Evaluating the robustness of DTI-ALPS in clinical context: a meta-analytic parallel on Alzheimer's and Parkinson's diseases.

In recent years, the glymphatic system has received increasing attention due to its possible implications in biological mechanisms associated with neurodegeneration. In the field of human brain mapping, this led to the development of diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. While this index has been repeatedly used to investigate possible differences between neurodegenerative disorders and healthy controls, a comprehensive evaluation of its stability across multiple measurements and different disorders is still missing. In this study, we perform a Bayesian meta-analysis aiming to assess the consistency of the DTI-ALPS results previously reported for 12 studies on Parkinson's disease and 11 studies on Alzheimer's disease. We also evaluated if the measured value of the DTI-ALPS index can quantitatively inform the diagnostic process, allowing disambiguation between these two disorders. Our results, expressed in terms of Bayes' Factor values, confirmed that the DTI-ALPS index is consistent in measuring the different functioning of the glymphatic system between healthy subjects and patients for both Parkinson's disease (Log10(BF10) = 30) and Alzheimer's disease (Log10(BF10) = 10). Moreover, we showed that the DTI-ALPS can be used to compare these two disorders directly, therefore providing a first proof of concept supporting the reliability of taking into consideration this neuroimaging measurement in the diagnostic process. Our study underscores the potential of the DTI-ALPS index in advancing our understanding of neurodegenerative pathologies and enhancing clinical diagnostics.

Association of glymphatic system dysfunction with cognitive impairment in temporal lobe epilepsy.

Objectives: To explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE). Methods: This study retrospectively included 38 patients with unilateral TLE and 26 age- and gender-matched healthy controls (HCs). The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), and cognitive assessment were obtained for each participant. Neuropsychological test batteries included Montreal Cognitive Assessment (MoCA), Minimum Mental State Examination, Arithmetic Test (AT), Digit Symbol Substitution Test (DSST), Digit Span Test (DST), Boston Naming Test, Block design, Phonological Fluency Test (PFT), and Semantic Verbal Fluency (SVF). Results: Compared to HCs, TLE patients had lower scores of MoCA, AT, DSST, DST, Block design, PFT and SVF (all p < 0.05) and lower values of mean DTI-ALPS index (1.491 ± 0.142 vs. 1.642 ± 0.123, p < 0.001). Significantly lower DTI-ALPS index values were observed in the ipsilateral hemisphere than in the contralateral hemisphere (1.466 ± 0.129 vs. 1.517 ± 0.175, p = 0.013) for patients with unilateral TLE. Correlation analyses found that SVF performance was significantly or borderline significantly associated with glymphatic function (FDR-corrected p < 0.05 for all DTI-ALPS index and FDR-corrected p = 0.057 for CPV) in TLE patients. Linear regression analyses showed that increased CPV and decreased DTI-ALPS index were independent risk factors for semantic fluency impairment (all p < 0.05). Furthermore, mediation analyses found the mediator role of the mean DTI-ALPS index in the relationship between choroid plexus enlargement and semantic fluency impairment (indirect effect: ß = -0.182, 95%CI = -0.486 to -0.037). Conclusion: These findings reveal the important role of the DTI-ALPS index and CPV in SVF performance in unilateral TLE. Decreased DTI-ALPS index and increased CPV are the independent risk factors for semantic fluency impairment. The DTI-ALPS index may fully mediate the relationship between CP enlargement and SVF performance. These insights provide a radiological foundation for further investigations into the mechanism of the glymphatic system in TLE pathophysiology.

May Glymphatic Drainage Improve Life Quality in Progressive Multiple Sclerosis Outpatients?

Background: The cerebral fluid-dynamic system plays a critical role in maintaining brain health and function. Recent studies identify the glymphatic system as primarily responsible for removing waste products and toxins from brain tissue. In recent years, we have achieved beneficial improvements in MS patients' symptoms and lifestyle using a specific Fluid Dynamic Intensive MAM (FD-MAM) protocol. Methods: We treated 40 outpatients with progressive MS, aged 45-55 years and with EDSS scores from 6 to 9. We applied FD-MAM in 10 daily sessions over two weeks. Before and after glymphatic drainage by FD-MAM, we assessed each patient's clinical status and quality of life using six validated questionnaires. Results: Data from the six validated questionnaires administered to the 40 MS patients show an improvement in 83% of the scores. At the same time, we observed a shift from pathological to physiological values in 50% of the pathological scores after 10 sessions of FD-MAM protocol. Conclusion: This study confirms the positive improvements on life quality in outpatients with progressive multiple sclerosis after one cycle of Fluid Dynamic Intensive MAM (FD-MAM) protocol. Initial follow-up on few patients treated with the FD-MAM protocol suggests that the results persist for six to ten months post-treatment. Future detailed studies, on MS outpatients' larger cohort, are essential to assess the duration of results and its effect on glymphatic system.

