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Objective: Idiopathic normal pressure hydrocephalus (INPH) is a treatable neurological condition, yet predicting which patients will benefit from a cerebrospinal fluid shunt remains challenging. Structural brain MRI is a core part of the diagnostic workup, but traditional radiological measures show limited predictive accuracy. This study aimed to assess whether deep learning and radiomics-based machine learning approaches can provide clinically useful predictions of shunt outcome based on preoperative MRI.

Methods: We investigated 149 shunted INPH patients with available preoperative T1-weighted, T2-weighted, and FLAIR images. Patients were classified as responders (n = 113) or non-responders (n = 36) based on postoperative gait speed improvement. For INPH, this is a large sample with typical outcome distribution. Three artificial intelligence approaches were tested: a late-fusion ensemble of multiple 3D convolutional neural networks; a multimodal intermediate fusion model; and radiomics-based machine learning models trained on features extracted from whole-brain masks. Models were assessed using 10-fold cross-validation. The best performing model on the validation set was selected from each approach. Performance metrics included the area under the receiving operating characteristic curve (AUROC), sensitivity, and specificity.

Results: Performance was considered poor in all models, and none reached an area under the receiving operating characteristic curve above 70%. Of the three methodologies, the best performance was achieved with a radiomics-based model (Linear Discriminant Analysis classifier on T1-weighted images) which achieved an AUROC of 63.7%. In a reduced subset of clearly separated responders and non-responders (n = 72), the best model (late fusion ensemble of 5 convolutional neural networks) reached an AUROC of 69.2%.

Conclusions: Despite the use of advanced artificial intelligence techniques, structural MRI alone were insufficient for reliably predicting gait outcome after surgery in idiopathic normal pressure hydrocephalus. To capture the complexity of the condition and enable clinically meaningful predictions, our findings indicate the need for research investigating multimodal input and using large multi-center datasets.

Background: Aquaporin-4 (AQP4) is crucial for brain fluid regulation and glymphatic system function. Idiopathic normal pressure hydrocephalus (INPH) is characterized by impaired CSF flow and is treated with shunt surgery. This study investigated AQP4 levels in INPH patients to explore its role in pathophysiology and as a potential biomarker for shunt response.

Methods: CSF samples from 233 INPH patients and 29 controls were analysed. AQP4 levels were compared between preoperative patients and controls, before and after shunt surgery (110 patients), and between shunt responders and non-responders (204 patients). A bead-based assay was used to measure AQP4, and outcomes were assessed by postoperative changes in maximum gait velocity.

Results: In unadjusted analyses, preoperative AQP4 levels were lower in INPH patients than in controls; however, this difference did not remain after adjustment for pre-analytical and demographic confounders (p = 0.87). Postoperative AQP4 levels were higher (median 1646 AU IQR 1347–1976) than preoperative levels (1166 AU IQR: 976–1345; p < 0.001) and the magnitude of increase showed a modest correlation with gait improvement (rₛ = 0.22, p = 0.022). Shunt responders had lower preoperative AQP4 levels median 1089 AU, IQR 971–1277) than non-responders (median 1213 AU, IQR 1074–1361; p = 0.008). Pre-analytical factors, including storage duration and sample processing, were strong determinants of measured AQP4 levels.

Conclusions: CSF AQP4 levels in INPH did not differ from those in controls and were highly sensitive to pre-analytical sample handling. CSF AQP4 levels increased following shunt surgery. A potential prognostic value of CSF AQP4 is suggested but requires further investigation.

BACKGROUND AND OBJECTIVES: Glymphatic function affects brain health and could be part of the pathophysiology in idiopathic normal-pressure hydrocephalus. Elevated intracranial pressure pulsatility and increased resistance to cerebrospinal fluid (CSF) outflow (Rout) are commonly observed in idiopathic normal-pressure hydrocephalus. Whether such alterations indicate impaired glymphatic function or affect ventricle volumetrics in ordinary elderly is unknown. We investigated the associations between CSF dynamics and changes in cognitive performance, gait, and brain MRI parameters over a 10-year period in a cohort of healthy older adults.

