Glymphatic Function Research Articles

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia.

Glymphatic function has not yet been explored in behavioral variant frontotemporal dementia (bvFTD). The spatial correlation between regional glymphatic function and bvFTD remains unknown. A total of 74 patients with bvFTD and 67 age- and sex-matched healthy controls (HCs) were selected from discovery dataset and replication dataset. All participants underwent neuropsychological assessment. Glymphatic measures including choroid plexus (CP) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling between blood-oxygen-level-dependent signals and cerebrospinal fluid signals (BOLD-CSF coupling), were compared between the two groups. Regional glymphatic function was evaluated by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, and posterior regions. The bvFTD-related metabolic pattern was identified using spatial covariance analysis based on l8 F-FDG-PET. Patients with bvFTD showed higher CP volume (p < 0.001); anterior and middle DTI-ALPS (p < 0.001); and weaker anterior BOLD-CSF coupling (p < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI-ALPS was negatively associated with the expression of the bvFTD-related metabolic pattern (r = -0.52, p = 0.034) and positively related with regional standardized uptake value ratios of l8 F-FDG-PET in bvFTD-related brain regions (r range: 0.49 to 0.62, p range: 0.017 to 0.047). Anterior and middle glymphatic functions were related to global cognition and disease severity. Our findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD. ANN NEUROL 2023;94:442-456.

The asymmetry of glymphatic system dysfunction in patients with temporal lobe epilepsy: A DTI-ALPS study

Background and purposeWhile the occurrence of glymphatic system dysfunction has been observed in temporal lobe epilepsy (TLE), the potential asymmetry of this system has yet to be investigated in the TLE context. We aimed to investigate the glymphatic system function in both hemispheres and to analyze asymmetric features of the glymphatic system in TLE patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Materials and methods43 patients (left TLE (LTLE), n = 20; right TLE (RTLE), n = 23) and 39 healthy controls (HC) were enrolled in this study. The DTI-ALPS index was calculated for the left (left ALPS index) and right (right ALPS index) hemispheres respectively. An asymmetry index (AI) was calculated by AI = (Right − Left)/ [(Right + Left)/2] to represent the asymmetric pattern. Independent two sample t-test, two-sample paired t-test or one-way ANOVA with Bonferroni correction were conducted to compare the differences in ALPS indices and AI among the groups. ResultsBoth left ALPS index (p = 0.040) and right ALPS index (p = 0.001) of RTLE patients were significantly decreased, while only left ALPS index of LTLE patients (p = 0.005) was reduced. Compared to contralateral ALPS index, the ipsilateral ALPS index was significantly decreased in TLE (p = 0.008) and RTLE (p = 0.009) patients. Leftward asymmetry of the glymphatic system was found in HC (p = 0.045) and RTLE (p = 0.009) patients. The LTLE patients presented reduced asymmetric traits when compared to RTLE patients (p = 0.029). ConclusionThe TLE patients exhibited altered ALPS indices, which could be triggered by glymphatic system dysfunction. Altered ALPS indices were more severe in ipsilateral than in the contralateral hemisphere. Moreover, LTLE and RTLE patients exhibited different change patterns of the glymphatic system. In addition, glymphatic system function presented asymmetric patterns in both normal adult brain and RTLE patients.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. Prospective. Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). 3-T, single-shot echo-planar imaging sequence. Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (β = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (β = 5.67, 95% CI 4.56, 6.97), executive function (β = 2.34, 95% CI 1.49, 3.20), and PSMD (β = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. 2 TECHNICAL EFFICACY: Stage 2.