Anti-seizure effects of norepinephrine-induced free fatty acid release.

The brain's ability to rapidly transition between sleep, quiet wakefulness, and states of high vigilance is remarkable. Cerebral norepinephrine (NE) plays a key role in promoting wakefulness, but how does the brain avoid neuronal hyperexcitability upon arousal? Here, we show that NE exposure results in the generation of free fatty acids (FFAs) within the plasma membrane from both astrocytes and neurons. In turn, FFAs dampen excitability by differentially modulating the activity of astrocytic and neuronal Na+, K+, ATPase. Direct application of FFA to the occipital cortex in awake, behaving mice dampened visual-evoked potential (VEP). Conversely, blocking FFA production via local application of a lipase inhibitor heightened VEP and triggered seizure-like activity. These results suggest that FFA release is a crucial step in NE signaling that safeguards against hyperexcitability. Targeting lipid-signaling pathways may offer a novel therapeutic approach for seizure prevention.

Multifaceted role of thrombin in subarachnoid hemorrhage: Focusing on cerebrospinal fluid circulation disorder.

Subarachnoid hemorrhage (SAH) is a severe neurological condition characterized by high morbidity and mortality. The unfavorable prognosis of SAH is closely associated with early brain injury (EBI) and delayed cerebral ischemia (DCI), wherein thrombin plays a role as part of the secondary injury components following hemorrhage in these two pathological processes. Additionally, thrombin contributes to disruptions in the circulation of cerebrospinal fluid (CSF), thereby giving rise to a spectrum of sequelae following SAH, including cerebral edema, hydrocephalus, cognitive impairments, and depressive symptoms. This review aims to provide a comprehensive understanding of the pathological role of thrombin in EBI, DCI, and CSF circulation following SAH, with a specific focus on its impact on the glymphatic-meningeal lymphatic system-a crucial mechanism for waste clearance and neurohomeostatic regulation. Additionally, this review offers an overview of current pharmacological interventions and treatment modalities targeting pathogenic mechanisms, aiming to mitigate brain injury and promote neurological recovery post-SAH.

Very Low-Intensity Ultrasound Facilitates Glymphatic Influx and Clearance via Modulation of the TRPV4-AQP4 Pathway.

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has previously been shown to be associated with several neurological diseases, including Alzheimer's disease, traumatic brain injury, and stroke. As such, it may serve as an important target for therapeutic interventions. In the present study, very low-intensity ultrasound (VLIUS) (center frequency, 1 MHz; pulse repetition frequency, 1 kHz; duty factor, 1%; spatial peak temporal average intensity [Ispta] = 3.68 mW cm2; and duration, 5 min) is found to significantly enhance the influx of cerebrospinal fluid tracers into the paravascular spaces of the brain, and further facilitate interstitial substance clearance from the brain parenchyma, including exogenous ß-amyloid. Notably, no evidence of brain damage is observed following VLIUS stimulation. VLIUS may enhance glymphatic influx via the transient receptor potential vanilloid-4-aquaporin-4 pathway in astrocytes. This mechanism may provide insights into VLIUS-regulated glymphatic function that modifies the natural course of central nervous system disorders related to waste clearance dysfunction.

A brain-wide solute transport model of the glymphatic system.

Brain waste is largely cleared via diffusion and advection in cerebrospinal fluid (CSF). CSF flows through a pathway referred to as the glymphatic system, which is also being targeted for delivering drugs to the brain. Despite the importance of solute transport, no brain-wide models for predicting clearance and delivery through perivascular pathways and adjacent parenchyma existed. We devised such a model by upgrading an existing model of CSF flow in the mouse brain to additionally solve advection-diffusion equations, thereby estimating solute transport. We simulated steady-state transport of 3 kDa dextran injected proximal to the perivascular space (PVS) of the middle cerebral artery, mimicking in vivo experiments. We performed a sensitivity analysis of 11 biological properties of PVSs and brain parenchyma by repeatedly simulating solute transport with varying parameter values. Parameter combinations that led to a large total pressure gradient, poor CSF perfusion or a steep solute gradient were deemed unrealistic. Solute concentrations in parenchyma were most sensitive to changes in pial PVS size, as this parameter linearly affects volume flow rates. We also found that realistic transport requires both highly permeable penetrating PVSs and high-resistance parenchyma. This study highlights the potential of brain-wide models to provide insights into solute transport processes.

