IntroductionCore cognitive deficits in iNPH include slowed information processing, psychomotor slowing and executive dysfunction. However, cognitive outcomes following shunt surgery are not well understood. This review synthesised evidence on cognitive assessment methods and outcomes following shunt surgery in iNPH.MethodsPubMed, Scopus, PsycINFO and Web of Science were searched for peer-reviewed studies including adults with iNPH who underwent shunt surgery and had within-subject cognitive evaluations pre- and post-operatively. Key data were extracted and study quality was assessed. Random-effects meta-analyses were performed on pooled baseline and post-shunt difference scores for frequently reported cognitive tests with comparable outcome data.ResultsOf 1,876 records, 195 met the inclusion criteria, comprising 11,445 patients. Cognitive evaluation methods ranged from subjective reports and NPH grading scales to brief screening tools and comprehensive test batteries. Over 193 distinct tests were reported and 54.4% of studies did not formally assess any core iNPH cognitive deficits. Post-shunt improvement rates, follow-up times and criteria for defining improvement varied widely. Eighty-five studies contributed data to meta-analyses of ten outcomes. Pooled estimates indicated post-shunt cognitive improvement, with Trail Making Test-A, Grooved Pegboard-Dominant and Trail Making Test-B showing changes exceeding thresholds for clinically significant improvement.ConclusionsCognitive assessment in iNPH is highly heterogeneous and frequently omits core domains, limiting detection of treatment effects. When domain-relevant cognitive measures are used, shunt surgery is associated with statistically and clinically significant cognitive improvement. These findings highlight the need for standardised iNPH-appropriate cognitive evaluation tools with validated criteria for detecting clinically meaningful change and have direct implications for clinical assessment, interpretation of shunt response and the selection of cognitive endpoints in future interventional studies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12987-026-00808-3.

CSF loss in spontaneous intracranial hypotension (SIH) has been related to alterations in glymphatic flow, which is poorly understood in this disease. Advanced multi-shell diffusion-weighted MRI (dMRI) enables quantification of the interstitial free water fraction, serving as a possible surrogate marker for glymphatic system function in patients with SIH. SIH Patients underwent dMRI before and after closure of a spinal CSF leak. The microstructural free water compartment (V-CSF) of the whole brain gray and white matter, corona radiata, amygdala, hippocampi and parahippocampal gyri was compared to 23 age-matched normal controls. Pre- and post-therapeutic volumetry encompassed the total ventricular, total gray and white matter compartments and mesial temporal structures. 23 SIH patients (50.3 ± 13.1 years, 15 women) were included. After leak closure, V-CSF increased in the global gray matter (mean pre 0.140 vs. mean post 0.151; p = 0.029), posterior corona radiata (mean pre 0.103 vs. mean post 0.108; p = 0.0055), hippocampi (mean pre 0.100 vs. mean post 0.105; p = 0.001), and parahippocampal gyri (mean pre 0.156 vs. mean post 0.177; p = 0.009). Compared to normal controls, V-CSF was decreased before leak closure in the hippocampi (mean pre 0.100 vs. mean NC 0.211; p = 0.0019) and posterior corona radiata (mean pre 0.103 vs. mean NC 0.118; p = 0.011). No significant change of total gray or white matter volume occurred after leak closure. Closure of the spinal CSF leak leads to an increase of interstitial fluid in gray matter, corona radiata, hippocampi, and parahippocampal gyri, respectively. Our results suggest, that SIH patients may have less interstitial fluid in the hippocampi and posterior corona radiata compared to normal controls. Whether shifts in brain interstitial fluid in eloquent cerebral regions contribute to cognitive decline in patients with CSF loss should be topic of further research.

Computational fluid dynamics (CFD) has been widely used to study cerebrospinal fluid (CSF) flow in Chiari Malformation Type I (CM-I). However, most approaches rely on limited patient-specific detail, and it remains unclear whether such minimal input is sufficient to yield physiologically realistic flow predictions. In this study, we construct a series of MRI-based models of the craniocervical CSF space in a CM-I patient, complemented with representations of microanatomical features derived from ex vivo measurements and patient MRI data, to assess how CFD predictions are influenced by the choice of boundary conditions in the numerical integrations and the inclusion or omission of nerve roots and denticulate ligaments in the anatomical model. Our results reveal that while increasing patient-specific detail in boundary conditions improves agreement with velocity fields measured via phase-contrast MRI, key flow features—most notably anterior–posterior compartmentalization and bidirectional patterns during flow reversal—only emerge when denticulate ligaments are included in the model. In contrast, inclusion of nerve roots has a more localized effect on the velocity field and a modest impact on pressure drops. Our findings not only clarify how more detailed boundary conditions and improved anatomical fidelity affect velocity and pressure predictions, but also provide a mechanistic explanation for flow patterns commonly observed in CM-I that have remained unexplained, highlighting the critical role of denticulate ligaments.