Excitability and glymphatic function in an animal model of Alzheimer’s disease

AbstractBackgroundAPPswe/PS1dE9 mice reproduce features of amyloid β (Aβ) pathology and neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. This leads to changes in sleep‐wake‐rhythm, downstream affecting brain clearance functionality. Our objective is to investigate the effect of circadian rhythm and Aβ pathology on clearance efficacy in APPswe/PS1dE9 mice.MethodFirst, we examined the brain wide distribution of an intrahippocampal injected fluorescent dye. Dye was injected at 6 am (post wake period) or 6 pm (post sleep period) and sampled 1 or 3 h post injection for histological analysis (Figure 1A) in n = 3 transgenic mice and n = 3 non‐transgenic mice per group. Secondly, in an in vivo approach we analyzed the brain wide distribution of a gadolinium based contrast agent using a T2‐RARE sequence in a 7 Tesla small animal MRI scanner (Bruker BioSpin GmbH, Germany) (Figure 1B) in n = 4 transgenic mice and n = 4 non‐transgenic mice. We measured values for brightness in manually defined regions of interest with PMOD software (version 3.7; PMOD Technologies LLC, Switzerland).ResultIn the first experiment, we were able to observe dye distribution in the brain parenchyma as surrogate for interstitial clearance net flux. Preliminary results point to an effect of circadian rhythm, as a trend of better dye distribution shortly after the sleep period was observed. Furthermore, a possible detrimental effect of the Aβ phenotype on clearance was observed in transgenic mice. In comparison to non‐transgenic mice they showed a trend of lesser dye distribution independent of day‐time. With the second approach, we were able to observe influx and efflux of applied contrast agent into cerebrospinal fluid. Preliminary data point to a trend of an increased slope of the influx as well as decreased slope of the efflux in transgenic mice.ConclusionHistological analysis of a stereotactic injected dye is a feasible method for investigation of dye distribution outlining a possible effect of daytime and amyloid pathology. However, MR‐imaging is a promising tool as we will be able to observe the disease progression in mice longitudinally. Further experiments will be needed to ensure these preliminary results and maybe also point to underlying mechanistic basis.

Neurofluids and the glymphatic system: anatomy, physiology, and imaging.

First described in 2012, the glymphatic system is responsible for maintaining homeostasis within the central nervous system, including nutrient delivery, waste clearance, and consistency of the ionic microenvironment. It is comprised of glial cells and barrier systems that modulate neurofluid production, circulation, and exchange. Experimental interrogation of neurofluid dynamics is restricted to ex vivo and in vitro studies in animals and humans, therefore diagnostic imaging plays an important role in minimally invasive evaluation. This review article will synthesize current knowledge and theories regarding neurofluid circulation and implications for neuroimaging. First, we will discuss the anatomy of the neurogliovascular unit, including paravascular and perivascular pathways of fluid exchange. In addition, we will summarize the structure and function of barrier systems including the blood-brain, blood-cerebrospinal fluid, and brain-cerebrospinal fluid barriers. Next, we will mention physiologic factors that yield normal variations in neurofluid circulation, and how various disease pathologies can disrupt glymphatic drainage pathways. Lastly, we will cover the spectrum of diagnostic imaging and interventional techniques with relevance to glymphatic structure, flow, and function. We conclude by highlighting current barriers and future directions for translational imaging and applications to neurologic disorders.

Emerging Perspectives on MRI Application in Multiple Sclerosis: Moving from Pathophysiology to Clinical Practice.

MRI plays a central role in the diagnosis of multiple sclerosis (MS) and in the monitoring of disease course and treatment response. Advanced MRI techniques have shed light on MS biology and facilitated the search for neuroimaging markers that may be applicable in clinical practice. MRI has led to improvements in the accuracy of MS diagnosis and a deeper understanding of disease progression. This has also resulted in a plethora of potential MRI markers, the importance and validity of which remain to be proven. Here, five recent emerging perspectives arising from the use of MRI in MS, from pathophysiology to clinical application, will be discussed. These are the feasibility of noninvasive MRI-based approaches to measure glymphatic function and its impairment; T1-weighted to T2-weighted intensity ratio to quantify myelin content; classification of MS phenotypes based on their MRI features rather than on their clinical features; clinical relevance of gray matter atrophy versus white matter atrophy; and time-varying versus static resting-state functional connectivity in evaluating brain functional organization. These topics are critically discussed, which may guide future applications in the field.

