in Research Archive Show summary

  The present study aimed to determine prevalence of non-hydrocephalic pineal cysts of different size and morphology in healthy individuals. In a cohort of healthy individuals who as part of research volunteered to undergo magnetic resonance imaging (MRI) of the brain, we performed a systematic search for occurrence of pineal cysts of different sizes, morphology and evidence of crowding of the pineal recess. Degree of crowding in the pineal recess was estimated by the imaging biomarkers anterior-posterior diameter and cyst-tectum-splenium (CTS) ratio at midsagittal MRI. The study included a cohort of 994 healthy individuals, aged 47.0 ±21.1 years in whom a pineal cyst was demonstrated in 337/994 (37.5%) individuals. A small cyst within a mainly solid gland was observed in 252/994 (25.4%) subjects and a mainly cystic gland in121/994 (12.2%). The pineal cysts were more frequent in women than men, and were associated with age, though not with reduced prevalence in aged individuals, as previously reported. Cysts with maximum anterior-posterior diameter ≥10 mm were seen in 51/ 994 (5.1%) individuals, and with CTS ratio ≥0.9 in 16/994 (1.6%) individuals. The occurrence of pineal cysts is frequent and is seen more frequently in women. It usually presents as a small cyst in a predominantly solid gland; however, pineal cysts causing crowding of the pineal recess with a CTS ratio ≥0.9 was seen in merely 1.6% of participants.

• Eide, Per Kristian; Lindstrøm, Erika Kristina; Pripp, Are Hugo; Valnes, Lars Magnus & Ringstad, Geir (2023). Physiological alterations of pineal recess crowding in symptomatic non-hydrocephalic pineal cysts. Brain Communications. 5(2). doi: 10.1093/braincomms/fcad078. Full text in Research Archive Show summary

  Pineal cysts are prevalent in the population. Due to more widespread use of magnetic resonance imaging, an increasing number of symptomatic patients with non-hydrocephalic pineal cysts are referred to neurologists and neurosurgeons. Currently, there is no gen- erally accepted theoretical framework for linking symptoms to a pineal cyst. We have previously suggested that cyst-induced crowding of the pineal recess may affect venous runoff from the deep cerebral veins crossing the cyst. However, evidence underpinning this hy- pothesis is sparse. In the present study, we asked whether crowding of the pineal recess without imaging signs of hydrocephalus may be accompanied with alterations in blood flow of the internal cerebral veins, cerebrospinal fluid flow in the Sylvian aqueduct and cere- brospinal fluid-mediated tracer clearance from the brain along extravascular pathways (referred to as glymphatic function). This pro- spective, observational study included symptomatic individuals with non-hydrocephalic pineal cysts who underwent a standardized magnetic resonance imaging protocol (n = 25): Eleven patients were treated surgically with craniotomy and cyst extirpation and 14 individuals were managed conservatively without surgery. Our findings suggest that cyst-induced crowding of the pineal recess may have brain-wide effects: (i) There was a significant negative correlation between degree of crowding within the pineal recess and change in maximum venous flow velocity at the cyst, and a significant positive correlation between maximum venous flow velocity change at the cyst and net cerebrospinal fluid flow in the Sylvian aqueduct; (ii) increased degree of crowding in the pineal recess was accompanied by significantly impaired glymphatic enrichment in the cerebral cortex and subcortical white matter, indicative of a brain-wide effect in this cohort who also reported markedly impaired subjective sleep quality; (iii) there was a significant negative correlation between the apparent diffusion coefficient (suggestive of interstitial water content) within the thalamus and glymphatic enrichment of tracer and (iv) pineal recess crowding associated with symptoms. Comparison of the surgical cases [in whom 10/11 (91%) reported marked clinical improvement at follow-up] and the conservatively managed cases [in whom 1/14 (7%) reported marked clinical improvement at follow-up] showed differences in pre-treatment glymphatic tracer enrichment as well as differences in tracer enrichment in subarachnoid cerebrospinal fluid spaces. Taken together, we interpret these observations to support the hy- pothesis that cyst-induced crowding of the pineal recess without hydrocephalus may alter blood flow of the internal cerebral veins and cerebrospinal fluid flow and even cause brain-wide impairment of glymphatic transport with possible implications for cerebro- spinal fluid transport of trophic factors such as melatonin.

• Melin, Erik; Pripp, Are Hugo; Eide, Per Kristian & Ringstad, Geir (2023). In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem. JCI Insight. 8(23). doi: 10.1172/jci.insight.173276. Full text in Research Archive Show summary

  BACKGROUND. Intrathecal injection is an attractive route through which drugs can be administered and directed to the spinal cord, restricted by the blood-spinal cord barrier. However, in vivo data on the distribution of cerebrospinal fluid (CSF) substances in the human spinal cord are lacking. We conducted this study to assess the enrichment of a CSF tracer in the upper cervical spinal cord and the brain stem. METHODS. After lumbar intrathecal injection of a magnetic resonance imaging (MRI) contrast agent, gadobutrol, repeated blood samples and MRI of the upper cervical spinal cord, brain stem, and adjacent subarachnoid spaces (SAS) were obtained through 48 hours. The MRI scans were then analyzed for tracer distribution in the different regions and correlated to age, disease, and amounts of tracer in the blood to determine CSF-to-blood clearance. RESULTS. The study included 26 reference individuals and 35 patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH). The tracer enriched all analyzed regions. Moreover, tracer enrichment in parenchyma was associated with tracer enrichment in the adjacent SAS and with CSF-to-blood clearance. Clearance from the CSF was delayed in patients with iNPH compared with younger reference patients. CONCLUSION. A CSF tracer substance administered to the lumbar thecal sac can access the parenchyma of the upper cervical spinal cord and brain stem. Since CSF-to-blood clearance is highly individual and is associated with tracer level in CSF, clearance assessment may be used to tailor intrathecal treatment regimes.

• Frič, Radek; Ringstad, Geir & Eide, Per Kristian (2023). Low versus High Intracranial Compliance in Adult Patients with Chiari Malformation Type 1–Comparison of Long-Term Outcome After Tailored Treatment. World Neurosurgery. ISSN 1878-8750. 173, p. e699–e707. doi: 10.1016/j.wneu.2023.02.134. Full text in Research Archive Show summary

  Background In patients with Chiari malformation type 1 (CMI) presenting with low intracranial compliance (ICC), foramen magnum decompression (FMD) often fails and the complication rate may be higher. We therefore routinely perform a preoperative assessment of ICC from intracranial pressure measurement. Patients with low ICC are treated with ventriculoperitoneal shunt (VPS) before FMD. In this study, we assess the outcome of patients with low ICC, compared with patients with high ICC treated with FMD alone. Methods We reviewed the clinical and radiologic data of all consecutive patients with CMI treated between April 2008 and June 2021. ICC was assessed by overnight measurement of the pulsatile intracranial pressure: mean wave amplitude (MWA) above a previously defined threshold for abnormality was considered a surrogate marker for low ICC. The outcome was scored by Chicago Chiari Outcome Scale. Results Of 73 patients, 23 with low ICC (average MWA 6.8 ± 1.2 mm Hg) received VPS before FMD, whereas 50 with high ICC (average MWA 4.4 ± 1.0 mm Hg) received only FMD. After a mean follow-up of 78.7 ± 41.4 months, 96% of all patients subjectively improved. The mean Chicago Chiari Outcome Scale score was 13.1 ± 2.2. Enlargement of cerebrospinal fluid space in the foramen magnum was achieved in 95% and regression of syringomyelia in 74% of cases. We found no significant difference in outcome between the patients with low and high ICC. Conclusions By identifying patients with CMI associated with low ICC and tailoring their treatment by VPS before FMD, we achieved favorable clinical and radiologic outcomes comparable to those with high ICC.