METHODS: Twenty-nine subjects (mean age 79 ± 6, range 71-92 years) were investigated with brain MRI, clinical testing, and a CSF infusion test. MRI and clinical testing were repeated after 10 years. An automated software program was used to calculate ventricle volumes, and linear ventricle radiological indices were calculated (Evan's index, callosal angle, and z-Evan's index). CSF dynamic parameters were correlated with longitudinal changes in clinical and MRI parameters.

RESULTS: In a multivariable regression model including age, sex, baseline cognitive performance, and CSF dynamic parameters, lower CSF outflow resistance was associated with better cognitive performance after 10 years (standardized β = 0.37, P =.047, n = 29). In a bivariate analysis, outflow resistance had a negative correlation to the difference in cognitive testing score between baseline and follow-up (r = −.44, 95% CI −0.701 to −0.08, P =.017, n = 29, Spearman's rho). CSF dynamic parameters were not associated with changes in gait performance or ventricle volume. Intracranial pressure pulsatility was associated with reduced callosal angle (standardized β = −0.35, P =.02, n = 29) and intracranial pressure with increased z-Evan's index (standardized β = 0.18, P =.003, n = 29).

CONCLUSION: Our results provide insight into the complexity of CSF physiology and its possible role in longitudinal change in brain function and structure. Measurement of CSF outflow characteristics hold potential in furthering the understanding of glymphatic performance with regard to change in cognitive function and warrants further investigation.

Purpose: Cerebrospinal fluid (CSF) flow oscillations have emerged as a potentially important marker related to brain clearance, but their acquisition often relies on specialized imaging MRI sequences. The purpose of this work was to enable quantitative assessment of CSF flow associated with cardiac, respiratory, and low-frequency cycles using widely available functional magnetic resonance imaging (fMRI) acquisitions.

Methods: A method was developed to translate fMRI-derived CSF inflow signals into quantitative flow rates. This approach modeled the spin-history of an oscillating ensemble of molecules. Validation was performed using phantom experiments with cardiac-, respiratory-, and low-frequency-like oscillatory flow. The method was further applied to resting-state data from 48 older adults (68–82 years, 19 women) to characterize CSF flow at the foramen magnum.

Results: Phantom experiments demonstrated excellent correlations between estimated and true velocities for cardiac- and respiratory-like frequencies (r = 0.94 and 0.97, respectively) and moderate correlation for the low-frequency-like oscillation (r = 0.58). In the population cohort, median CSF stroke volumes were 0.77 [0.57, 1.09] mL for the cardiac cycle, 0.38 [0.26, 0.88] mL for the respiratory cycle, and 0.26 [0.14, 0.39] mL for the low-frequency cycle.

Conclusion: The proposed spin-history modeling method enabled quantitative estimation of CSF flow components using a conventional fMRI dataset and showed that the cardiac cycle dominates CSF motion at the foramen magnum.

According to glymphatic system theory, cerebrospinal fluid (CSF) perfuses the brain’s interstitial space to support waste clearance, but the magnitude of this flow and the outflow pathway of interstitial fluid (ISF) in humans remain uncertain. To achieve flow quantification, we applied a compartment-model approach applied in conjunction with serial quantitative MRI data acquired after intrathecal gadolinium administration. Using the method, we estimated CSF-to-ISF inflow to 45 ± 20 mL/h, in patients with suspected idiopathic normal pressure hydrocephalus. Tissue-specific contributions were 34 ± 14 mL/h in cortical gray matter, 11±6 mL/h in white matter, and 0.4 ± 0.3 mL/h in subcortical gray matter, suggesting that CSF perfusion occurs primarily in superficial regions near the subarachnoid space. A lack of correlation between inflow and total craniospinal system outflow (r = 0.03, P = 0.91) suggested that ISF recirculates back into CSF rather than exiting the craniospinal system via a separate route. Independent experiments in healthy older individuals using intravenous gadolinium administration supported ISF-to-CSF recirculation, where contrast material that presumably crossed the blood–brain barrier subsequently appeared in the subarachnoid space, allowing ISF-to-CSF flow quantification. These findings provide a quantitative framework for studying brain clearance in humans and support subarachnoid space recirculation as an important efflux route.

