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Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI) 1 . Noradrenaline levels are increased after TBI 2 – 4 , and the amplitude of the increase in noradrenaline predicts both the extent of injury 5 and the likelihood of mortality 6 . Glymphatic impairment is both a feature of and a contributor to brain injury 7 , 8 , but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI. Acute oedema after traumatic brain injury is accompanied by the suppression of glymphatic and lymphatic fluid flow due to excessive systemic release of noradrenaline.

•Spectral ADC shows anesthesia-specific interstitial and microvascular space changes•K/X increases, ISO decreases CSF tracer influx compared with awake condition•ADC and IVIM do not correlate with CSF tracer transport measured by DCE-MRI•IVIM modeling cannot reliably separate slow and fast MR diffusivities across states•DWI alone cannot quantify state-related interstitial volume and transport changes This study investigated whether magnetic resonance (MR) diffusivity parameters derived from diffusion-weighted imaging (DWI) can serve as biomarkers of glymphatic function in awake and anesthetized mice. Spectral apparent diffusion coefficient (ADC) analysis, obtained using an inverse Laplace transform, revealed that both Isoflurane (ISO) and Ketamine/Xylazine (K/X) anesthesia reduced the magnitude and range of diffusivities associated with interstitial fluid space (≤1 µm²/ms) compared with the awake state. Perfusion-related diffusivities (20–80 µm²/ms) increased under ISO but decreased under K/X. Monoexponential ADC and biexponential intravoxel incoherent motion (IVIM) modeling showed that ISO dose-dependently elevated, while K/X reduced, both slow and fast diffusivities across the brain. Dynamic contrast-enhanced MRI (DCE-MRI) indicated intermediate glymphatic influx in awake mice relative to both anesthetic conditions, without regional correlation to DWI-derived parameters. Perfusion micro–computed tomography (µCT) further demonstrated that ADC and IVIM metrics correlated regionally with mean transit time, suggesting a confounding by cerebral blood flow (CBF). Two-photon microscopy confirmed anesthesia-induced changes in cortical microvessel diameters consistent with perfusion alterations. Collectively, these findings indicate that MR diffusivity measures are strongly influenced by state-dependent physiological changes, and in particular perfusion. This represents an important limitation that warrants caution when using DWI to compare extracellular space, interstitial fluid flow, or glymphatic activity across different physiological or anesthetic states. Therefore, although technically challenging, we suggest that DWI studies aimed at assessing glymphatic or interstitial dynamics should be performed in awake conditions to minimize variability and anesthesia-related perfusion confounds across studies.

Background: The therapeutic effects of vortioxetine on mood and cognition have been documented in major depressive disorder (MDD). This study aims to examine whether vortioxetine can improve brain glymphatic system function and connections among functional brain networks and to explore the underlying relationships among these changes. Methods: A total of 34 patients with MDD and 41 healthy controls (HCs) were recruited in the study. All participants underwent mood and cognitive assessment, and diffusion tensor imaging (DTI) and resting‐state functional MRI scans at baseline and 8‐week follow‐up. The DTI analysis along the perivascular space (DTI‐ALPS) index, and functional connectivity (FC) were assessed. Cognitive assessment was conducted using the Chinese version of Measurement Consensus Cognitive Battery (MCCB). Correlation analysis was subsequently performed to explore underlying association among these indexes. Results: Compared to HCs, patients with MDD showed decreased DTI‐ALPS indexes at baseline; patients with MDD showed increased the default mode network (DMN) FC between the posterior cingulate cortex (PCC)–precuneus; patients with MDD displayed decreased attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Treatment with vortioxetine, patients with MDD displayed reduced depressive symptoms, increased DTI‐ALPS indexes, decreased DMN FC, and improved attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Moreover, the increased DTI‐ALPS indexes correlated with improved global cognition, and decreased DMN FC in MDD, respectively. Conclusions: The current study indicated vortioxetine improves glymphatic system function and brain connections within the DMN in MDD. Furthermore, the restoration of glymphatic function is linked to improved brain function and cognition. Trial Registration : ClinicalTrials.gov identifier: ChiCTR2200057820