• Eide, Per Kristian; Lashkarivand, Aslan; Pripp, Are Hugo; Valnes, Lars Magnus; Hovd, Markus Herberg & Ringstad, Geir [Show all 8 contributors for this article] (2023). Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders. Nature Communications. 14, p. 1–14. doi: 10.1038/s41467-023-37685-5. Full text in Research Archive Show summary

  Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegen- eration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to- blood clearance variables from pharmacokinetic modeling (proxy of menin- geal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neuro- degeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function.

• Sperre, Anette; Karsrud, Ina; Rodum, Anja; Lashkarivand, Aslan; Valnes, Lars Magnus & Ringstad, Geir [Show all 7 contributors for this article] (2023). Prospective Safety Study of Intrathecal Gadobutrol in Different Doses. American Journal of Neuroradiology. ISSN 0195-6108. 44(5), p. 511–516. doi: 10.3174/ajnr.A7841. Full text in Research Archive
• Eide, Per Kristian; Lashkarivand, Aslan; Pripp, Are Hugo; Valnes, Lars Magnus; Hovd, Markus & Ringstad, Geir [Show all 8 contributors for this article] (2023). Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation. Brain Communications. 5(6). doi: 10.1093/braincomms/fcad343. Full text in Research Archive Show summary

  Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-β 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation (n = 7) or were allowed free sleep (n = 21). The magnetic resonance imaging contrast agent gadobutrol was injected intrathecally, serving as a cerebrospinal fluid tracer. Population pharmacokinetic model parameters of gadobutrol cerebrospinal fluid-to-blood clearance were utilized as a proxy of meningeal lymphatic clearance capacity and intrathecal contrast-enhanced magnetic resonance imaging as a proxy of glymphatic function. After one night of acute sleep deprivation, the plasma concentrations of amyloid-β 40 and 42 were reduced, but not the ratio, and concentrations of the other biomarkers were unchanged. The overnight change in amyloid-β 40 and 42 plasma concentrations in the sleep group correlated significantly with indices of meningeal lymphatic clearance capacity, while this was not seen for the other neurodegeneration biomarkers. However, overnight change in plasma concentrations of amyloid-β 40 and 42 did not correlate with the glymphatic marker. On the other hand, the overnight change in plasma concentration of phosphorylated tau peptide 181 correlated significantly with the marker of glymphatic function in the sleep deprivation group but not in the sleep group. The present data add to the evidence of the role of sleep and sleep deprivation on plasma neurodegeneration concentrations; however, the various neurodegeneration biomarkers respond differently with different mechanisms behind sleep-induced alterations in amyloid-β and tau plasma concentrations. Clearance capacity of meningeal lymphatics seems more important for sleep-induced changes in amyloid-β 40 and 42 plasma concentrations, while glymphatic function seems most important for change in plasma concentration of phosphorylated tau peptide 181 during sleep deprivation. Altogether, the present data highlight diverse mechanisms behind sleep-induced effects on concentrations of plasma neurodegeneration biomarkers.

• Agarwal, Nivedita; Lewis, Laura D.; Hirschler, Lydiane; Rivera, Leonardo Rivera; Naganawa, Shinji & Levendovszky, Swati Rane [Show all 22 contributors for this article] (2023). Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 “ISMRM Imaging Neurofluids Study group” Workshop in Rome. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. doi: 10.1002/jmri.28759. Full text in Research Archive
• Kolnes, Anders Jensen; Øystese, Kristin Astrid Berland; Sjöstedt, Evelina; Olarescu, Nicoleta Cristina; Heck, Ansgar & Pahnke, Jens [Show all 12 contributors for this article] (2023). TGFBR3L is associated with gonadotropin production in non-functioning gonadotroph pituitary neuroendocrine tumours. Pituitary. ISSN 1386-341X. 26, p. 227–236. doi: 10.1007/s11102-023-01310-x. Full text in Research Archive Show summary

  Purpose Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data. Methods 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHβ and LHβ was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells. Results TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHβ (median 2 [IQR 0–3] in TGFBR3L negative and median 6 [IQR 3–9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHβ (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9–9.6] and median 3.0 [IQR 1.8–5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9–3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L. Conclusion TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHβ staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.

• Ringstad, Geir; Valnes, Lars Magnus; Vatnehol, Svein Are Sirirud; Pripp, Are Hugo & Eide, Per Kristian (2023). Prospective T1 mapping to assess gadolinium retention in brain after intrathecal gadobutrol. Neuroradiology. ISSN 0028-3940. 65(9), p. 1321–1331. doi: 10.1007/s00234-023-03198-7. Full text in Research Archive Show summary

  Purpose A possible pathway behind gadolinium retention in brain is leakage of contrast agents from blood to cerebrospi- nal fluid and entry into brain along perivascular (glymphatic) pathways. The object of this study was to assess for signs of gadolinium retention in brain 4 weeks after intrathecal contrast enhanced MRI. Methods We prospectively applied standardized T1 mapping of the brain before and 4 weeks after intrathecal administration of 0.5 mmol gadobutrol in patients under work-up of cerebrospinal fluid circulation disorders. Due to methodological limita- tions, a safety margin for percentage change in T1 time was set to 3%. Region-wise differences were assessed by pairwise comparison using t-tests and forest plots, and statistical significance was accepted at .05 level (two-tailed). Results In a cohort of 76 participants (mean age 47.2 years ± 17.9 [standard deviation], 47 women), T1 relaxation times remained unchanged in cerebral cortex and basal ganglia 4 weeks after intrathecal gadobutrol. T1 was reduced from 1082 ± 46.7 ms to 1070.6 ± 36.5 ms (0.98 ±2.9%) (mean [standard deviation]) (p=0.001) in white matter, thus within the pre- defined 3% safety margin. The brain stem and cerebellum could not be assessed due to poor alignment of posterior fossa structures at scans from different time points. Conclusion Gadolinium retention was not detected in the cerebral hemispheres 4 weeks after an intrathecal dose of 0.5 mmol gadobutrol, implying that presence of contrast agents in cerebrospinal fluid is of minor importance for gadolinium retention in brain.

• Eide, Per Kristian; Lashkarivand, Aslan; Hagen-Kersten, Åsmund Aleksander; Gjertsen, Øivind; Nedregaard, Bård & Sletteberg, Ruth [Show all 11 contributors for this article] (2022). Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus. Frontiers in Neurology. 13, p. 1–21. doi: 10.3389/fneur.2022.857328. Full text in Research Archive Show summary

  Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.

• Hornkjøl, Martin; Valnes, Lars Magnus; Ringstad, Geir; Rognes, Marie Elisabeth; Eide, Per Kristian & Mardal, Kent-Andre [Show all 7 contributors for this article] (2022). CSF circulation and dispersion yield rapid clearance from intracranial compartments. Frontiers in Bioengineering and Biotechnology. 10, p. 1–14. doi: 10.3389/fbioe.2022.932469. Full text in Research Archive Show summary

  In this paper, we used a computational model to estimate the clearance of a tracer driven by the circulation of cerebrospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate, and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the choroid plexus in line with observations on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the subarachnoid space yields rapid clearance from both the SAS and the brain interstitial fluid and can speed up intracranial clearance from years, as would be the case for purely diffusive transport, to days.