Purpose: The aim was to estimate T1 relaxivity of gadobutrol and gadoteric acid in cerebrospinal fluid (CSF) at 3T, to support research on CSF-flow and the glymphatic system in humans utilizing T1 mapping after intrathecal injection.

Methods: Using a phantom, relaxivity was estimated for gadobutrol and gadoteric acid in lumbar CSF and an isotonic solution. All samples were scanned simultaneously using the variable flip angle method with B1 correction, repeated six times on one 3T scanner, and once on a second 3T scanner. Difference in relaxivity between CSF and the isotonic solution were evaluated from the repeated measurements.

Results: There was a significant difference in relaxivity between CSF and the isotonic solution for both gadobutrol and gadoteric acid. The relaxivity for gadobutrol for the respective scanners was estimated to 3.02 ± 0.09 vs. 3.63 L mmol⁻¹ s⁻¹ in CSF and 2.35 ± 0.05 vs. 2.74 L mmol⁻¹ s⁻¹ in isotonic solution. For gadoteric acid, corresponding results were 2.47 ± 0.02 vs. 2.91 L mmol⁻¹ s⁻¹ in CSF and 2.37 ± 0.03 vs. 2.8 L mmol⁻¹ s⁻¹ in isotonic solution. Between the scanners, there was a high correlation (R2 0.998) but an 18% scaling difference in the T1 relaxation rates and corresponding relaxivities.

Conclusions: The relaxivity was higher in CSF than in the isotonic solution, particularly for gadobutrol. Systematic differences in relaxivity between scanners may potentially be corrected using a scaling factor derived from the T1 time of baseline CSF. For CSF studies using T1 mapping with a gadolinium-based contrast agent, we recommend using a CSF-specific relaxivity constant.

After more than 50 years, there still remains a challenge and an interest to know more as well as extend and deepen our understanding of the small rapid wavelets, the oscillatory potentials (OPs), of the electroretinogram (ERG) and the neuronal adaptation of the retina. This paper summarizes the current knowledge of the rapid oscillatory response and its role in the process of neuronal adaptation in the retina. An effort has been made to enhance our ability and possibility, especially in the clinic, to interpret and use this response. The first section in short presents historic aspects, definitions and understanding of neuronal adaptation and the OPs. The second part deals with different and modern techniques and possibilities to record and measure the OPs, ffERG (full-field ERG), mfERG (multifocal ERG), fmERG (focal macular ERG) and optimal adaptational recording conditions. The third section overviews the current apprehension of the origin(s) of the OPs. The fourth part describes the normal development of the OPs from prematurity to old age. The last section enlightens the importance of the OPs as indicators of disturbed retinal, neuronal adaptive function in different diseases in the retina.

Background: Idiopathic normal-pressure hydrocephalus is a neurologic disorder characterized by impaired gait, balance, cognition, and bladder control in older adults. The disorder is treated with shunt surgery, but the effectiveness of shunting is unclear.

Methods: We conducted a double-blind, randomized, placebo-controlled trial involving participants selected for shunt surgery on the basis of gait-velocity improvement with cerebrospinal fluid (CSF) drainage. Participants were randomly assigned to an open-shunt valve setting (opening pressure, 110 mm of water) or a placebo valve setting (opening pressure, >400 mm of water) of a noninvasively adjustable shunt. The primary outcome was the change in gait velocity 3 months after surgery. Secondary outcomes were the change at 3 months in the Tinetti scale total score (range, 0 to 28; lower scores indicate worse gait and balance), Montreal Cognitive Assessment (MoCA) score (range, 0 to 30; lower scores indicate worse cognition), and Overactive Bladder Questionnaire score (range, 0 to 100; higher scores indicate worse urinary incontinence).