0089 Chronic sleep disruption increases amyloid beta deposition and gliosis in the 5xFAD mouse model

Abstract Introduction Recent studies have found that mid-life sleep disruption is associated with the development of Alzheimer’s disease-related neuropathology, including the deposition of amyloid beta. Yet, the mechanism connecting sleep disruption, particularly over chronic timescales, and downstream Alzheimer’s pathology remains unclear. Methods In this study, we evaluated the impact chronic sleep disruption has on the development of neuroinflammation and amyloid beta plaques in the 5xFAD amyloidosis mouse model. Chronic sleep disruption in male and female C57BL/6 and 5xFAD+ mice was performed in Lafayette sleep fragmentation cages from 10-18 weeks of age. Glymphatic function was assessed by measuring the influx of fluorescent cerebrospinal fluid tracers into brain tissue. Aquaporin-4 localization, amyloid-beta plaque deposition, and markers of astroglial and microglial activation were assessed by immunofluorescence. Results We observed that chronic sleep disruption increased neuropathological outcomes in 5xFAD+ and littermate controls. This was evident in significantly increased amyloid-beta plaque deposition and significantly increased gliosis, indicated by increases in both astrocyte (GFAP) and microglial (Iba1) expression. The impact on glymphatic function, evaluated through both cerebrospinal fluid tracer distribution and assessment of aquaporin-4 mislocalization, was assessed in parallel and correlated with neuropathological outcomes. Conclusion These findings highlight the critical association between dysfunctional sleep and the development of Alzheimer’s-related amyloid beta pathology. They indicate that there is an interaction between chronic sleep disruption, neuroinflammation, and amyloid □ deposition. Support (if any)

0096 Short sleep duration and poor sleep quality associated with elevated serum NfL and mild cognitive impairment in older Veterans

Abstract Introduction Ten percent of adults aged ≥ 65 and 50% of adults ≥ 85 years exhibit cognitive impairment. In addition, 50% of older adults experience poor sleep quality. Veterans are more vulnerable to sleep disturbances and potential cognitive impairment as long-term consequences of on-duty responsibilities, co-morbidities, and conditions such as post-traumatic stress disorder. Previous studies demonstrated a relationship between sleep and cognitive impairment through impaired glymphatic function and neurodegeneration. Biomarkers such as neurofilament light (NfL) are elevated in neurodegeneration and dementia. Here, we sought to investigate NfL levels in cognitive-intact older Veterans exhibiting poor sleep quality. Methods A cross-sectional study with eighteen Veterans aged 65-86 without a clinical diagnosis of dementia. Self-reported sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), while time in bed (TIB), and total sleep time (TST) were retrieved from Fitbit Charge. Cognitive function was evaluated with the St. Louis University Mental Status Exam (VA-SLUMS). We used an automated multiplex immunoassay system to identify dementia biomarkers using an enzyme-linked lectin assay. T-tests, one-way or two-way ANOVAs with Tukey’s post-hoc (with or without repeated measures) were used for the analysis. Results Participants were classified as good sleepers (PSQI&amp;gt;5) and poor sleepers (PSQI&amp;lt; 5). Poor sleepers spent less TIB (Fitbit 5.3h vs. 7.7h, p =0.001) and slept fewer hours (Fitbit 4.7h vs. 7.2h, p =0.001) when compared to good sleepers. Additionally, poor sleepers exhibited mild cognitive impairment (VA SLUMS 26.9, p, =0.01). Lastly, poor sleepers exhibited higher serum NfL (mean 66.7, p=0.04). Conclusion Poor sleep quality was associated with short sleep duration, mild cognitive impairment, and higher serum levels of NfL in older Veterans without a dementia diagnosis. Results may contribute to the early identification of dementia and sleep-centered treatment guidance. Further studies with more extensive and diverse samples are warranted before clinical recommendations. Support (if any) Carleara Weiss, Ph.D., MS, RN. 1K99AG079117-01 (PI), National Institute on Aging.

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.

Vascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer's disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD. Male, middle-aged Wistar rats (10-12 m), subjected to MMI, were randomly assigned to MMI and MMI + AV-001 treatment groups. A sham group was included as reference group. MMI was induced by injecting 800 ± 200, 70-100 μm sized, cholesterol crystals into the internal carotid artery. Animals were treated with AV-001 (1 μg/Kg, i.p.) once daily starting at 24 h after MMI. At 14 days after MMI, inflammatory factor expression was evaluated in cerebrospinal fluid (CSF) and brain. Immunostaining was used to evaluate white matter integrity, perivascular space (PVS) and perivascular Aquaporin-4 (AQP4) expression in the brain. An additional set of rats were prepared to test glymphatic function. At 14 days after MMI, 50 μL of 1% Tetramethylrhodamine (3 kD) and FITC conjugated dextran (500 kD) at 1:1 ratio were injected into the CSF. Rats (4-6/group/time point) were sacrificed at 30 min, 3 h, and 6 h from the start of tracer infusion, and brain coronal sections were imaged using a Laser scanning confocal microscope to evaluate tracer intensities in the brain. Treatment of MMI with AV-001 significantly improves white matter integrity in the corpus callosum at 14 days after MMI. MMI induces significant dilation of the PVS, reduces AQP4 expression and impairs glymphatic function compared to Sham rats. AV-001 treatment significantly reduces PVS, increases perivascular AQP4 expression and improves glymphatic function compared to MMI rats. MMI significantly increases, while AV-001 significantly decreases the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), chemokine ligand 9) and anti-angiogenic factors (endostatin, plasminogen activator inhibitor-1, P-selectin) in CSF. MMI significantly increases, while AV-001 significantly reduces brain tissue expression of endostatin, thrombin, TNF-α, PAI-1, CXCL9, and interleukin-6 (IL-6). AV-001 treatment of MMI significantly reduces PVS dilation and increases perivascular AQP4 expression which may contribute to improved glymphatic function compared to MMI rats. AV-001 treatment significantly reduces inflammatory factor expression in the CSF and brain which may contribute to AV-001 treatment induced improvement in white matter integrity and cognitive function.

Age- and time-of-day dependence of glymphatic function in the human brain measured via two diffusion MRI methods.

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow-b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21-75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test-retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21-38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization.

Functional assessment of the dural lymphatic vessels using dynamic contrast MRI in multiple sclerosis.

The discovery of glymphatic function in the human brain has generated interest in waste clearance mechanisms in neurological disorders such as multiple sclerosis (MS). However, noninvasive in vivo functional assessment is currently lacking. This work studies the feasibility of a novel intravenous dynamic contrast MRI method to assess the dural lymphatics, a purported pathway contributing to glymphatic clearance. This prospective study included 20 patients with MS (17 women; age=46.4 [27, 65] years; disease duration=13.6 [2.1, 38.0] years, expanded disability status score (EDSS)=2.0 [0, 6.5]). Patients were scanned on a 3.0T MRI system using intravenous contrast-enhanced fluid-attenuated inversion recovery MRI. Signal in the dural lymphatic vessel along the superior sagittal sinus was measured to calculate peak enhancement, time to maximum enhancement, wash-in and washout slopes, and the area under the time-intensity curve (AUC). Correlation analysis was performed to examine the relationship between the lymphatic dynamic parameters and the demographic and clinical characteristics, including the lesion load and the brain parenchymal fraction (BPF). Contrast enhancement was detected in the dural lymphatics in most patients 2-3min after contrast administration. BPF had a significant correlation with AUC (p<.03), peak enhancement (p<.01), and wash-in slope (p=.01). Lymphatic dynamic parameters did not correlate with age, BMI, disease duration, EDSS, or lesion load. Moderate trends were observed for correlation between patient age and AUC (p=.062), BMI and peak enhancement (p=.059), and BMI and AUC (p=.093). Intravenous dynamic contrast MRI of the dural lymphatics is feasible and may be useful in characterizing its hydrodynamics in neurological diseases.