• Zapf, Bastian; Haubner, Johannes; Kuchta, Miroslav; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2022). Investigating molecular transport in the human brain from MRI with physics-informed neural networks. Scientific Reports. 12. doi: 10.1038/s41598-022-19157-w. Full text in Research Archive Show summary

  In recent years, a plethora of methods combining neural networks and partial differential equations have been developed. A widely known example are physics-informed neural networks, which solve problems involving partial differential equations by training a neural network. We apply physics-informed neural networks and the finite element method to estimate the diffusion coefficient governing the long term spread of molecules in the human brain from magnetic resonance images. Synthetic testcases are created to demonstrate that the standard formulation of the physics-informed neural network faces challenges with noisy measurements in our application. Our numerical results demonstrate that the residual of the partial differential equation after training needs to be small for accurate parameter recovery. To achieve this, we tune the weights and the norms used in the loss function and use residual based adaptive refinement of training points. We find that the diffusion coefficient estimated from magnetic resonance images with physics-informed neural networks becomes consistent with results from a finite element based approach when the residuum after training becomes small. The observations presented here are an important first step towards solving inverse problems on cohorts of patients in a semi-automated fashion with physics-informed neural networks.

• Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege & Ringstad, Geir [Show all 7 contributors for this article] (2022). Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders. Fluids and Barriers of the CNS. 19(1). doi: 10.1186/s12987-022-00352-w. Full text in Research Archive Show summary

  Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. Methods Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. Results Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. Conclusions The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.

• Eide, Per Kristian; Pripp, Are Hugo; Berge, Benedikte; Hrubos-Strøm, Harald; Ringstad, Geir & Valnes, Lars Magnus (2022). Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 42(9), p. 1676–1692. doi: 10.1177/0271678X221090747. Full text in Research Archive Show summary

  Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.

• Eide, Per Kristian; Pripp, Are Hugo; Ringstad, Geir & Valnes, Lars Magnus (2021). Impaired glymphatic function in idiopathic intracranial hypertension. Brain Communications. 3:fcab043(2), p. 1–14. doi: 10.1093/braincomms/fcab043. Full text in Research Archive Show summary

  Idiopathic intracranial hypertension is a brain disease incorporating cerebrospinal fluid disturbance, increased intracranial pressure and visual failure, but with unknown cause. This study examined a hypothesis that glymphatic function is impaired in idiopathic intracranial hypertension patients. The MRI contrast agent gadobutrol was utilized as a cerebrospinal fluid tracer following intrathecal administration. Consecutive standardized T1 MRI acquisitions over 48 h were done to assess tracer distribution within brain of 15 idiopathic intracranial hypertension patients and 15 reference individuals who were comparable in age and gender distribution. Using FreeSurfer software, we semi-quantified tracer level in multiple brain regions as T1 MRI signal change. The tracer enriched the entire brain of idiopathic intracranial hypertension and reference subjects. In idiopathic intracranial hypertension, tracer enrichment was increased and clearance of tracer delayed from a wide range of brain regions, including both grey and white matter. Differences were most evident in frontal and temporal regions. The pulsatile intracranial pressure was measured overnight and tracer propagation in brain compared between individuals with pathological and normal pulsatile intracranial pressure. In individuals with pathological pulsatile intracranial pressure, tracer enrichment was stronger and clearance from brain delayed, particularly in regions nearby large artery trunks at the brain surface. The present in vivo observations provide evidence for impaired glymphatic function in several brain regions of idiopathic intracranial hypertension patients. Glymphatic failure may imply altered clearance of metabolic byproducts, which may precede neurodegeneration. Further studies are needed to characterize glymphatic failure in idiopathic intracranial hypertension.

• Eide, Per Kristian & Ringstad, Geir (2021). Cerebrospinal fluid egress to human parasagittal dura and the impact of sleep deprivation. Brain Research. ISSN 0006-8993. 1772. doi: 10.1016/j.brainres.2021.147669. Full text in Research Archive Show summary

  Emerging evidence suggests that the glymphatic system and meningeal lymphatic vessels are instrumental for clearance of toxic metabolites from the brain. Animal and human studies suggest that glymphatic circulation is up-regulated during sleep. Meningeal lymphatic clearance may be more efficient in the wake state, as shown in rodents. We have previously shown clearance of cerebrospinal fluid directly from the subarachnoid space to the parasagittal dura, which harbors meningeal lymphatic vessels. Hence, assessing molecular clearance from parasagittal dura provides an opportunity to decipher the role of sleep/sleep deprivation in human lymphatic clearance function. In this study, we applied magnetic resonance imaging to explore whether sleep deprivation modifies molecular clearance from human parasagittal dura, utilizing an intrathecal magnetic resonance imaging contrast agent as tracer. We hypothesized that tracer enhancement in parasagittal dura would differ after sleep deprivation. One group of individuals (n = 7) underwent one night’s total sleep deprivation while a control group (n = 9) was allowed unrestricted sleep. There were no sleep restrictions after the 24-hour time point. After one night of sleep deprivation (at 24 h), we found neither evidence for altered tracer enrichment in the parasagittal dura, nor after a day of unrestricted sleep (at 48 h). The hypothesis of altered molecular egress to parasagittal dura after sleep deprivation was not supported by our data. Further studies are required to determine the role of sleep for molecular clearance from cerebrospinal fluid to meningeal lymphatic vessels in humans.

• Bjørke, Agnes Balint; Østby, Ylva; Grahl, Simon Gevert; Larsson, Pål Gunnar; Olsen, Ketil Berg & Nævra, Marianne C. Johansen [Show all 11 contributors for this article] (2021). Cognition in adult patients with newly diagnosed non-lesional temporal lobe epilepsy. Epilepsy & Behavior. ISSN 1525-5050. 116. doi: 10.1016/j.yebeh.2021.107771. Full text in Research Archive Show summary

  Objective To evaluate whether cognitive performance is affected in newly diagnosed temporal lobe epilepsy (TLE) and to determine the most vulnerable cognitive domains. Methods In this baseline longitudinal study, differences in memory and non-memory cognitive functions were assessed using comprehensive neuropsychological test batteries in 21 adult patients with newly diagnosed non-lesional TLE and individually matched controls. In addition, the analyses included ratings of self-perceived emotional status. Results The patients performed more poorly than the control group regarding delayed visual memory (p = 0.013) and executive function tasks related to switching (Trail Making Test and verbal fluency shifting; p = 0.025 and p = 0.03, respectively). We found no differences in verbal learning and memory, attention/working memory/processing speed, and other executive functions. Significance Our results show that patients with TLE often have specific cognitive deficits at time of diagnosis, even in the absence of structural brain abnormalities. This supports the hypothesis that memory dysfunction is linked to an underlying pathology rather than to the effect of recurrent seizures, long-term use of anti-seizure medication, or other epilepsy-related factors. As certain executive functions are affected at an early stage, the pathology may involve brain regions beyond the temporal lobe and may comprise larger brain networks. These results indicate the need for greater awareness of cognition at the time of diagnosis of TLE and before initiation of treatment, and integration of neuropsychological assessment into early routine clinical care.

