Open research questions in Cerebrospinal fluid and hydrocephalus
552 gap statements mined from Cerebrospinal fluid and hydrocephalus papers in our 7.9M-paper local library, which holds 1,775 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The exact mechanisms of glymphatic dysfunction in AD are not fully understood. The relationship between glymphatic dysfunction and cognitive decline, structural changes, and disease progression in AD is not well established. There is a need for more research on the use of MRI biomarkers for identifying glymphatic impairment and its association with AD.
Exploring the role of glymphatic system in Alzheimer’s disease with insights from MRI-based studies: a systematic review · 2026 · DOIThe relationship between sleep disturbances and neurodegenerative diseases is not fully understood. The role of glymphatic dysfunction in this association needs further research. Current understanding of the glymphatic system's regulatory mechanisms is incomplete.
The optimal surgical strategy for the management of intraventricular empyema complicated by secondary complex hydrocephalus is unclear. There is a need for further studies to clarify the indications for neuroendoscopic intervention. The available evidence on the use of neuroendoscopic evacuation and lavage for pyogenic ventriculitis is limited.
A case report of secondary complex hydrocephalus following surgical treatment of bilateral intraventricular empyema · 2026 · DOIThe paper identifies a gap in the understanding of how the glymphatic system is initiated and sustained. It highlights the need to reconcile the glymphatic system with venous hemodynamics and meningeal lymphatics. The paper notes that prior models of brain clearance have limitations, including the inability to explain the rapid clearance of macromolecules.
The Glymphatic–Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers · 2025 · DOIHow pathogenic autoantibodies enter and are cleared from the brain parenchyma remains poorly understood.
Glymphatic System Is Enhanced in Anti-NMDAR Encephalitis and Facilitates Antibody Influx and Clearance in the Brain · 2026 · DOIThis exploratory study aimed to provide preliminary insights into how these agents might modulate the glymphatic pathway and influence early functional recovery in an experimental SAH model, addressing a gap in understanding the mechanistic effects of these standard treatments.
Nimodipine and enoxaparin improve neurological outcomes and reduce cerebral edema by modulating glymphatic perivascular spaces in a rabbit model of subarachnoid hemorrhage · 2026 · DOIWhile nimodipine and enoxaparin are commonly used in clinical practice, their influence on perivascular clearance mechanisms remains unexplored.
Nimodipine and enoxaparin improve neurological outcomes and reduce cerebral edema by modulating glymphatic perivascular spaces in a rabbit model of subarachnoid hemorrhage · 2026 · DOIArtesunate (ART) has shown neuroprotective potential, but its effects on glymphatic-related fluid transport in Parkinson's disease (PD) remain unclear.
A Pilot Study Evaluating the Effect of Artesunate on Glymphatic‐Related Fluid Transport in Parkinson's Disease Mouse Models In Vivo and Ex Vivo · 2026 · DOIPerivascular spaces (PVS) are MRI-visible markers of cerebrovascular and glymphatic function, but their regional determinants in preclinical Alzheimer's disease (AD), regarding sex and AD biomarkers, remain poorly understood.
EXPRESS: Multidomain determinants of perivascular spaces indicate early cerebrovascular vulnerability in individuals at risk of Alzheimer’s disease · 2026 · DOIHowever, longitudinal dynamics of glymphatic function during the chronic stroke phase (3-12 months) and links to cognitive recovery remain unclear.
Chronic Glymphatic Dysfunction Modulates Domain‐Specific Cognitive Recovery After Stroke: A DTI ‐ ALPS Lesion Stratification Study · 2025 · DOIThe association between glymphatic function and pathological hallmark in neuroimaging remains unknown.
Relationships Between Glymphatic System Activity and Tau Burden, Dopaminergic Impairment, Abnormal Glucose Metabolism in Progressive Supranuclear Palsy · 2025 · DOIHowever, the risk factors of glymphatic system such as age, gender, metabolic factors, cardiovascular disease, and lifestyle are not fully investigated.
While some studies have linked tDCS to astrocytes inositol trisphosphate (IP 3)/Ca 2+ signaling, the impact of tDCS on CSF-ISF exchange dynamics remains unclear.
Transcranial direct current stimulation alters cerebrospinal fluid-interstitial fluid exchange in mouse brain · 2024 · DOINevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated.
Glymphatic dysfunction mediates the influence of choroid plexus enlargement on information processing speed in patients with white matter hyperintensities · 2024 · DOIHowever, to better understand the exact microstructural changes in enlarged MLVs and their impact on drainage functionality in the context of neurodegenerative diseases, further investigation is needed – both in terms of normal aging and disease. Evidence of how fluid and cells from CSF drain into MLVs is scarce, considering the separation of those compartments through the arachnoid barrier cell layer.
Artificial intelligence-based segmentation of perisinusoidal tissue along the superior sagittal sinus in human brain magnetic resonance imaging · 2026 · DOIDeveloping novel therapeutic approaches to address the unmet need in iNPH treatment. Integrating single-cell RNA sequencing data with computational compound prioritization to identify potential drug candidates.