Gray matter reserve determines glymphatic system function in young-onset Alzheimer's disease: Evidenced by DTI-ALPS and compared with age-matched controls.

The diffusion tensor imaging analysis along the perivascular space (ALPS)-index can be used to model the glymphatic system in vivo. This study explores putative mechanisms between prediction of ALPS-index and cognitive outcomes in young-onset Alzheimer's disease (YOAD) and age-matched controls (CTLs) and analyzes whether the link was mediated by the integrity of ALPS-index-anchored cerebral gray matter (GM). We enrolled 130 patients with YOAD and 137 CTLs. All participants underwent three-dimensional T1 -weighted MRI, diffusion tensor imaging and cognitive tests. We constructed GM regions correlated with the ALPS-index in the YOAD and CTL groups. For the GM regions significantly correlated with the ALPS-index and cognitive measures, we extracted a 4-mm radius sphere. In the YOAD and CTL groups, we used mediator analysis to explore the ALPS-index as predictor, GM partitions as mediators, and significant cognitive test scores as outcomes. Patient group had significantly lower ALPS-index. The ALPS-index was associated with GM volume in the cerebellar gray, dorsolateral prefrontal, thalamus, superior frontal, amygdala and hippocampus, and these coherent regions coincided with those showing GM atrophy in the YOAD group. Mediation analysis of the YOAD group suggested that the relationships between the ALPS-index and cognitive performance were fully mediated by the integrity of ALPS-index coherent GM areas. Reserved GM mediates the link between the glymphatic system and cognition. Our findings suggest that GM integrity rather than the glymphatic system could serve as a direct cognitive test scores predictor in patients with YOAD.

Reproducibility of automated calculation technique for diffusion tensor image analysis along the perivascular space.

The method of diffusion tensor image analysis along the perivascular space (DTI-ALPS) was gathering attention to evaluate the brain's glymphatic function or interstitial fluid dynamics. However, to the best knowledge, no study was conducted on the reproducibility of these automated methods for ALPS index values. Therefore, the current study evaluated the ALPS index reproducibility based on DTI-ALPS using two major automated calculation techniques in scan and rescan of the same subject on the same day. This study included 23 participants, including 2 with Alzheimer's disease, 15 with mild cognitive impairment, and 6 with cognitive normals. Scan and rescan data of diffusion magnetic resonance images were obtained, as well as automatically index for ALPS (ALPS index) and ALPS index maintaining tensor vector orientation information (vALPS index) with region of interest on the template fractional anisotropy map calculated by FSL software.These ALPS indices were compared in terms of scan and rescan reproducibility. The absolute difference in ALPS-index values between scan and rescan was larger in the ALPS index than in the vALPS index by approximately 0.6% as the relative difference. Cohen's d for the left and right ALPS indices between methods were 0.121 and 0.159, respectively. The vALPS index based on DTI-ALPS maintaining tensor vector orientation information has higher reproducibility than the ALPS index. This result encourages a multisite study on the ALPS index with a large sample size and helps detect a subtle pathological change in the ALPS index.

Altered Brain Glymphatic Flow at Diffusion-Tensor MRI in Rapid Eye Movement Sleep Behavior Disorder.