• Eide, Per Kristian; Mariussen, Espen; Uggerud, Hilde Thelle; Pripp, Are Hugo; Lashkarivand, Aslan & Hassel, Bjørnar [Show all 9 contributors for this article] (2021). Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood. JCI Insight. 6(9), p. 1–13. doi: 10.1172/jci.insight.147063. Full text in Research Archive Show summary

  BACKGROUND. Methodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances. METHODS. The MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours. RESULTS. In a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4). CONCLUSION. Assessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity. FUNDING. The work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

• Eide, Per Kristian; Vinje, Vegard; Pripp, Are Hugo; Mardal, Kent-Andre & Ringstad, Geir (2021). Sleep deprivation impairs molecular clearance from the human brain. Brain. ISSN 0006-8950. 144(3), p. 863–874. doi: 10.1093/brain/awaa443. Full text in Research Archive
• Eide, Per Kristian; Valnes, Lars Magnus; Lindstrøm, Erika Kristina; Mardal, Kent-Andre & Ringstad, Geir (2021). Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases. Fluids and Barriers of the CNS. 18(1). doi: 10.1186/s12987-021-00251-6. Full text in Research Archive Show summary

  Background Several central nervous system diseases are associated with disturbed cerebrospinal fluid (CSF) flow patterns and have typically been characterized in vivo by phase-contrast magnetic resonance imaging (MRI). This technique is, however, limited by its applicability in space and time. Phase-contrast MRI has yet to be compared directly with CSF tracer enhanced imaging, which can be considered gold standard for assessing long-term CSF flow dynamics within the intracranial compartment. Methods Here, we studied patients with various CSF disorders and compared MRI biomarkers of CSF space anatomy and phase-contrast MRI at level of the aqueduct and cranio-cervical junction with dynamic intrathecal contrast-enhanced MRI using the contrast agent gadobutrol as CSF tracer. Tracer enrichment of cerebral ventricles was graded 0–4 by visual assessment. An intracranial pressure (ICP) score was used as surrogate marker of intracranial compliance. Results The study included 94 patients and disclosed marked variation of CSF flow measures across disease categories. The grade of supra-aqueductal reflux of tracer varied, with strong reflux (grades 3–4) in half of patients. Ventricular tracer reflux correlated with stroke volume and aqueductal CSF pressure gradient. CSF flow in the cerebral aqueduct was retrograde (from 4th to 3rd ventricle) in one third of patients, with estimated CSF net flow volume about 1.0 L/24 h. In the cranio-cervical junction, net flow was cranially directed in 78% patients, with estimated CSF net flow volume about 4.7 L/24 h. Conclusions The present observations provide in vivo quantitative evidence for substantial variation in direction and magnitude of CSF flow, with re-direction of aqueductal flow in communicating hydrocephalus, and significant extra-cranial CSF production. The grading of ventricular reflux of tracer shows promise as a clinical useful method to assess CSF flow pattern disturbances in patients.

• Ringstad, Geir & Eide, Per Kristian (2021). Molecular trans-dural efflux to skull bone marrow in humans with CSF disorders. Brain. ISSN 0006-8950. 145(4), p. 1464–1472. doi: 10.1093/brain/awab388. Full text in Research Archive Show summary

  Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through CSF. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We used MRI and a CSF tracer to investigate in vivo whether intracranial molecules can move via dura to skull bone marrow in patients with suspicion of CSF disorders. Tracer enrichment in CSF, dural regions and within skull bone marrow was assessed up to 48 h after intrathecal administration of gadobutrol (0.5 ml, 1 mmol/ml) in 53 patients. In participants diagnosed with disease, tracer enrichment within diploe of skull bone marrow was demonstrated nearby the parasagittal dura, nearby extensions of parasagittal dura into diploe, and in diploe of skull bone remote from the dura extensions. This crossing of meningeal and skull barriers suggests that bone marrow may contribute in brain immune surveillance also in humans.

• Eide, Per Kristian; Pripp, Are Hugo & Ringstad, Geir (2020). Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamicsâin idiopathic normal pressure hydrocephalus. Brain Communications. 2(2). doi: 10.1093/braincomms/fcaa187. Full text in Research Archive Show summary

  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.

• Melin, Erik; Eide, Per Kristian & Ringstad, Geir (2020). In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans. Scientific Reports. 10(1). doi: 10.1038/s41598-020-72031-5. Full text in Research Archive Show summary

  Extra-vascular molecular clearance routes from the brain and cerebrospinal fluid (CSF) remain insufficiently characterized in humans. Animal studies consistently suggest that the cribriform plate and nasal lymphatic vessels are crucial for molecular clearance from CSF. In this study, we aimed to examine human in vivo transport of a CSF tracer from CSF to nasal mucosa. We hypothesised a CSF tracer would enrich in nasal mucosa provided that nasal lymphatic drainage has a significant role in CSF molecular clearance. Consecutive magnetic resonance imaging during 48 h after intrathecal administration of a tracer (gadobutrol) was performed in 24 patients. Despite a strong enrichment of CSF tracer in CSF spaces nearby the cribriform plate, there was no significant enrichment of CSF tracer in nasal mucosa, as measured in superior, medial and inferior turbinates, or in the nasal septum. Therefore, this in vivo study questions the importance of CSF drainage to the human nasal mucosa and emphasizes the need of further human studies.

• Halvorsen, Merete; Edeklev, Camilla; Fraser-Green, Jorunn; Løvland, Grethe; Vatnehol, Svein Are Sirirud & Gjertsen, Øivind [Show all 10 contributors for this article] (2020). Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols. Neuroradiology. ISSN 0028-3940. 63(1), p. 51–61. doi: 10.1007/s00234-020-02519-4. Full text in Research Archive Show summary

  Purpose Magnetic resonance imaging (MRI) contrast agents have been used off-label for diagnosis of cerebrospinal fluid (CSF) leaks and lately also for assessment of the glymphatic system and meningeal lymphatic drainage. The purpose of this study was to further evaluate the short- and long-term safety profile of intrathecal MRI contrast agents. Methods In this prospective study, we compared the safety profile of different administration protocols of intrathecal gadobutrol (GadovistTM; 1.0 mmol/ml). Gadobutrol was administered intrathecal in a dose of 0.5 mmol, with or without iodixanol (VisipaqueTM 270 mg I/ml; 3 ml). In addition, a subgroup was given intrathecal gadobutrol in a dose of 0.25 mmol. Adverse events were assessed at 1 to 3 days, 4 weeks, and after 12 months. Results Among the 149 patients, no serious adverse events were seen in patients without history of prior adverse events. The combination of gadobutrol with iodixanol did not increase the occurrence of non-serious adverse events after days 1–3. Intrathecal gadobutrol in a dose of 0.25 mmol caused less severity of nausea, as compared with the dose of 0.5 mmol. The clinical diagnosis was the major determinant for occurrence of non-serious adverse events after intrathecal gadobutrol. Conclusion This prospective study showed that intrathecal administration of gadobutrol in a dose of 0.5 mmol is safe. Non-serious adverse events were to a lesser degree affected by the administration protocols, though preliminary data are given that side effects of intrathecal gadobutrol are dose-dependent.