Investigating DTI-ALPS index and its association with cognitive impairments in patients with alcohol use disorder: A diffusion tensor imaging study.

BACKGROUND: The glymphatic system, a physiological pathway recently identified, has attracted considerable attention for its potential role in the pathophysiology of neurological disorders. Despite significant research efforts, the exact contribution of the glymphatic system to alcohol use disorder (AUD) remains largely elusive. This study was a secondary analysis by analyzing a subset of the original data to examine changes in the ALPS index and determine its association with cognitive abilities in individuals with AUD. METHODS: We recruited 40 individuals with AUD and 40 healthy controls (HC). All subjects underwent MRI scans and clinical cognitive scale assessments. Diffusion tensor imaging along the perivascular space (DTI-ALPS) index was used to estimate the differences in glymphatic activity between both groups, and linear regression analysis was used to examine the association between ALPS index and cognitive performance measures. RESULTS: A statistically significant difference in the ALPS index was observed between both groups (p < 0.001), with the AUD group showing statistically lower ALPS index compared with the HC group (p < 0.001). Additionally, a positive correlation was identified between the ALPS index and MoCA/MMSE scores, indicating that higher ALPS index is indicative of better cognitive performance in individuals with AUD. CONCLUSIONS: The findings of this study provide evidence of ALPS index in individuals with AUD and establish a link between the ALPS index and the cognitive impairments observed in AUD patients. These findings might suggest the importance of glymphatic activity in the emergence of cognitive deficits among those impacted by AUD, but a stronger link between ALPS index and glymphatic system is needed to better understand the relationship between glymphatic function and healthy outcomes.

Glymphatic system dysfunction and risk of clinical milestones in patients with Parkinson disease.

BACKGROUND AND PURPOSE: Glymphatic dysfunction may play a significant role in the development of neurodegenerative diseases. We aimed to evaluate the association between glymphatic dysfunction and the risk of malignant event/clinical milestones in Parkinson disease (PD). METHODS: This study included 236 patients from August 2014 to December 2020. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index was calculated as an approximate measure of glymphatic function. The primary outcomes were four clinical milestones including recurrent falls, wheelchair dependence, dementia, and placement in residential or nursing home care. The associations of DTI-ALPS with the risk of clinical milestones were examined using multivariate Cox proportional hazards regression models. Then, logistic regression was repeated using clinical variables and DTI-ALPS index individually and in combination of the two to explore the ability to distinguish patients who reached clinical milestones within a 5-year period. RESULTS: A total of 175 PD patients with baseline DTI-ALPS index and follow-up clinical assessments were included. A lower DTI-ALPS was independently associated with increased risk of recurrent falls, wheelchair dependence, and dementia. Additionally, in 103 patients monitored over 5 years, a logistic regression model combining clinical variables and DTI-ALPS index showed better performance for predicting wheelchair dependence within 5 years than a model using clinical variables or DTI-ALPS index alone. CONCLUSIONS: Glymphatic dysfunction, as measured by the DTI-ALPS index, was associated with increased risk of clinical milestones in patients with PD. This finding implies that therapy targeting the glymphatic system may serve as a viable strategy for slowing down the progression of PD.

Alterations in the DTI-ALPS index and choroid plexus volume are associated with clinical symptoms in participants with narcolepsy type 1.