Systems biology prioritizes drug candidates for an interferonresponse-high monocyte state in idiopathic normal pressure hydrocephalus · 2026 · DOIFew studies have focused on the causal effects of the dysfunction of the glymphatic circulation pathways (inflow and outflow pathway) on WMH and cognitive function.
The Relationship Between Glymphatic Function, White Matter Hyperintensity and Cognition: A Structural Equation Model MRI Study · 2025 · DOISleep is a major driver of waste clearance from the brain, but the mechanisms underpinning brain cleansing during sleep, which are also important for immunological functions, are poorly understood.
Most available studies include relatively small cohorts, - originate from single centers, - are retrospectively designed and use heterogeneous diagnostic approaches, - Differences in inclusion criteria, α-synuclein detection methods and outcome measurements limit direct comparison between studies, - longitudinal studies evaluating whether α-synuclein positivity could predict future cognitive decline, development…
α-Synuclein Pathology in Idiopathic Normal Pressure Hydrocephalus: Evidence for Concomitant Synucleinopathy and Clinical Implications · 2026 · DOIResearch should focus on deepening our understanding of the glymphatic system and its regulatory mechanisms - Integrating clinical practice to explore new research…
Investigating the role of pericytes and microvascular gating in clearance regulation - Examining the implications of lymphatic contractility and plasticity for neurodegenerative diseases - Developing novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, to study clearance…
The Glymphatic–Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers · 2025 · DOIThe patient group in a recent study was limited (13), - We do not know which IMT parameters are best suited for this patient population and for their subtypes, - We do not know the optimal load to overcome during inspiration, - The study does not provide information on how to modulate training…
The Glymphatic System and Diaphragmatic Dysfunction in Patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure: The Importance of Inspiratory Rehabilitation Training · 2025 · DOIResearch should focus on the relationship between the glymphatic/CSF system and CD in patients with CHF and COPD, - Studies should investigate the optimal IMT parameters for this patient population, - Research should explore how to align IMT with other rehabilitation sessions, - Further studies should examine how to modulate training intensity to avoid overtraining…
The Glymphatic System and Diaphragmatic Dysfunction in Patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure: The Importance of Inspiratory Rehabilitation Training · 2025 · DOIThe lack of understanding of the ocular glymphatic system - The need for a comprehensive summary of the current understanding of the ocular glymphatic…
These preliminary findings support further investigation of ART as a potential modulator of brain fluid transport-related pathways in PD.
A Pilot Study Evaluating the Effect of Artesunate on Glymphatic‐Related Fluid Transport in Parkinson's Disease Mouse Models In Vivo and Ex Vivo · 2026 · DOI
Most-cited papers in Cerebrospinal fluid and hydrocephalus
- Circadian control of brain glymphatic and lymphatic fluid flow · Nature Communications · 2020 · 690 citations
- Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model · Brain · 2020 · 665 citations
- Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus · Neurologia medico-chirurgica · 2021 · 576 citations
- Glymphatic clearance function in patients with cerebral small vessel disease · NeuroImage · 2021 · 486 citations
- Cerebrospinal fluid influx drives acute ischemic tissue swelling · Science · 2020 · 480 citations
- The Glymphatic System: A Novel Component of Fundamental Neurobiology · Journal of Neuroscience · 2021 · 447 citations
- Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy · Nature · 2021 · 415 citations
- Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics · Cellular and Molecular Life Sciences · 2021 · 374 citations
- Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease · Nature Medicine · 2021 · 345 citations
- Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep · Cell · 2025 · 315 citations
Most recent work
- Comparing Glymphatic Function Measures: Diffusion Tensor Image Analysis Along Perivascular Spaces (DTI-ALPS) versus Intrathecal Contrast-Enhanced MRI · Radiology · 2026
- Deep cervical lymphatic–venous anastomosis attenuates cognitive dysfunction and biomarker abnormalities in severe Alzheimer's disease: A prospective single‐arm study · Alzheimer s & Dementia · 2026
- Therapeutic Hypothermia Alleviates Hydrocephalus and Neurological Dysfunction Post Intraventricular Hemorrhage by Enhancing Drainage of Glymphatic‐Meningeal Lymphatic‐Deep Cervical Lymphatic System · CNS Neuroscience & Therapeutics · 2026
- Resolving cognitive heterogeneity in white matter hyperintensities through integrated analyses of microbiome, metabolome, and brain glymphatic function · Alzheimer s & Dementia · 2026
- Mapping the Brain’s Glymphatic System · Biomedicines · 2026
- Early glymphatic failure in AppNL-F knock-in mice is linked to parenchymal border macrophages loss · Brain · 2026
- Beyond immune privilege: the brain as a dynamic immunological interface · Cell Death and Disease · 2026
- Putative glymphatic function and free water in schizophrenia: A 7T DTI study across psychosis stages · Neuropsychopharmacology · 2026
- Surrogates of glymphatic metrics decline and coupled sleep rhythms disruption in Alzheimer’s disease · Alzheimer s Research & Therapy · 2026
- Deep learning enhanced ALPS reveals genetic and environmental factors of brain glymphatic function · EBioMedicine · 2026
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