• Ringstad, Geir & Eide, Per Kristian (2020). Glymfatisk MR. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(1), p. 1–2. doi: 10.4045/tidsskr.19.0651. Full text in Research Archive
• Kolnes, Anders Jensen; Øystese, Kristin Astrid; Olarescu, Nicoleta Cristina; Ringstad, Geir Andre; Berg-Johnsen, Jon & Casar-Borota, Olivera [Show all 8 contributors for this article] (2020). FSH Levels Are Related to E-cadherin Expression and Subcellular Location in Nonfunctioning Pituitary Tumors. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 105(8), p. 1–8. doi: 10.1210/clinem/dgaa281. Full text in Research Archive Show summary

  Abstract Context Gonadotroph pituitary neuroendocrine tumors (PitNETs) can express follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or be hormone negative, but they rarely secrete hormones. During tumor development, epithelial cells develop a mesenchymal phenotype. This process is characterized by decreased membranous E-cadherin and translocation of E-cadherin to the nucleus. Estrogen receptors (ERs) regulate both E-cadherin and FSH expression and secretion. Whether the hormone status of patients with gonadotroph PitNETs is regulated by epithelial-to-mesenchymal transition (EMT) and ERs is unknown. Objectives To study the effect of EMT on hormone expression in gonadotroph nonfunctioning (NF)-PitNETs. Design Molecular and clinical analyses of 105 gonadotroph PitNETs. Immunohistochemical studies and real-time quantitative polymerase chain reaction were performed for FSH, LH, E-cadherin, and ERα. Further analyses included blood samples, clinical data, and radiological images. Setting All patients were operated on in the same tertiary referral center. Results NF-PitNET with high FSH expression had decreased immunohistochemical staining for membranous E-cadherin (P &amp;lt; .0001) and increased staining for nuclear E-cadherin (P &amp;lt; .0001). Furthermore, high FSH expression was associated with increased ERα staining (P = .0002) and ERα mRNA (P = .0039). Circulating levels of plasma-FSH (P-FSH) correlated with FSH staining in gonadotroph NF-PitNET (P = .0025). Tumor size and invasiveness was not related to FSH staining, E-cadherin, or ERα. LH expression was not associated with E-cadherin or ERα. Conclusion In gonadotroph PitNETs, FSH staining is related to E-cadherin, ERα expression, and circulating levels of P-FSH. There was no association between FSH staining and invasiveness. The clinical significance of these findings will be investigated in ongoing prospective studies.

• Ringstad, Geir & Eide, Per Kristian (2020). Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nature Communications. 11(1). doi: 10.1038/s41467-019-14195-x. Full text in Research Archive Show summary

  The mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study utilized magnetic resonance imaging along with cerebrospinal fluid tracer to visualize clearance pathways to human dural lymphatics in vivo. In 18 subjects with suspicion of various types of cerebrospinal fluid disorders, 3D T2-Fluid Attenuated Inversion Recovery, T1-black-blood, and T1 gradient echo acquisitions were obtained prior to intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as a cerebrospinal fluid tracer. Propagation of tracer was followed with T1 sequences at 3, 6, 24 and 48 h after the injection. The tracer escaped from cerebrospinal fluid into parasagittal dura along the superior sagittal sinus at areas nearby entry of cortical cerebral veins. The findings demonstrate that trans-arachnoid molecular passage does occur and suggest that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.

• Jacobsen, Henrik Holvin; Sandell, Tiril; Jørstad, Øystein Kalsnes; Moe, Morten Carsten; Ringstad, Geir & Eide, Per Kristian (2020). In vivo evidence for impaired glymphatic function in the visual pathway of patients with normal pressure hydrocephalus. Investigative Ophthalmology and Visual Science. ISSN 0146-0404. 61:24(13), p. 1–11. doi: 10.1167/IOVS.61.13.24. Full text in Research Archive Show summary

  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.

• Valnes, Lars Magnus; Mitusch, Sebastian; Ringstad, Geir; Eide, Per Kristian; Funke, Simon Wolfgang & Mardal, Kent-Andre (2020). Apparent diffusion coefficient estimates based on 24 hours tracer movement support glymphatic transport in human cerebral cortex. Scientific Reports. 10(1). doi: 10.1038/s41598-020-66042-5. Full text in Research Archive Show summary

  The recently proposed glymphatic system suggests that bulk flow is important for clearing waste from the brain, and as such may underlie the development of e.g. Alzheimer’s disease. The glymphatic hypothesis is still controversial and several biomechanical modeling studies at the micro-level have questioned the system and its assumptions. In contrast, at the macro-level, there are many experimental findings in support of bulk flow. Here, we will investigate to what extent the CSF tracer distributions seen in novel magnetic resonance imaging (MRI) investigations over hours and days are suggestive of bulk flow as an additional component to diffusion. In order to include the complex geometry of the brain, the heterogeneous CSF flow around the brain, and the transport over the time-scale of days, we employed the methods of partial differential constrained optimization to identify the apparent diffusion coefficient (ADC) that would correspond best to the MRI findings. We found that the computed ADC in the cortical grey matter was 5–26% larger than the ADC estimated with DTI, which suggests that diffusion may not be the only mechanism governing transport.

• Lindstrøm, Erika; Ringstad, Geir; Sorteberg, Angelika; Sorteberg, Wilhelm; Mardal, Kent-Andre & Eide, Per (2019). Magnitude and direction of aqueductal cerebrospinal fluid flow: large variations in patients with intracranial aneurysms with or without a previous subarachnoid hemorrhage. Acta Neurochirurgica. ISSN 0001-6268. 161. Full text in Research Archive
• Lashkarivand, Aslan; Ringstad, Geir & Eide, Per Kristian (2019). Surgery for Brainstem Cavernous Malformations: Association between Preoperative Grade and Postoperative Quality of Life. Operative Neurosurgery. ISSN 2332-4252. 18(6), p. 590–598. doi: 10.1093/ons/opz337. Full text in Research Archive
• Edeklev, Camilla; Halvorsen, Merete; Løvland, Grethe; Vatnehol, Svein Are Sirirud; Gjertsen, Øivind & Nedregaard, Bård [Show all 9 contributors for this article] (2019). Intrathecal use of gadobutrol for glymphatic MR imaging: Prospective safety study of 100 patients. American Journal of Neuroradiology. ISSN 0195-6108. 40(8), p. 1257–1264. doi: 10.3174/ajnr.A6136. Full text in Research Archive
• Frič, Radek; Ringstad, Geir & Eide, Per Kristian (2019). Chiari-malformasjon type 1 – diagnostikk og behandling. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(10), p. 1–8. doi: 10.4045/tidsskr.18.0455. Full text in Research Archive
• Jacobsen, Henrik Holvin; Ringstad, Geir; Jørstad, Øystein Kalsnes; Moe, Morten Carsten; Sandell, Tiril & Eide, Per Kristian (2019). The Human Visual Pathway Communicates Directly With the Subarachnoid Space. Investigative Ophthalmology and Visual Science. ISSN 0146-0404. 60(7), p. 2773–2780. doi: 10.1167/iovs.19-26997. Full text in Research Archive Show summary

  Purpose: Explore in vivo whether there is direct communication between the cerebrospinal fluid (CSF) and extravascular compartment of human visual pathway structures. Methods: A prospective and observational study included 10 subjects who underwent intrathecal gadolinium–enhanced magnetic resonance imaging (MRI) for suspected CSF circulation disorder, but with a negative result and with no known ophthalmic diseases. After precontrast T1-weighted MRI, 0.5 mL of gadobutrol (Gadovist, 1.0 mmol/mL) was injected intrathecally. Gadobutrol distributes in the extravascular space, and served as a CSF tracer. Consecutive MRI scans were obtained throughout 24 to 48 hours. To assess gadobutrol contrast enrichment, regions of interest (ROIs) were placed at multiple locations along the visual pathway, from the primary visual cortex to the eye's vitreous body. CSF tracer dependent T1 signal was measured in each ROI. A linear mixed-model was used for statistical analyses. Results: CSF tracer enrichment was found within the optic nerve, optic chiasm, optic tract, and primary visual cortex (P < 0.001). Peak tracer enrichment in the visual pathway generally occurred after 24 hours and was preceded by peak enhancement in the prechiasmatic cistern after 4 to 6 hours. Conclusions: The results indicate direct communication between CSF of subarachnoid space and the extravascular space of the human visual pathway. Extravascular entry of the CSF tracer is a prerequisite for a glymphatic system, the present findings may suggest its presence. The existence of a glymphatic system in the human visual pathway could bring novel perspectives on the pathophysiology and treatment of ophthalmic diseases.