BACKGROUND: Narcolepsy type 1 (NT1) is a sleep disorder characterized by excessive daytime sleepiness accompanied by cataplexy. Sleep disorders have been shown to affect the glymphatic system. This study aimed to evaluate changes in the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus (CP) volume in NT1 participants, and to further explore their clinical significance. METHODS: We prospectively enrolled participants diagnosed with NT1 based on cerebrospinal fluid hypocretin-1 concentration and multiple sleep latency tests at our hospital. All participants underwent MRI to allow analysis of the DTI-ALPS index and CP volume. We subsequently performed correlation analyses between the DTI-ALPS index, CP volume, and important clinical parameters, including the Epworth Sleepiness Scale (ESS) score, Narcolepsy Severity Scale (NSS) score, stage rapid eye movement sleep (REM) ratio, stage 1 non-REM (N1) ratio, stage 2 non-REM (N2) ratio, and stage 3 non-REM (N3) ratio, among the NT1 participants. Inter-group and correlation analyses of DTI-ALPS index and CP volume were performed using age, sex, body mass index, and lateral ventricle volume as covariates. RESULTS: This study enrolled 41 NT1 participants and 42 healthy controls (HC). The DTI-ALPS index of NT1 participants was significantly lower than HC (1.444 ± 0.119 vs.1.661 ± 0.135, P < 0.001), while the CP volume of NT1 participants was significantly larger than those of HC (0.831 ± 0.146 vs. 0.645 ± 0.137, P < 0.001). The DTI-ALPS index was negatively correlated with both the ESS (PFDR-corrected<0.001) and NSS scores (PFDR-corrected = 0.010), but positively correlated with the Stage N3 ratio (PFDR-corrected = 0.033). The CP volume of NT1 participants was positively correlated with ESS (PFDR-corrected = 0.047) and NSS scores (PFDR-corrected = 0.047), but negatively correlated with the stage N3 ratio (PFDR-corrected = 0.047). CONCLUSION: Our study suggests that the DTI-ALPS index was lower and CP volume was larger in NT1 participants. The DTI-ALPS index and CP volume in the NT1 participants were related to disease severity and sleep structure. These findings may provide new insights into the mechanisms underlying NT1.

The Dysregulation of the Glymphatic System in Patients with Psychosis Spectrum Disorders Minimally Exposed to Antipsychotics: La dérégulation du système glymphatique en présence de troubles psychotiques chez des patients peu exposés à des antipsychotiques.

OBJECTIVE: The pathophysiological mechanisms influencing psychosis spectrum disorders are largely unknown. The glymphatic system, which is a brain waste clearance pathway, has recently been implicated in its pathophysiology and has also been shown to be disrupted in various neurodegenerative and vascular diseases. Initial studies examining the glymphatic system in psychosis spectrum disorders have reported disruptions, but the findings have been confounded by medication effects as they included antipsychotic-treated patients. In this study, we used diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) as a technique to measure the functionality of the glymphatic system in a sample of antipsychotic-minimally exposed patients with psychosis spectrum disorders and healthy controls. METHODS: The study included 13 antipsychotic-minimally exposed (2 weeks antipsychotic exposure in the past 3 months/lifetime) patients with psychosis spectrum disorders and 114 healthy controls. We quantified water diffusion metrics along the x-, y-, and z-axes in both projection and association fibres to derive the DTI-ALPS index, a proxy for glymphatic activity. Between-group differences were analyzed using two-way ANCOVA controlling for age and sex. Partial correlations were used to assess the association between the ALPS index and clinical variables. RESULTS: Analyses revealed that antipsychotic-minimally exposed psychosis spectrum disorder patients had a lower DTI-ALPS index value than healthy controls in both hemispheres and the whole brain (all P < 0.005). Significant differences were also observed between the x and y projections/associations between patients and healthy controls (P < 0.001). Furthermore, we did not find any significant correlations (all P > 0.05) between the DTI-ALPS index with age, body mass index, symptomatology, and metabolic parameters. CONCLUSION: This study shows that the glymphatic system is dysregulated in antipsychotic-minimally exposed patients with psychosis spectrum disorders. Understanding the mechanisms that influence the glymphatic system may help to understand the pathophysiology of psychosis spectrum disorders as proper waste clearance is needed for normal brain functioning.

Continuous theta burst stimulation ameliorates cognitive deficits in microinfarcts mice via inhibiting glial activation and promoting paravascular CSF-ISF exchange.