Results: A total of 99 participants underwent randomization and received the assigned intervention. At 3 months, gait velocity had increased in the open-shunt group (mean [+/- SD] change, 0.23 +/- 0.23 m per second; assessed in 49 participants) and was unchanged in the placebo group (mean change, 0.03 +/- 0.23 m per second; assessed in 49 participants), resulting in a treatment difference of 0.21 m per second (95% confidence interval, 0.12 to 0.31; P<0.001). A significantly greater improvement in the open-shunt group than the placebo group was seen for the Tinetti scale score (mean change, 2.9 points vs. 0.5 points; P=0.003) but not the MoCA score (1.3 points vs. 0.3 points) or the Overactive Bladder Questionnaire score (-3.3 points vs. -1.5 points). The results regarding adverse events were mixed, with more participants in the placebo group reporting falls (46% vs. 24%), an equal percentage having cerebral bleeding (2% in both groups), and more participants in the open-shunt group having subdural bleeding (12% vs. 2%) and positional headaches (59% vs. 28%).

Conclusions: Among participants with idiopathic normal-pressure hydrocephalus who had a response to temporary CSF drainage, shunting resulted in significant improvements at 3 months in gait velocity and a measure of gait and balance but not in measures of cognition or incontinence. (Funded by the National Institute of Neurological Disorders and Stroke and the Trial Innovation Network; PENS ClinicalTrials.gov number, NCT05081128.)

Higher-Level Gait Disorder (HLGD) is a type of gait disorder estimated to affect up to 6% of the older population. By definition, its symptoms originate from the higher-level nervous system, yet its association with brain morphology remains unclear. This study hypothesizes that there are patterns in brain morphology linked to HLGD. For the first time in the literature, this work investigates whether deep learning, in the form of convolutional neural networks, can capture patterns in magnetic resonance images to identify individuals affected by HLGD. To handle this new classification task, we propose setting up an ensemble of models. This leverages the benefits of combining classifiers instead of determining which network is the most suitable, developing a new architecture, or customizing an existing one. We introduce a computationally cost-effective search algorithm to find the optimal ensemble by leveraging a cost function of both traditional performance scores and the diversity among the models. Using a unique dataset from a large population-based cohort (VESPR), the ensemble identified by our algorithm demonstrated superior performance compared to single networks, other ensemble fusion techniques, and the best linear radiological measure. This emphasizes the importance of implementing diversity into the cost function. Furthermore, the results indicate significant morphological differences in brain structure between HLGD-affected individuals and controls, motivating research about which areas the networks base their classifications on, to get a better understanding of the pathophysiology of HLGD.

A single, arterial-optimized 4D-flow MRI acquisition may enable fast assessment of both cerebral arterial and venous flow. However, arteries and veins require different velocity encoding (VENC) settings for optimal velocity-to-noise ratio (VNR). Consequently, venous measurements using arterial-optimized VENC settings are subject to reduced VNR and require further evaluation. This study compared cerebral venous flow and pulsatility assessments using a high-VENC (110 cm/s, adapted to the arterial system) and a low-VENC (40 cm/s, adapted to the venous system) 4D-flow MRI sequence at 3 Tesla. Flow and pulsatility index (PI) were calculated for cerebral veins, sinuses and internal jugular veins in 36 elderly volunteers (79 ± 5 years). The high-VENC acquisitions allowed visualization of nearly all venous structures. Mean flow differences were small and the correlation, strong, when comparing both acquisitions across sinuses (R = 0.90–0.99, difference = -8–7%) and cortical veins (R = 0.93, difference = − 6%). Inflow-outflow differences at the confluence of sinuses were similar between acquisitions. PI showed moderate to strong agreement except in the straight sinus. Both the vein of Galen and the jugular veins suffered from aliasing in the venous VENC acquisitions. In summary, this study demonstrated that a VENC setting adapted for the arterial cerebral circulation was feasible for studying cerebral venous flow and pulsatility.