• Øystese, Kristin Astrid Berland; Hisanawi, Sheren; Zucknick, Manuela; Bollerslev, Jens & Ringstad, Geir (2019). Are volume measurements of non-functioning pituitary adenomas reliable? Endocrine. ISSN 1355-008X. 63(1), p. 171–176. doi: 10.1007/s12020-018-1752-8. Full text in Research Archive
• Eide, Per Kristian; Valnes, Lars Magnus; Pripp, Are Hugo; Mardal, Kent-Andre & Ringstad, Geir (2019). Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 40(9), p. 1849–1858. doi: 10.1177/0271678X19874790. Full text in Research Archive
• Vinje, Vegard; Ringstad, Geir; Lindstrøm, Erika Kristina; Valnes, Lars Magnus; Rognes, Marie Elisabeth & Eide, Per Kristian [Show all 7 contributors for this article] (2019). Respiratory influence on cerebrospinal fluid flow – a computational study based on long-term intracranial pressure measurements. Scientific Reports. 9, p. 1–13. doi: 10.1038/s41598-019-46055-5. Full text in Research Archive Show summary

  Current theories suggest that waste solutes are cleared from the brain via cerebrospinal fluid (CSF) flow, driven by pressure pulsations of possibly both cardiac and respiratory origin. In this study, we explored the importance of respiratory versus cardiac pressure gradients for CSF flow within one of the main conduits of the brain, the cerebral aqueduct. We obtained overnight intracranial pressure measurements from two different locations in 10 idiopathic normal pressure hydrocephalus (iNPH) patients. The resulting pressure gradients were analyzed with respect to cardiac and respiratory frequencies and amplitudes (182,000 cardiac and 48,000 respiratory cycles). Pressure gradients were used to compute CSF flow in simplified and patient-specific models of the aqueduct. The average ratio between cardiac over respiratory flow volume was 0.21 ± 0.09, even though the corresponding ratio between the pressure gradient amplitudes was 2.85 ± 1.06. The cardiac cycle was 0.25 ± 0.04 times the length of the respiratory cycle, allowing the respiratory pressure gradient to build considerable momentum despite its small magnitude. No significant differences in pressure gradient pulsations were found in the sleeping versus awake state. Pressure gradients underlying CSF flow in the cerebral aqueduct are dominated by cardiac pulsations, but induce CSF flow volumes dominated by respiration.

• Eide, Per; Sorteberg, Angelika; Sorteberg, Wilhelm; Lindstrøm, Erika; Mardal, Kent-Andre & Ringstad, Geir (2018). “Bucket” cerebrospinal fluid bulk flow: when the terrain disagrees with the map. Acta Neurochirurgica. ISSN 0001-6268. 161(2). doi: 10.1007/s00701-018-3775-6. Full text in Research Archive
• Eide, Per Kristian; Vatnehol, Svein Are Sirirud; Emblem, Kyrre Eeg & Ringstad, Geir (2018). Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Scientific Reports. 8(1). doi: 10.1038/s41598-018-25666-4. Full text in Research Archive Show summary

  Pre-clinical research in rodents provides evidence that the central nervous system (CNS) has functional lymphatic vessels. In-vivo observations in humans, however, are not demonstrated. We here show data on CNS lymphatic drainage to cervical lymph nodes in-vivo by magnetic resonance imaging (MRI) enhanced with an intrathecal contrast agent as a cerebrospinal fluid (CSF) tracer. Standardized MRI of the intracranial compartment and the neck were acquired before and up to 24–48 hours following intrathecal contrast agent administration in 19 individuals. Contrast enhancement was radiologically confirmed by signal changes in CSF nearby inferior frontal gyrus, brain parenchyma of inferior frontal gyrus, parahippocampal gyrus, thalamus and pons, and parenchyma of cervical lymph node, and with sagittal sinus and neck muscle serving as reference tissue for cranial and neck MRI acquisitions, respectively. Time series of changes in signal intensity shows that contrast enhancement within CSF precedes glymphatic enhancement and peaks at 4–6 hours following intrathecal injection. Cervical lymph node enhancement coincides in time with peak glymphatic enhancement, with peak after 24 hours. Our findings provide in-vivo evidence of CSF tracer drainage to cervical lymph nodes in humans. The time course of lymph node enhancement coincided with brain glymphatic enhancement rather than with CSF enhancement.

• Lindstrøm, Erika Kristina; Ringstad, Geir; Sorteberg, Angelika; Sorteberg, Wilhelm; Mardal, Kent-Andre & Eide, Per Kristian (2018). Magnitude and direction of aqueductal cerebrospinal fluid flow: large variations in patients with intracranial aneurysms with or without a previous subarachnoid hemorrhage. Acta Neurochirurgica. ISSN 0001-6268. 161(2), p. 247–256. doi: 10.1007/s00701-018-3730-6. Full text in Research Archive Show summary

  Background Net cerebrospinal fluid (CSF) flow within the cerebral aqueduct is usually considered to be antegrade, i.e., from the third to the fourth ventricle with volumes ranging between 500 and 600 ml over 24 h. Knowledge of individual CSF flow dynamics, however, is hitherto scarcely investigated. In order to explore individual CSF flow rate and direction, we assessed net aqueductal CSF flow in individuals with intracranial aneurysms with or without a previous subarachnoid hemorrhage (SAH). Methods A prospective observational study was performed utilizing phase-contrast magnetic resonance imaging (PCMRI) to determine the magnitude and direction of aqueductal CSF flow with an in-depth, pixel-by-pixel approach. Estimation of net flow was used to calculate CSF flow volumes over 24 h. PC-MRI provides positive values when flow is retrograde. Results The study included eight patients with intracranial aneurysms. Four were examined within days after their SAH; three were studied in the chronic stage after SAH while one patient had an unruptured intracranial aneurysm. There was a vast variation in magnitude and direction of aqueductal CSF flow between individuals. Net aqueductal CSF flow was retrograde, i.e., directed towards the third ventricle in 5/8 individuals. For the entire patient cohort, the estimated net aqueductal CSF volumetric flow rate (independent of direction) was median 898 ml/24 h (ranges 69 ml/24 h to 12.9 l/ 24 h). One of the two individuals who had a very high estimated net aqueductal CSF volumetric flow rate, 8.7 l/24 h retrograde, later needed a permanent CSF shunt. Conclusions The magnitude and direction of net aqueductal CSF flow vary extensively in patients with intracranial aneurysms. Following SAH, PC-MRI may offer the possibility to perform individualized assessments of the CSF circulation.