Microinfarcts are widespread in the elderly, accompanied by varying degrees of cognitive decline. Continuous theta burst stimulation (cTBS) has been demonstrated to be neuroprotective on cognitive dysfunction, but the underlying cellular mechanism has been still not clear. In the present study, we evaluated the effects of cTBS on cognitive function and brain pathological changes in mice model of microinfarcts. The spatial learning and memory was assessed by Morris water maze (MWM), Glymphatic clearance efficiency was evaluated using in vivo two-photon imaging. The loss of neurons, activation of astrocytes and microglia, the expression and polarity distribution of the astrocytic aquaporin-4 (AQP4) were assessed by immunofluorescence staining. Our results showed that cTBS treatment significantly improved the spatial learning and memory, accelerated the efficiency of glymphatic clearance, up-regulated the AQP4 expression and improved the polarity distribution of AQP4 in microinfarcts mice. Besides, cTBS treatment increased the number of surviving neurons, whereas decreased the activated astrocytes and microglia. Our study suggested that cTBS accelerated glymphatic clearance and inhibited the excessive gliogenesis, which ultimately exerted neuroprotective effects on microinfarcts mice.

Effect of glymphatic system function on cognitive function in patients with chronic kidney disease.

Objectives: Studies have recently shown an alteration of the structural connectivity and a dysfunctional glymphatic system in patients with chronic kidney disease (CKD). In this study, we aimed to investigate the effects of the structural connectivity and glymphatic system on the cognitive function of patients with CKD. Methods: We prospectively enrolled patients with CKD and healthy controls. The CKD group was divided into two regarding their cognitive function. All patients received brain magnetic resonance imaging, including diffusion tensor imaging (DTI). We calculated the measures of structural connectivity and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, a neuroimaging marker of the glymphatic system function, and compared the indices between groups. Results: The mean clustering coefficient, local efficiency, and small-worldness index in patients with CKD were lower than those in healthy controls (0.125 ± 0.056 vs. 0.167 ± 0.082, p = 0.008; 1.191 ± 0.183 vs. 1.525 ± 0.651, p = 0.002; 0.090 ± 0.043 vs. 0.143 ± 0.102, p = 0.003; respectively). The DTI-ALPS index was lower in patients with CKD than in healthy controls (1.436 vs. 1.632, p < 0.001). Additionally, the DTI-ALPS index differed significantly between CKD patients with and without cognitive impairment. Notably, this index was lower in patients with CKD and cognitive impairment than in patients without cognitive impairment (1.338 vs. 1.494, p = 0.031). However, there were no differences of the structural connectivity between CKD patients with and without cognitive impairment. Conclusion: We found lower DTI-ALPS index in patients with CKD, which could be related with glymphatic system dysfunction. Moreover, those with cognitive impairment in the CKD group had a lower index than those without, indicating a link between the glymphatic system function and cognitive function.

Crucial role of Aquaporin-4 extended isoform in brain water Homeostasis and Amyloid-ß clearance: implications for Edema and neurodegenerative diseases.

The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-ß (Aß) removal was assessed using a fluorescent Aß intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aß clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aß removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aß. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's.

Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.

The Cerebrovascular Side of Plasticity: Microvascular Architecture across Health and Neurodegenerative and Vascular Diseases.

The delivery of nutrients to the brain is provided by a 600 km network of capillaries and microvessels. Indeed, the brain is highly energy demanding and, among a total amount of 100 billion neurons, each neuron is located just 10-20 µm from a capillary. This vascular network also forms part of the blood-brain barrier (BBB), which maintains the brain's stable environment by regulating chemical balance, immune cell transport, and blocking toxins. Typically, brain microvascular endothelial cells (BMECs) have low turnover, indicating a stable cerebrovascular structure. However, this structure can adapt significantly due to development, aging, injury, or disease. Temporary neural activity changes are managed by the expansion or contraction of arterioles and capillaries. Hypoxia leads to significant remodeling of the cerebrovascular architecture and pathological changes have been documented in aging and in vascular and neurodegenerative conditions. These changes often involve BMEC proliferation and the remodeling of capillary segments, often linked with local neuronal changes and cognitive function. Cerebrovascular plasticity, especially in arterioles, capillaries, and venules, varies over different time scales in development, health, aging, and diseases. Rapid changes in cerebral blood flow (CBF) occur within seconds due to increased neural activity. Prolonged changes in vascular structure, influenced by consistent environmental factors, take weeks. Development and aging bring changes over months to years, with aging-associated plasticity often improved by exercise. Injuries cause rapid damage but can be repaired over weeks to months, while neurodegenerative diseases cause slow, varied changes over months to years. In addition, if animal models may provide useful and dynamic in vivo information about vascular plasticity, humans are more complex to investigate and the hypothesis of glymphatic system together with Magnetic Resonance Imaging (MRI) techniques could provide useful clues in the future.