Brain waste is cleared via a cerebrospinal fluid (CSF) pathway, the glymphatic system, whose dysfunction may underlie many brain conditions. Previous studies show coherent vascular oscillation, measured by blood oxygenation level-dependent (BOLD) fMRI, couples with CSF inflow to drive fluid flux. Yet, how this coupling is regulated, whether it mediates waste clearance, and why it is impaired remain unclear. Here we demonstrate that cholinergic neurons modulate BOLD-CSF coupling and glymphatic function. We find BOLD-CSF coupling correlates cortical cholinergic activity in aged humans. Lesioning basal forebrain cholinergic neurons in female mice impairs glymphatic efflux and associated changes in BOLD-CSF coupling, arterial pulsation and glymphatic influx. An acetylcholinesterase inhibitor alters these dynamics, primarily through peripheral mechanisms. Our results suggest cholinergic loss impairs glymphatic function by a neurovascular mechanism, potentially contributing to pathological waste accumulation. This may provide a basis for developing diagnostics and treatments for glymphatic dysfunction. The authors find cholinergic neurons regulate glymphatic waste clearance via neurovascular mechanisms, with their loss impairing this process. This finding suggests targets for diagnostics and treatment.

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.

The glymphatic system maintains brain homeostasis through cerebrospinal fluid transport and waste clearance. Its potential involvement in chemotherapy‐related cognitive impairment remains largely unexplored due to limited in vivo evidence. In this prospective longitudinal study, 126 female breast cancer patients underwent multiparametric brain MRI and neuropsychological assessments at three time points: baseline (bc1), after the first cycle of neoadjuvant chemotherapy (bc2), and upon completion of neoadjuvant chemotherapy (bc3). Glymphatic function was assessed using four MRI‐derived metrics: choroid plexus (CP) volume, perivascular space (PVS) volume fraction, free water (FW), and Diffusion Tensor Imaging–Along the Perivascular Space (DTI‐ALPS) index. Brain tissue segmentation was conducted to quantify the volume fractions of gray matter (GM) in cortex and subcortex, white matter (WM), and cerebrospinal fluid (CSF) relative to intracranial volume. Neuropsychological assessments included the Self‐Rating Anxiety Scale (SAS), the Functional Assessment of Cancer Therapy–Cognitive Function (FACT‐Cog), and a battery of objective cognitive tests. Longitudinal changes and interrelationships were analyzed using linear mixed‐effects models, correlation analyses, and cross‐lagged panel analysis. During chemotherapy, CP volume increased (p < 0.001), while PVS volume fraction decreased (p = 0.003); no significant changes were found in FW or DTI‐ALPS. GM volumes in both cortex and subcortex declined (both p = 0.02). SAS scores increased (p = 0.02), and FACT‐Cog scores decreased (p < 0.001), with no significant changes in objective test scores. From bc2 to bc3, increases in CP volume were negatively correlated with reductions in PVS volume fraction (r = −0.40, p < 0.001). From bc1 to bc3, reductions in PVS volume fraction were associated with decreases in both cortical GM volumes (r = 0.32, p < 0.001). At bc2, cortical GM atrophy was correlated with increased SAS scores (r = −0.30, p = 0.002). Cross‐lagged panel analysis showed that CP enlargement at bc2 preceded PVS volume fraction reduction at bc3 (β = −1.66, p = 0.007). During neoadjuvant chemotherapy, breast cancer patients exhibited a unique pattern of glymphatic system alterations, suggesting its potential as an imaging marker of treatment‐related brain changes. Using longitudinal multiparametric glymphatic MRI metrics, we found early choroid plexus enlargement and subsequent perivascular space narrowing in breast cancer patients undergoing neoadjuvant chemotherapy. These changes were associated with brain atrophy, suggesting a sequential disruption of glymphatic pathways that may contribute to chemotherapy‐related brain changes.

BackgroundThe glymphatic system has recently been proposed to function as a brain-wide macroscopic system for the clearance of potentially harmful molecules, such as amyloid beta (e.g., Aβ), from the brain parenchyma. Previous literatures have established that the glymphatic function is dramatically suppressed by aging, traumatic brain injury, and some diseases. However, the effect of chronic stress on the glymphatic function and its underlying mechanism remains largely unknown.MethodsAdult mice were randomly divided into four groups: chronic unpredictable mild stress (CUMS)–treated group, CUMS simultaneously treated with mifepristone (MFP) group, dexamethasone (DEX)-treated group, and control group. Stress response was observed by assessing the change of body weight, plasma corticosterone level, and behavior tests. The level of Aβ42 in cerebral tissue was assessed by ELISA. The glymphatic function was determined by using fluorescence tracer injection. The expression and localization of aquaporin-4 (AQP4) were evaluated by immunohistochemistry and western blot. The transcription level of AQP4 and anchoring molecules was evaluated by real-time PCR.FindingsCompared with control group, CUMS-treated mice exhibited the impairment of global glymphatic function especially in the anterior brain. This change was accompanied by the decreased expression and polarization of AQP4, reduced transcription of AQP4, agrin, laminin, and dystroglycan in the anterior cortex. Similarly, the glucocorticoid receptor (GR) agonist DEX exposure could reduce the glymphatic function and AQP4 expression. Moreover, the GR antagonist MFP treatment could significantly rescue the glymphatic function and reverse the expression and polarization of AQP4 impaired by CUMS.ConclusionChronic stress could impair the AQP4-mediated glymphatic transport in the brain through glucocorticoid signaling. Our results also suggest that GR antagonist could be beneficial to rescue the glymphatic function suppressed by chronic stress.