• Ringstad, Geir; Valnes, Lars Magnus; Dale, Anders; Pripp, Are Hugo; Vatnehol, Svein Are Sirirud & Emblem, Kyrre Eeg [Show all 8 contributors for this article] (2018). Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. Journal of Clinical Investigation. ISSN 0021-9738. 3(13), p. 1–16. doi: 10.1172/jci.insight.121537. Full text in Research Archive Show summary

  To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

• Eide, Per Kristian & Ringstad, Geir (2018). Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 39(7), p. 1355–1368. doi: 10.1177/0271678X18760974. Full text in Research Archive
• Lindstrøm, Erika Kristina; Ringstad, Geir; Mardal, Kent-Andre & Eide, Per Kristian (2018). Cerebrospinal fluid volumetric net flow rate and direction in idiopathic normal pressure hydrocephalus. NeuroImage: Clinical. 20, p. 731–741. doi: 10.1016/j.nicl.2018.09.006. Full text in Research Archive Show summary

  The aim of the present study was to examine cerebrospinal fluid (CSF) volumetric net flow rate and direction at the cranio-cervical junction (CCJ) and cerebral aqueduct in individuals with idiopathic normal pressure hydrocephalus (iNPH) using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI). An in-depth, pixel-by-pixel analysis of regions of interest from the CCJ and cerebral aqueduct, respectively, was done in 26 iNPH individuals, and in 4 healthy subjects for validation purposes. Results from patients were compared with over-night measurements of static and pulsatile intracranial pressure (ICP). In iNPH, CSF net flow at CCJ was cranially directed in 17/22 as well as in 4/4 healthy subjects. Estimated daily CSF volumetric net flow rate at CCJ was 6.9 ± 9.9 L/24 h in iNPH patients and 4.5 ± 5.0 L/24 h in healthy individuals. Within the cerebral aqueduct, the CSF net flow was antegrade in 7/21 iNPH patients and in 4/4 healthy subjects, while it was retrograde (i.e. towards ventricles) in 14/21 iNPH patients. Estimated daily CSF volumetric net flow rate in cerebral aqueduct was 1.1 ± 2.2 L/24 h in iNPH while 295 ± 53 mL/24 h in healthy individuals. Magnitude of cranially directed CSF net flow in cerebral aqueduct was highest in iNPH individuals with signs of impaired intracranial compliance. The study results indicate CSF flow volumes and direction that are profoundly different from previously assumed. We hypothesize that spinal CSF formation may serve to buffer increased demand for CSF flow through the glymphatic system during sleep and during deep inspiration to compensate for venous outflow.

• Lindstrøm, Erika Kristina; Schreiner, Jakob Emil; Ringstad, Geir; Haughton, Victor; Eide, Per Kristian & Mardal, Kent-Andre (2018). Comparison of phase-contrast MR and flow simulations for the study of CSF Dynamics in the cervical spine. The Neuroradiology Journal (NRJ). ISSN 1971-4009. 31(3), p. 292–298. doi: 10.1177/1971400918759812. Full text in Research Archive
• Rosa-Carrillo, Daniel de la; Vindenes, Harald Bjarte; Kinsler, Veronica A; Rønnestad, Arild Erlend; Ringstad, Geir & Müller, Lil-Sofie Ording [Show all 10 contributors for this article] (2018). Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple, NRAS and BRAF mutation-negative nodules. Pediatric dermatology. ISSN 0736-8046. 35(5), p. e281–e285. doi: 10.1111/pde.13595. Full text in Research Archive Show summary

  We report the case of a newborn boy with multinodular NRAS- and BRAF-mutation negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a high number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died five months old. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus, or a congenital melanoma.

• Brix, Maiken K.; Westman, Eric; Simmons, Andrew; Ringstad, Geir; Eide, Per Kristian & Wagner-Larsen, Kari [Show all 9 contributors for this article] (2017). The Evans’ Index revisited: New cut-off levels for use in radiological assessment of ventricular enlargement in the elderly. European Journal of Radiology. ISSN 0720-048X. 95, p. 32–32. doi: 10.1016/j.ejrad.2017.07.013. Full text in Research Archive
• Gadde, Judith A; Shah, Vinil; Liebo, Greta B; Ringstad, Geir; Pomeraniec, I Jonathan & Bakke, Søren Jacob [Show all 11 contributors for this article] (2017). Anatomical features of the cervical spinal canal in Chiari I deformity with presyrinx: A case-control study. The Neuroradiology Journal (NRJ). ISSN 1971-4009. 30(5), p. 405–409. doi: 10.1177/1971400917718842. Full text in Research Archive
• Jain, Kartik; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2017). Direct numerical simulation of transitional hydrodynamcis of the cerebrospinal fluid in Chiari I malformation: The role of cranio-vertebral junction. International Journal for Numerical Methods in Biomedical Engineering. ISSN 2040-7939. 33(9), p. 1–15. doi: 10.1002/cnm.2853. Full text in Research Archive Show summary

  Obstruction to the cerebrospinal fluid (CSF) outflow caused by the herniation of cerebellar tonsils as a result of Chiari malformation type I leads to altered CSF hydrodynamics. This contribution explores the minutest characteristics of the CSF hydrodynamics in cervical subarachnoid space (SAS) of a healthy subject and 2 Chiari patients by performing highly resolved direct numerical simulation. The lattice Boltzmann method is used for the simulations because of its scalability on modern supercomputers that allow us to simulate up to approximately 109 cells while resolving the Kolmogorov microscales. The results depict that whereas the complex CSF flow remains largely laminar in the SAS of a healthy subject, constriction of the cranio-vertebral junction in Chiari I patients causes manifold fluctuations in the hydrodynamics of the CSF. These fluctuations resemble a flow that is in a transitional regime rather than laminar or fully developed turbulence. The fluctuations confine near the cranio-vertebral junction and are triggered due to the tonsillar herniation, which perturbs the flow as a result of altered anatomy of the SAS.

• Øystese, Kristin Astrid Berland; Zucknick, Manuela; Casar-Borota, Olivera; Ringstad, Geir & Bollerslev, Jens (2017). Early postoperative growth in non-functioning pituitary adenomas; A tool to tailor safe follow-up. Endocrine. ISSN 1355-008X. 57(1), p. 35–45. doi: 10.1007/s12020-017-1314-5. Full text in Research Archive
• Ringstad, Geir; Vatnehol, Svein Are Sirirud & Eide, Per Kristian (2017). Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. ISSN 0006-8950. 140(10), p. 2691–2705. doi: 10.1093/brain/awx191. Full text in Research Archive Show summary

  The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.