Cerebrospinal fluid tap test (CSF TT) is a key predictive method commonly used to identify candidates for shunt surgery in idiopathic Normal Pressure Hydrocephalus (iNPH), however, the sensitivity of this procedure is limited. The aim was to compare sensitivity of a broad set of physiotherapy-based clinical tests for assessing changes following CSF TT in a group of selected iNPH patients and to explore potential sex-based differences in the responses. Ninety-five selected iNPH patients (mean age 77, SD 6, 57% male), underwent CSF TT prior to shunt surgery. Clinical tests comprised different static balance tests in varying conditions including feet and heels apart and together; eyes open and closed; on floor and foam cushion, followed by gait and functional performance measures including 10-meter walk test (10MWT), 3-meter backward walking (3MBW), Timed-up and Go (TUG) and 6-minute walking test (6MWT). Duration in seconds (sec) and distance were noted. Assessments were conducted at set time points before and after the drainage procedure. Changes in performance were analyzed, and responses compared between sexes. Significant increase was observed across most static balance tests except tandem eyes closed (EC) and one-legged stance tests. The largest enhancements were seen in the Romberg test (4.9 s), followed by foam cushion-eyes open (EO) tests (feet together: 3.9 s and heels together: 3.8 s), heels together-EC (3.8 s) and tandem-EO (3.1 s). Gait and functional tests significantly improved (p < 0.001) and 3MBW showed the largest change, with a 32% reduction in sec and a 23% reduction in steps, followed by decrease in TUG sec (27%) and 10-MWT sec (21%), and 6MWT distance increase (25%). Males demonstrated significant increase in heels together-EO and feet together-EO duration which were not observed in females; after adjusting for baseline performances, no significant sex-related differences in responsiveness to CSF TT were found. Challenging comprehensive physiotherapy tests, including gait assessments in direction and capacity, such as 3MBW and 6MWT, together with postural control evaluations using foam cushion and tandem stance increases the sensitivity to change and are suggested to be used to detect functional changes after CSF TT in patients with iNPH. The project is registered in "FoU inSweden” (Research and Development in Sweden) ID: 285356.

Cerebrospinal fluid (CSF) enters the brain along perivascular spaces in a manner that depends on aquaporin-4 (AQP4) polarization, facilitating brain clearance and is called the glymphatic system. While physiological factors such as cardiovascular activity and respiration are known to influence glymphatic function, the effects of hypothermia remain poorly understood. In this study, we used quantitative optical and light-sheet microscopy to track fluorescent CSF tracers in mice under ketamine–xylazine (KX) anesthesia at normothermia (37 °C), mild hypothermia (33 °C), and moderate hypothermia (30 °C). Acute mild hypothermia did not affect CSF influx, indicating tolerance to modest temperature fluctuations in KX anesthetized mice, whereas acute moderate hypothermia markedly impaired glymphatic transport by reducing tracer penetration and CSF outflow. Notably, repeated exposure to moderate hypothermia over four consecutive days induced a sustained suppression of glymphatic influx, which persisted even when assessed under normothermic conditions. This persistent dysfunction strongly correlated with the loss of perivascular AQP4 polarization. These findings demonstrate that repeated hypothermia exerts cumulative effects on glymphatic function, which may compromise brain waste clearance and contribute to cognitive impairment in vulnerable populations with impaired thermoregulatory capacity.

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are critical regulators of angiogenesis and vascular homeostasis. While VEGF signaling has been extensively studied in endothelial cells, emerging evidence suggests it also plays roles in non-endothelial brain cells. However, its spatial and cell-type-specific function within the hypothalamus, and more specifically at the level of the blood/CSF barrier, remains poorly defined. In particular, little is known about VEGF receptor expression in tanycytes, a specialized glial population that lines the third ventricle and regulates body-brain communication within the median eminence (ME), a key neurovascular interface located at the tuberal region of the hypothalamus. We used a multi-modal approach including single-cell RNA sequencing (scRNA-seq) reanalysis, RNAscope in situ hybridization, immunohistochemistry, FACS-isolated qPCR in male and female mice, and human spatial transcriptomics to map the expression of VEGFR1 (Flt1), VEGFR2 (Kdr), and VEGF ligands in hypothalamic tanycytes across gender, development, and aging. Our data reveal a striking spatial compartmentalization of VEGFR expression in tanycytes within the ME and the arcuate (ARH), ventromedial (VMH) and dorsomedial (DMH) hypothalamus. VEGFR2 is preferentially expressed in ARH-tanycytes, while VEGFR1 is confined to VMH/DMH-tanycytes; and none of these receptors are expressed in ME-tanycytes. This pattern is unique to the ME and not observed in other circumventricular organs. VEGFR1 expression is established neonatally in mice (P0) and remains stable throughout life, whereas VEGFR2 expression becomes progressively refined postnatally, localizing to ARH-tanycytes in adulthood and showing a significant decline with aging. VEGFA is broadly expressed in all hypothalamic tanycytes, including ME-tanycytes, supporting a paracrine model of signaling. Importantly, despite species-specific differences in the spatial organization of VEGF receptors in tanycytes, the presence of VEGF ligands (Vegfa and Vegfb) and receptors in tanycytes of both mice and humans supports partial evolutionary conservation of VEGF signaling at the brain-blood interface. Our findings unveil, for the first time a non-endothelial VEGF signaling system in hypothalamic tanycytes that is spatially compartmentalized, developmentally programmed and age-dependent. These insights reveal new roles for VEGF signaling in neurovascular and neuroendocrine function, raising important considerations for central effects of VEGF-targeted therapies in aging and disease.