Neurodegenerative disorders, including Alzheimer’s disease (AD), are a growing problem in aging society. The amyloid cascade hypothesis has recently been questioned, and therapies based on it have not yielded the expected results. However, the role of amyloid-β (Aβ) in AD pathogenesis cannot be rejected. It appears that some of the key players in the pathogenesis of the disease are the soluble amyloid-β oligomers. Soluble amyloid-β oligomers have neurotoxic effects by disrupting intracellular Ca2+ homeostasis and impairing mitochondrial function. The glymphatic system is an important pathway for the removal of soluble amyloid forms from the brain. The decline in the activity of this system is observed in aging brains, which is correlated with the occurrence of Alzheimer’s disease, primarily among the elderly population. Therefore, the question arises as to whether the glymphatic system could be another potential target for therapeutic interventions in Alzheimer’s disease. In this regard, it is imperative to pay attention to the factors that contribute to the pathogenesis of Alzheimer’s disease and also impact the glymphatic system, such as sleep, physical activity, alcohol consumption, and supplementation with polyunsaturated fatty acids. The question remains whether the glymphatic system will become the key to treating Alzheimer’s disease.

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Age-related changes of glymphatic–lymphatic clearance lead to the accumulation beta-amyloid (Aβ) in dementia models. In this study, focused ultrasound treatment in combination with microbubbles (FUS-MB) improved Aβ drainage in early dementia model mice, 5XFAD. FUS-MB enhanced solute Aβ clearance from brain, but not plaques, to cerebrospinal fluid (CSF) space and then deep cervical lymph node (dCLN). dCLN ligation exaggerated memory impairment and progress of plaque formation and also the beneficial effects of FUS-MB upon Aβ removal through CSF-lymphatic routes. In this ligation model, FUS-MB improved memory despite accumulation of Aβ in CSF. In conclusion, FUS-MB enhances glymphatic–lymphatic clearance of Aβ mainly by increasing brain-to-CSF Aβ drainage. We suggest that FUS-MB can delay dementia progress in early period and benefits of FUS-MB depend on the effect of Aβ disposal through CSF-lymphatics.

Perivascular spaces (PVS) are fluid filled compartments surrounding the small blood vessels in the brain. The impact of radiotherapy and chemotherapy on PVS remains unclear. The aim of this study is to investigate treatment effects of radiotherapy and chemotherapy at four time points (TPs) in pediatric medulloblastoma (MB) patients. We examined 778 scans from 241 MB patients at baseline (0M), after 12 weeks (about 3 months) of radiotherapy and rest (3M), after chemotherapy completion (12M), and a follow-up (FollowUp) at 18- or 21-months post-baseline. PVS was segmented by applying Frangi filter on the white matter regions on T1 weighted images acquired at 3T Siemens MRI scanner using MPRAGE. PVS volume and ratio, defined as the ratio of PVS volume to the white matter volume, were measured at the four TPs. The data was first statistically analyzed using a full model where all data were included, then a paired model, which included only patients who completed consecutive measurements under the same anesthesia and shunt conditions. Both the full model and paired model showed that PVS (including ratio and volume) increased at 3M post-radiotherapy compared to baseline. During chemotherapy, PVS decreased significantly from 3M to 12M. Subsequently, from 12M to FollowUp, PVS increased again. MRI exams under anesthesia exhibited significantly lower PVS than those without anesthesia. Patients who had undergone a shunt procedure exhibited a significantly reduced PVS compared to those who had not undergone the procedure. We concluded that craniospinal irradiation led to an elevated PVS. Conversely, chemotherapy or time post-irradiation decreased PVS. Anesthesia and shunt procedures can also influence perivascular space ratio or volume.