Modeling CSF circulation and the glymphatic system during infusion using subject specific intracranial pressures and brain geometries.

BACKGROUND: Infusion testing is an established method for assessing CSF resistance in patients with idiopathic normal pressure hydrocephalus (iNPH). To what extent the increased resistance is related to the glymphatic system is an open question. Here we introduce a computational model that includes the glymphatic system and enables us to determine the importance of (1) brain geometry, (2) intracranial pressure, and (3) physiological parameters on the outcome of and response to an infusion test. METHODS: We implemented a seven-compartment multiple network porous medium model with subject specific geometries from MR images using the finite element library FEniCS. The model consists of the arterial, capillary and venous blood vessels, their corresponding perivascular spaces, and the extracellular space (ECS). Both subject specific brain geometries and subject specific infusion tests were used in the modeling of both healthy adults and iNPH patients. Furthermore, we performed a systematic study of the effect of variations in model parameters. RESULTS: Both the iNPH group and the control group reached a similar steady state solution when subject specific geometries under identical boundary conditions was used in simulation. The difference in terms of average fluid pressure and velocity between the iNPH and control groups, was found to be less than 6% during all stages of infusion in all compartments. With subject specific boundary conditions, the largest computed difference was a 75% greater fluid speed in the arterial perivascular space (PVS) in the iNPH group compared to the control group. Changes to material parameters changed fluid speeds by several orders of magnitude in some scenarios. A considerable amount of the CSF pass through the glymphatic pathway in our models during infusion, i.e., 28% and 38% in the healthy and iNPH patients, respectively. CONCLUSIONS: Using computational models, we have found the relative importance of subject specific geometries to be less important than individual differences in resistance as measured with infusion tests and model parameters such as permeability, in determining the computed pressure and flow during infusion. Model parameters are uncertain, but certain variations have large impact on the simulation results. The computations resulted in a considerable amount of the infused volume passing through the brain either through the perivascular spaces or the extracellular space.

The perivascular space is a conduit for cerebrospinal fluid flow in humans: A proof-of-principle report.

The glymphatic pathway was defined in rodents as a network of perivascular spaces (PVSs) that facilitates organized distribution of cerebrospinal fluid (CSF) into the brain parenchyma. To date, perivascular CSF and cerebral interstitial fluid exchange has not been shown in humans. Using intrathecal gadolinium contrast-enhanced MRI, we show that contrast-enhanced CSF moves through the PVS into the parenchyma, supporting the existence of a glymphatic pathway in humans.

T2 MRI visible Perivascular Spaces in Parkinson`s Disease: clinical significance and association with polysomnography measured sleep.

Poor sleep quality might contribute to the risk and progression of neurodegenerative disorders via deficient cerebral waste clearance functions during sleep. In this retrospective cross-sectional study, we explore the link between enlarged perivascular spaces (PVS), a putative marker of sleep-dependent glymphatic clearance, with sleep quality and motor symptoms in Parkinson`s disease (PD) patients. T2-weighted MRI images of 20 patients and 17 healthy control subjects were estimated visually for PVS in the basal ganglia (BG) and centrum semiovale (CSO). The patient group additionally underwent a single-night polysomnography. Readouts included polsyomnographic sleep features and slow-wave activity (SWA), a quantitative EEG marker of sleep depth. Associations between PVS counts, PD symptoms (MDS-UPDRS scores) and sleep parameters were evaluated using correlation and regression analyses. Intra- and inter-rater reproducibility was assessed with weighted Cohen`s kappa coefficient. BG and CSO PVS counts in both patients and controls did not differ significantly between groups. In patients, PVS in both brain regions were negatively associated with SWA (1-2Hz) (BG: r(15)=-0.58, padj=0.015 and CSO: r(15)=-0.6, padj=0.015). Basal ganglia PVS counts were positively associated with motor symptoms of daily living (IRR=1.05, CI [1.01, 1.09], p=0.007, padj=0.026) and antidepressant use (IRR=1.37, CI [1.05, 1.80], p=0.021, padj=0.043) after controlling for age. Centrum Semiovale PVS counts in patients were positively associated with a diagnosis of REM sleep behaviour disorder (IRR=1.39, CI [1.06 , 1.84]), p=0.018, padj=0.11). These results add evidence that sleep deterioration may play a role in impairing glymphatic clearance via altered perivascular function, potentially contributing to disease severity in PD patients.