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BackgroundThe adequacy of leptomeningeal collateral flow has a pivotal role in determining clinical outcome in acute ischemic stroke. The American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral score is among the most commonly used scales for measuring this flow. It is based on the extent and rate of retrograde collateral flow to the impaired territory on angiography.ObjectiveTo evaluate inter- and intraobserver agreementin angiographic leptomeningeal collateral flow assessment.Materials and methodsThirty pretreatment angiogram video loops (frontal and lateral view), chosen from the randomized controlled trial THRombectomie des Artères CErebrales (THRACE), were sent for grading in an electronic file. 19 readers participated, including eight who had access to a training set before the first grading. 13 readers made a double evaluation, 3 months apart.ResultsOverall agreement among the 19 observers was poor (κ = 0,16 ± 6,5.10 -3), and not improved with prior training (κ = 0,14 ± 0,016). Grade 4 showed the poorest interobserver agreement (κ=0.18±0.002) while grades 0 and 1 were associated with the best results (κ=0.52±0.001 and κ=0.43±0.004, respectively). Interobserver agreement increased (κ = 0,27± 0,014) when a dichotomized score, ‘poor collaterals’ (score of 0, 1 or 2) versus ‘good collaterals’ (score of 3 or 4) was used. The intraobserver agreements varied between slight (κ=0.18±0.13) and substantial (κ=0.74±0.1), and were slightly improved with the dichotomized score (from κ=0.19±0.2 to κ=0.79±0.11).ConclusionInter- and intraobserver agreement of collateral circulation grading using the ASITN/SIR score was poor, raising concerns about comparisons among publications. A simplified dichotomized judgment may be a more reproducible assessment when images are rated by the same observer(s) in randomized trials.

Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (PD). However, there is no direct evidence in humans to support this role 1 – 5 . In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD. Reduced meningeal lymphatic flow detected in patients with idiopathic Parkinson’s disease compared to patients with atypical Parkinsonian disorders and cognitively normal controls.

Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases. How does the brain rid itself of waste products? Other organs in the body achieve this via a system called the lymphatic system. A network of lymphatic vessels extends throughout the body in a pattern similar to that of blood vessels. Waste products from cells, plus bacteria, viruses and excess fluids drain out of the body’s tissues into lymphatic vessels, which transfer them to the bloodstream. Blood vessels then carry the waste products to the kidneys, which filter them out for excretion. Lymphatic vessels are also a highway for circulation of white blood cells, which fight infections, and are therefore an important part of the immune system. Unlike other organs, the brain does not contain lymphatic vessels. So how does it remove waste? Some of the brain’s waste products enter the fluid that bathes and protects the brain – the cerebrospinal fluid – before being disposed of via the bloodstream. However, recent studies in rodents have also shown the presence of lymphatic vessels inside the outer membrane surrounding the brain, the dura mater. Absinta, Ha et al. now show that the dura mater of people and marmoset monkeys contains lymphatic vessels too. Spotting lymphatic vessels is challenging because they resemble blood vessels, which are much more numerous. In addition, Absinta, Ha et al. found a way to visualize the lymphatic vessels in the dura mater using brain magnetic resonance imaging, and could confirm that lymphatic vessels are present in autopsy tissue using special staining methods. For magnetic resonance imaging, monkeys and human volunteers received an injection of a dye-like substance called gadolinium, which travels via the bloodstream to the brain. In the dura mater, gadolinium leaks out of blood vessels and collects inside lymphatic vessels, which show up as bright white areas on brain scans. To confirm that the white areas were lymphatic vessels, the experiment was repeated using a different dye that does not leak out of blood vessels. As expected, the signals observed in the previous brain scans did not appear. By visualizing the lymphatic system, this technique makes it possible to study how the brain removes waste products and circulates white blood cells, and to examine whether this process is impaired in aging or disease.

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain. Studies in animal models have visualized drainage of interstitial or cerebrospinal fluid via lymphatic vessels, but there is limited data on in humans. Here, the authors non-invasively visualize lymphatic structures in the human brain, including evidence of lymphatic flow from cranial nerves to cervical lymph nodes, and differences by age and sex, without use of contrast agents.

Regular voluntary exercise has been shown to increase waste transport through the glymphatic system in mice. Here, we investigate the impact of physical exercise on both upstream and downstream brain waste clearance in healthy volunteers via noninvasive MR imaging. Putative glymphatic influx, evaluated using intravenous contrast-enhanced dynamic T1 mapping, increases significantly at the putamen after 12 weeks of long-term exercise using a cycle ergometer. The putative meningeal lymphatic vessel size and flow, measured by intravenous contrast-enhanced black-blood imaging and IR-ALADDIN technique, increase significantly after long-term exercise. Plasma proteomics reveals significant changes in inflammation-related and immune-related proteins (down-regulated: S100A8, S100A9, PSMA3, and DEFA1A3; up-regulated: J chain) after long-term exercise, which correlate with putative glymphatic influx or mLV flow. Our results suggest that increased glymphatic and mLV flow may be the potential mechanism underlying the neuroprotective effects of exercise on cognition, highlighting the importance of long-term, regular exercise. This study shows that long-term exercise improves brain waste clearance by enhancing glymphatic influx and mLV flow through neuroinflammation reduction, highlighting exercise as a promising non-drug strategy to prevent neurodegenerative diseases.

Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report an assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Individuals with the APOE4 allele have a lifetime enhanced risk for Alzheimer's disease (AD) including earlier average onset of amyloid and tau. [F-18]MK6240 is a PET radioligand that binds to tau aggregates in AD, however, variable MK6240 off-target signal in the meninges adjacent to target regions can influence PET quantification. Previous studies (Smith, 2021) have identified higher MK6240 meninges signal in females and a PET signal dependence on scanner model. The goal of this study is to compare the magnitude and distribution of meninges MK6240 signal observed in APOE4 carrier and non-carrier populations. All participants (n = 1051) were scanned at the University of Wisconsin-Madison from 90-110 minutes on a Biograph Horizon mCT or ECAT HR+ (Table 1). MK6240 PET images were processed using a standardized pipeline to generate SUVR images using the inferior cerebellar grey matter reference region and smoothed to a common 6mm resolution. The meninges ROI used was created by diluting the MNI-152 cortical brain mask by 5mm and then subtracting the original mask. This mask was then warped into native space for analysis. APOE4 carriers and non-carriers were compared using a multiple regression model inlcuding meninges SUVR with APOE4 carriage, sex, scanner model and the interaction terms between variables. In a subgroup of the study a sensitivity analysis including female participants imaged on the HR+ (n = 349) was performed with a student's t-test comparing carriers and non-carriers. Higher average meninges signal was observed for APOE4 carriers (p = 0.03), females (p < 0.001) and participants imaged on the mCT (p < 0.001). No significant interaction terms were observed. In the sensitivity analysis female APOE4 carriers on the HR+ had significantly higher meninges signal (p = 0.009). Similar results were observed with female participants on the mCT (p = 0.05), although the differences for males were not significant on either scanner (p = 0.24, p = 0.15). Spill-in effects from MK6240 meninges signal can potentially bias tracer outcomes in target analysis regions. Meninges signal can be highly variable, but the relationships between APOE4 carriage and sex on this measure should be accounted for in MK6240 quantification and population-based comparisons.

Individuals with the APOE4 allele have a lifetime enhanced risk for Alzheimer's disease (AD) including earlier average onset of amyloid and tau. [F-18]MK6240 is a PET radioligand that binds to tau aggregates in AD, however, variable MK6240 off-target signal in the meninges adjacent to target regions can influence PET quantification. Previous studies (Smith, 2021) have identified higher MK6240 meninges signal in females and a PET signal dependence on scanner model. The goal of this study is to compare the magnitude and distribution of meninges MK6240 signal observed in APOE4 carrier and non-carrier populations. All participants (n = 1051) were scanned at the University of Wisconsin-Madison from 90-110 minutes on a Biograph Horizon mCT or ECAT HR+ (Table 1). MK6240 PET images were processed using a standardized pipeline to generate SUVR images using the inferior cerebellar grey matter reference region and smoothed to a common 6mm resolution. The meninges ROI used was created by diluting the MNI-152 cortical brain mask by 5mm and then subtracting the original mask. This mask was then warped into native space for analysis. APOE4 carriers and non-carriers were compared using a multiple regression model inlcuding meninges SUVR with APOE4 carriage, sex, scanner model and the interaction terms between variables. In a subgroup of the study a sensitivity analysis including female participants imaged on the HR+ (n = 349) was performed with a student's t-test comparing carriers and non-carriers. Higher average meninges signal was observed for APOE4 carriers (p = 0.03), females (p < 0.001) and participants imaged on the mCT (p < 0.001). No significant interaction terms were observed. In the sensitivity analysis female APOE4 carriers on the HR+ had significantly higher meninges signal (p = 0.009). Similar results were observed with female participants on the mCT (p = 0.05), although the differences for males were not significant on either scanner (p = 0.24, p =  0.15). Spill-in effects from MK6240 meninges signal can potentially bias tracer outcomes in target analysis regions. Meninges signal can be highly variable, but the relationships between APOE4 carriage and sex on this measure should be accounted for in MK6240 quantification and population-based comparisons.

Variability in meningeal signal has been observed with various tau-PET tracers. Differences have been observed in sex and age. Furthermore, the potential role of glymphatic clearance in this variability remains unclear. Here we compare meningeal signal of [ F]MK6240 and [ F]FTP tau-PET tracers in cognitively unimpaired (CU) amyloid-β- (Aβ-) individuals, in relation to age, sex and glymphatic clearance. 92 CU Aβ- (7 CU young [18-35yo] and 85 CU old) underwent [ F]MK6240 and [ F]FTP tau-PET scans, structural MRI, and resting-state functional MRI (rsfMRI). In native space, we defined nine distinct levels representing meningeal regions, organized from those closest to the cortex (1) to those furthest away (9). Glymphatic clearance, measured as gBOLD/CSF coupling, was calculated for each participant; a lower value means a more efficient glymphatic clearance. Associations between meningeal tracer signal and factors such as sex, age, and glymphatic clearance were analyzed using t-tests and linear regression models. All 9 meningeal regions were tested and rendered similar results; we will be showing those for meninges level 2. [ F]MK6240 and [ F]FTP meningeal signal significantly correlated with each other in both sexes (Figure 1). We observed higher [ F]MK6240 meningeal signal in females compared to males while no difference was found for [ F]FTP signal (Figure 2). In females, [ F]MK6240 meningeal signal did not show a significant association with age, whereas in males, a significant relationship was observed. Both males and females exhibited lower [ F]FTP meningeal signal with increasing age (Figure 3A). Additionally, glymphatic clearance was significantly associated with age for females with [ F]MK6240. No significant associations were found in males with [ F]MK6240 or in either sex for [ F]FTP (Figure 3B). Our findings demonstrate that meningeal signal of [ F]MK6240 is significantly associated with glymphatic clearance in females, while in males, it is associated with age. In contrast, [ F]FTP signal is primarily influenced by age in both sexes. These results highlight the distinct relationship between [ F]MK6240 signal and glymphatic function in females, while age appears to play a significant role in both males and females for other tracer signal patterns.