• Brix, Maiken Kirkegaard; Westman, Eric; Simmons, Andrew; Ringstad, Geir; Eide, Per Kristian & Wagner-Larsen, Kari Strøno [Show all 9 contributors for this article] (2017). The Evans' Index revisited: New cut-off levels for use in radiological assessment of ventricular enlargement in the elderly. European Journal of Radiology. ISSN 0720-048X. 95, p. 28–32. doi: 10.1016/j.ejrad.2017.07.013. Full text in Research Archive

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• Ringstad, Geir (2023). The Glymphatic System. Springer Nature. ISBN 9783319614236. 14 p. Full text in Research Archive
• Eide, Per Kristian & Ringstad, Geir (2018). Cerebrospinal Fluid Flow and Glymphatic Function in Idiopathic Normal Pressure Hydrocephalus (book chapter) p.71-84 in: Cerebrospinal Fluid Disorders - Lifelong Implications (Springer Nature, 2018). Springer Nature. ISBN 9783319979281. 14 p. Full text in Research Archive

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• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Acar, Evrim & Mardal, Kent-Andre (2026). Data-driven insights from glymphatic MRI​. Full text in Research Archive
• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Nordengen, Kaja & Mardal, Kent-Andre (2026). Image registration as a tool for modeling and analysis of brain solute transport​. Full text in Research Archive
• Hernes, Susanne Miriam Sørensen; Nordnes, Per Raymond; Hol, Haakon Ramsland; Ringstad, Geir Andre; Knapskog, Anne-Brita & Emhjellen, Petter Espeseth [Show all 9 contributors for this article] (2026). The REACT MCI study: a randomized controlled clinical trial on the effect of repeated advanced cognitive training in mild cognitive impairment. doi: 10.1186/s13063-026-09711-6. Full text in Research Archive Show summary

  Background Mild cognitive impairment (MCI) and its course have multiple determining factors with both detrimental and compensatory processes in the brain. Computerized working memory training can improve cognitive function and individuals with MCI are potential targets. Since more than 1/3 of these individuals develop dementia within 5 years, any intervention postponing the progression will be immensely important. We aim to investigate the efficiency and cost-effectiveness of working memory training in MCI. Methods In this blinded randomized controlled trial, 213 participants will be allocated to three groups: (1) one 5-week period of working memory training, (2) two 5-week periods of working memory training, or (3) the active control group. The participants are followed for a period of 48 months (3, 6, 12, 24, and 48 months). Furthermore, we investigate microstructural effects of working memory training on magnetic resonance imaging and seek to identify high responders to training by assessing the association with function in the glymphatic system and genetic variations. Finally, the impact of working memory training on quality of life and relatives’ stress, and whether it is a cost-effective approach in MCI, will be assessed. Discussion Effective therapy for MCI is lacking. Finding an intervention postponing the progression of MCI is of great importance for patients as well as for the global economy and health care.

• Solheim, Andreas; Ringstad, Geir; Valnes, Lars Magnus; Eide, Per Kristian & Mardal, Kent-Andre (2025). The role of brain geometry in glymphatic modeling. Full text in Research Archive
• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2025). An image registration-based approach for model order reduction in brain geometries. Full text in Research Archive
• Edwin, Trine Holt; Nordnes, Per Raymond; Knapskog, Anne-Brita; Løhaugen, Gro; Ringstad, Geir Andre & Hol, Haakon Ramsland [Show all 8 contributors for this article] (2025). Computerized Working Memory Training vs Active Control in Mild Cognitive Impairment. Alzheimer's & Dementia. ISSN 1552-5260. 21(S4). doi: 10.1002/alz70858_100914. Full text in Research Archive Show summary

  Background: Working memory training may enhance cognitive function in Mild Cognitive Impairment (MCI). Given that one-third of individuals with MCI progress to dementia within five years, interventions that delay progression are critical. This study investigates the effect of home-based computerized working memory training on cognitive function in MCI. Method: In this multi-center randomized controlled trial, participants with MCI were assigned to either a five-week home-based computerized working memory training program (n = 94) or an active control group playing web-based solitaire (n = 53). All participants received weekly coaching by telephone. We analyzed the change in working memory, measured by the Spatial Span Backwards subtest (higher score indicates better working memory), from baseline to 3 months post-intervention. A mixed-effects model with robust standard errors was employed to account for both fixed and random effects. Fixed effects included treatment group, age, sex, and General Ability Index (GAI), while the random effect accounted for variability between centers. Result: Among 147 participants (mean age 68 years; standard deviation 7.5; 43% women), the Spatial Span Backwards score improved significantly in the working memory training group compared to the active control group at 3 months (least squares mean difference, 0.60; 95% confidence interval, 0.44 to 0.75 p <0.001). Conclusion: In individuals with MCI, home-based computerized working memory training significantly improved working memory after 3 months compared to active controls.

• Ringstad, Geir (2024). Glymphatic imaging: a critical look at the DTI-ALPS index. Neuroradiology. ISSN 0028-3940. 66(2), p. 157–160. doi: 10.1007/s00234-023-03270-2. Full text in Research Archive
• Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege & Ringstad, Geir [Show all 7 contributors for this article] (2023). CSF to blood clearance differs substantially across individuals and patients with CSF disorders. Fluids and Barriers of the CNS. 19. doi: 10.1186/s12987-022-00397-x. Full text in Research Archive
• Melin, Erik; Eide, Per Kristian & Ringstad, Geir (2023). Author Correction: In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans (Scientific Reports, (2020), 10, 1, (14974), 10.1038/s41598-020-72031-5). Scientific Reports. 13(1). doi: 10.1038/s41598-023-43372-8. Full text in Research Archive
• Ringstad, Geir & Eide, Per Kristian (2023). The pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain. Nature Communications. 14. doi: 10.1038/s41467-023-40508-2. Full text in Research Archive
• Ringstad, Geir Andre (2023). The Glymfatic System, The Glymphatic System. Springer Nature. ISSN 9783319614236. p. 1–14. Full text in Research Archive
• Jacob, Ina Lovise; Ringstad, Geir; Enriquez, Brian Anthony & Jusufovic, Mirza (2023). Arterielt spinalt infarkt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(4). doi: 10.4045/tidsskr.22.0355. Full text in Research Archive
• Ringstad, Geir & Eide, Per Kristian (2021). Safety of Intrathecal Gadolinium-based Contrast Agents and Benefit versus Risk. Radiology. ISSN 0033-8419. 229(1), p. E223–E224. doi: 10.1148/radiol.2021203351. Full text in Research Archive
• Eide, Per Kristian & Ringstad, Geir (2019). Intracranial Pulsatility, Cerebrospinal Fluid Flow, and Glymphatic Function in Idiopathic Normal Pressure Hydrocephalus. In Jr., David D. Limbrick & Reonard, Jeffrey R. (Ed.), Cerebrospinal Fluid Disorders Lifelong Implications. Springer Nature. ISSN 9783319979274. p. 71–84. doi: 10.1007/978-3-319-97928-1. Full text in Research Archive
• Vinje, Vegard; Ringstad, Geir; Rognes, Marie; Eide, Per & Mardal, Kent-Andre (2018). Respiratory influence on intracranial pressure gradients and aqueductal flow in normal pressure hydrocephalus. Full text in Research Archive Show summary

  Phase contrast MRI does not take into account the role of respiration on cerebrospinal fluid (CSF) flow. We used in vivo pressure measurements from two locations in the intracranial space to calculate a pulsatile pressure gradient. This pressure data was used as input to an idealized model of the aqueduct to calculate CSF flow. We found the cardiac and respiratory cycle to contribute equally to CSF flow. The total flow volume was dominated by respiration, and all subjects showed variability in pressure gradients over time resulting also in variability in CSF flow.

• Vinje, Vegard; Ringstad, Geir; Rognes, Marie; Eide, Per & Mardal, Kent-Andre (2018). The Influence of Breathing on Cerebrospinal Fluid Movement in the Brain. Full text in Research Archive
• Eide, Per Kristian; Sorteberg, Angelika; Sorteberg, Wilhelm; Lindstrøm, Erika Kristina; Mardal, Kent-Andre & Ringstad, Geir (2018). "Bucket" cerebrospinal fluid bulk flow: when the terrain disagrees with the map. Acta Neurochirurgica. ISSN 0001-6268. 161(2), p. 259–261. doi: 10.1007/s00701-018-3775-6. Full text in Research Archive

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