Background Brain glymphatic dysfunction may contribute to the development of α-synucleinopathies. Yet, noninvasive imaging and quantification remain lacking. Purpose To examine glymphatic function of the brain in isolated rapid eye movement sleep behavior disorder (RBD) and its relevance to phenoconversion with use of diffusion-tensor imaging (DTI) analysis along the perivascular space (ALPS). Materials and Methods This prospective study included consecutive participants diagnosed with RBD, age- and sex-matched control participants, and participants with Parkinson disease (PD) who were enrolled and examined between May 2017 and April 2020. All study participants underwent 3.0-T brain MRI including DTI, susceptibility-weighted and susceptibility map-weighted imaging, and/or dopamine transporter imaging using iodine 123-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane SPECT at the time of participation. Phenoconversion status to α-synucleinopathies was unknown at the time of MRI. Participants were regularly followed up and monitored for any signs of α-synucleinopathies. The ALPS index reflecting glymphatic activity was calculated by a ratio of the diffusivities along the x-axis in the projection and association neural fibers to the diffusivities perpendicular to them and compared according to the groups with use of the Kruskal-Wallis and Mann-Whitney U tests. The phenoconversion risk in participants with RBD was evaluated according to the ALPS index with use of a Cox proportional hazards model. Results Twenty participants diagnosed with RBD (12 men; median age, 73 years [IQR, 66-76 years]), 20 control participants, and 20 participants with PD were included. The median ALPS index was lower in the group with RBD versus controls (1.53 vs 1.72; P = .001) but showed no evidence of a difference compared with the group with PD (1.49; P = .68). The conversion risk decreased with an increasing ALPS index (hazard ratio, 0.57 per 0.1 increase in the ALPS index [95% CI: 0.35, 0.93]; P = .03). Conclusion DTI-ALPS in RBD demonstrated a more severe reduction of glymphatic activity in individuals with phenoconversion to α-synucleinopathies. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Filippi and Balestrino in this issue.

Associations of Enlarged Perivascular Spaces With Brain Lesions, Brain Age, and Clinical Outcomes in Chronic Traumatic Brain Injury.

Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes. Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions. This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (β = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (β = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02). TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period.

Normal glymphatic system function in patients with new daily persistent headache using diffusion tensor image analysis along the perivascular space.

To investigate the glymphatic function in patients with new daily persistent headache (NDPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. NDPH, a rare and treatment-refractory primary headache disorder, is poorly understood. There is limited evidence to suggest that headaches are associated with glymphatic dysfunction. Thus far, no studies have evaluated glymphatic function in patients with NDPH. In this cross-sectional study conducted in the Headache Center of Beijing Tiantan Hospital, patients with NDPH and healthy controls were enrolled. All participants underwent brain magnetic resonance imaging examinations. Clinical characteristics and neuropsychological evaluation were examined in patients with NDPH. ALPS indexes for both hemispheres were measured to determine the glymphatic system function in patients with NDPH and healthy controls. In total, 27 patients with NDPH (14 males, 13 females; age [mean ± standard deviation (SD)]: 36.6 ± 20.6) and 33 healthy controls (15 males, 18 females; age [mean ± SD]: 36.0 ± 10.8) were included in the analysis. No significant differences between groups were observed in the left ALPS index (1.583 ± 0.182 vs. 1.586 ± 0.175, mean difference = 0.003, 95% confidence interval [CI] of difference = -0.089 to 0.096, p = 0.942), or right ALPS index (1.578 ± 0.230 vs. 1.559 ± 0.206, mean difference = -0.027, 95% CI of difference = -0.132 to 0.094, p = 0.738). Additionally, ALPS indexes were not correlated with clinical characteristics or neuropsychiatric scores. No glymphatic dysfunction was detected in patients with NDPH by means of the ALPS method. Additional studies with larger samples are needed to confirm these preliminary findings and improve the understanding of glymphatic function in NDPH.

Limb Remote Ischemic Postconditioning Improves Glymphatic Dysfunction After Cerebral Ischemia–Reperfusion Injury

BackgroundDelayed neuronal damage can be caused or aggravated after cerebral ischemia–reperfusion (I/R) injury. Recent studies have shown that glymphatic system dysfunction after cerebral ischemia–reperfusion injury is involved in ischemic brain edema and neuroinflammation, thereby regulating cerebral ischemia–reperfusion injury. The aim of this study is to investigate the changes of glymphatic system after cerebral ischemia–reperfusion injury and whether limb remote ischemic postconditioning (LRIP) can improve the function of glymphatic system to protect the brain. MethodsTo establish a focal brain I/R injury mouse model, this study utilized the middle cerebral artery occlusion/reperfusion (MCAO/R) method. The present study classified eight-week-old C57BL/6 male mice into three groups. The changes in glymphatic function in different periods of ischemia and reperfusion were analyzed through immunofluorescence, transmission electron microscopy (TEM), and Western-Blot (WB) assays. The contents of the evaluation included cerebrospinal fluid flow, swelling degree of brain tissue, aquaporin-4 (AQP4) expression and polarization, and amyloid-β (Aβ) excretion. ResultsIn the early stages of cerebral ischemia, cerebrospinal fluid (CSF) flow is disturbed, accompanied by a decrease in AQP4 polarization. The polarity of AQP4 decreased from 12 h to 72 h of reperfusion, the Aβ deposition. LRIP can increase the expression of β-DG and AQP4 polarization, reduce the deposition of Aβ, improve the function of the glymphatic system, and reduce the expression of AQP4 to play A protective role in brain. ConclusionGlymphatic system impaired after cerebral ischemia–reperfusion injury in mice. LRIP may play a neuroprotective role by improving glymphatic function after I/R.

Examining Glymphatic Flow after Traumatic Brain Injury Using Diffusion Tensor Imaging. (N5.002)

<h3>Objective:</h3> To examine the relationship between traumatic brain injury (TBI) and a biomarker of glymphatic function, diffusion tensor image analysis along the perivascular space (DTI-ALPS). <h3>Background:</h3> The glymphatic system is responsible for waste drainage via the movement of fluids along the perivascular spaces. Dysfunction of the glymphatic system is implicated in several neurological conditions but has not been well-studied in human TBI. The DTI-ALPS index has been proposed as a noninvasive biomarker of glymphatic function. <h3>Design/Methods:</h3> DTI was performed in patients with TBI at 2-weeks and 6-months post-injury, as well as in demographically matched healthy controls. Regions-of-interest were manually placed in the major fiber bundles at the level of the lateral ventricles, where they are orthogonal to perivascular spaces. DTI-ALPS index was computed by normalizing diffusivity along the orientation of these perivascular spaces to diffusivity in the perpendicular direction. <h3>Results:</h3> 85 individuals with TBI (mean age 38.5 years, 73% male, 86% mild TBI) and 44 controls (31.6 years, 61% male) were included. Pearson’s correlation analyses revealed a significant negative correlation between DTI-ALPS and age (r = −0.313, <i>p</i> = 0.0035). There was no relationship with sex, Glasgow Coma Scale, or head CT status. Compared to controls (1.61 ± 0.16), DTI-ALPS at 2-weeks (1.56 ± 0.19) and 6-months post-TBI (1.58 ± 0.22) was not significantly different (<i>p</i> &gt; 0.05). Additionally, the subset of individuals with a 6-month scan (n=43) showed no significant change over time in DTI-ALPS (<i>p</i> &gt; 0.05). <h3>Conclusions:</h3> We did not find evidence for glymphatic system dysfunction associated with primarily mild TBI in the subacute post-injury period using the DTI-ALPS index in the periventricular white matter. Further research is necessary to ascertain whether glymphatic dysfunction is present in moderate to severe TBI or whether more global assessments identify subtle glymphatic dysfunction in milder TBI. <b>Disclosure:</b> Mr. Nelson has nothing to disclose. Alexa Walter has nothing to disclose. Dr. Gugger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ceribell. The institution of Dr. Gugger has received research support from American Epilepsy Society. Dr. Schneider has nothing to disclose. The institution of Dr. Sandsmark has received research support from NINDS. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ischemix, Inc. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pinteon Therapeutics. Dr. Diaz-Arrastia has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BrainBox, LLC. Dr. Diaz-Arrastia has received stock or an ownership interest from BrainBox, LLC. Dr. Diaz-Arrastia has received stock or an ownership interest from NovaSignal . Dr. Diaz-Arrastia has received stock or an ownership interest from Nia Therpeutics. The institution of Dr. Diaz-Arrastia has received research support from National Institutes of Health. The institution of Dr. Diaz-Arrastia has received research support from Department of Defense. Jeffrey Ware has nothing to disclose.

Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders

Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegeneration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to-blood clearance variables from pharmacokinetic modeling (proxy of meningeal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neurodegeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function.