Meningeal origins and dynamics of perivascular fibroblast development on the mouse cerebral vasculature.

Perivascular fibroblasts (PVFs) are a fibroblast-like cell type that reside on large-diameter blood vessels in the adult meninges and central nervous system (CNS). PVFs contribute to fibrosis following injury but their homeostatic functions are not defined. PVFs were previously shown to be absent from most brain regions at birth and are only detected postnatally within the cerebral cortex. However, the origin, timing and cellular mechanisms of PVF development are not known. We used Col1a1-GFP and Col1a2-CreERT2 transgenic mice to track PVF development postnatally. Using lineage tracing and in vivo imaging we show that brain PVFs originate from the meninges and are first seen on parenchymal cerebrovasculature at postnatal day (P) 5. After P5, PVF coverage of the cerebrovasculature expands via local cell proliferation and migration from the meninges. Finally, we show that PVFs and perivascular macrophages develop concurrently. These findings provide the first complete timeline for PVF development in the brain, enabling future work into how PVF development is coordinated with cell types and structures in and around the perivascular spaces to support normal CNS vascular function.

Imaging of brain barrier inflammation and brain fluid drainage in human neurological diseases.

The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.

Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Development and validation of a perivascular space segmentation method in multi-center datasets.

BACKGROUND: Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) are significant markers associated with various neurological diseases. Although quantitative analysis of PVS may enhance sensitivity and improve consistency across studies, the field lacks a universally validated method for analyzing images from multi-center studies. METHODS: We annotated PVS on multi-center 3D T1-weighted (T1w) images acquired using scanners from three major vendors (Siemens, General Electric, and Philips). A neural network, mcPVS-Net (multi-center PVS segmentation network), was trained using data from 40 subjects and then tested in a separate cohort of 15 subjects. We assessed segmentation accuracy against ground truth masks tailored for each scanner vendor. Additionally, we evaluated the agreement between segmented PVS volumes and visual scores for each scanner. We also explored correlations between PVS volumes and various clinical factors such as age, hypertension, and white matter hyperintensities (WMH) in a larger sample of 1020 subjects. Furthermore, mcPVS-Net was applied to a new dataset comprising both T1w and T2-weighted (T2w) images from a United Imaging scanner to investigate if PVS volumes could discriminate between subjects with differing visual scores. We also compared the mcPVS-Net with a previously published method that segments PVS from T1 images. RESULTS: In the test dataset, mcPVS-Net achieved a mean DICE coefficient of 0.80, with an average Precision of 0.81 and Recall of 0.79, indicating good specificity and sensitivity. The segmented PVS volumes were significantly associated with visual scores in both the basal ganglia (r = 0.541, p < 0.001) and white matter regions (r = 0.706, p < 0.001), and PVS volumes were significantly different among subjects with varying visual scores. Segmentation performance was consistent across different scanner vendors. PVS volumes exhibited significant associations with age, hypertension, and WMH. In the United Imaging scanner dataset, PVS volumes showed good associations with PVS visual scores evaluated on either T1w or T2w images. Compared to a previously published method, mcPVS-Net showed a higher accuracy and improved PVS segmentation in the basal ganglia region. CONCLUSION: The mcPVS-Net demonstrated good accuracy for segmenting PVS from 3D T1w images. It may serve as a useful tool for future PVS research.

Enlarged brain perivascular spaces correlate with blood plasma osmolality in the healthy population: A longitudinal study.

Enlarged perivascular spaces (EPVS) are increasingly recognized as an MRI detectable feature of neuroinflammatory processes and age-related neurodegenerative changes. Understanding perivascular characteristics in healthy individuals is crucial for their applicability as a reference for pathological changes. Limited data exists on the EPVS load and interhemispheric asymmetry in distribution among young healthy subjects. Despite the known impact of hydration on brain morphometric studies, blood plasma osmolality's effect on EPVS remains unexplored. This study investigated the influence of age, total intracranial volume (TIV), and blood plasma osmolality on EPVS characteristics in 59 healthy adults, each undergoing MRI and osmolality assessment twice within 14.8 months (mean ± 4 months). EPVS analysis was conducted in the centrum semiovale using high-resolution automated segmentation, followed by an optimization algorithm to enhance EPVS segmentation accuracy. Linear Mixed Effects model was used for the statistical analysis, which unveiled significant inter-individual variability in EPVS load and inter-hemispheric asymmetry. EPVS volume increased with age, higher TIV and lower blood plasma osmolality levels. Our findings offer valuable insights into EPVS characteristics among the healthy population, establishing a foundation to further explore age-related and pathological changes.

Systematic review and meta-analysis of automated methods for quantifying enlarged perivascular spaces in the brain.

Research into magnetic resonance imaging (MRI)-visible perivascular spaces (PVS) has recently increased, as results from studies in different diseases and populations are cementing their association with sleep, disease phenotypes, and overall health indicators. With the establishment of worldwide consortia and the availability of large databases, computational methods that allow to automatically process all this wealth of information are becoming increasingly relevant. Several computational approaches have been proposed to assess PVS from MRI, and efforts have been made to summarise and appraise the most widely applied ones. We systematically reviewed and meta-analysed all publications available up to September 2023 describing the development, improvement, or application of computational PVS quantification methods from MRI. We analysed 67 approaches and 60 applications of their implementation, from 112 publications. The two most widely applied were the use of a morphological filter to enhance PVS-like structures, with Frangi being the choice preferred by most, and the use of a U-Net configuration with or without residual connections. Older adults or population studies comprising adults from 18 years old onwards were, overall, more frequent than studies using clinical samples. PVS were mainly assessed from T2-weighted MRI acquired in 1.5T and/or 3T scanners, although combinations using it with T1-weighted and FLAIR images were also abundant. Common associations researched included age, sex, hypertension, diabetes, white matter hyperintensities, sleep and cognition, with occupation-related, ethnicity, and genetic/hereditable traits being also explored. Despite promising improvements to overcome barriers such as noise and differentiation from other confounds, a need for joined efforts for a wider testing and increasing availability of the most promising methods is now paramount.

Spaceflight-associated neuro-ocular syndrome: potential etiologies and connections to the glymphatic system.

The etiology of spaceflight-associated neuro-ocular syndrome (SANS) is a developing field of research, with many current hypotheses receiving varying degrees of support. This syndrome affects ∼70% of astronauts both during and after long-duration space missions, resulting in impaired near vision and visual scotomas (blind spots). In this article, three prominent risk factors for SANS including zero gravity conditions, extraterrestrial hypercapnic environments, and individual genetic predisposition are described. These risk factors are then compared and their pathophysiological pathways are divided into five current hypotheses for the development of SANS. Finally, glymphatic system impairment is explored as a potential mutual end point for these pathways in the development of SANS.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

A "glympse" into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin-4 for the assessment of glymphatic system in Alzheimer's disease and other dementias.

The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage.

Effects of prospective motion correction on perivascular spaces at 7T MRI evaluated using motion artifact simulation.

PURPOSE: The effectiveness of prospective motion correction (PMC) is often evaluated by comparing artifacts in images acquired with and without PMC (NoPMC). However, such an approach is not applicable in clinical setting due to unavailability of NoPMC images. We aim to develop a simulation approach for demonstrating the ability of fat-navigator-based PMC in improving perivascular space (PVS) visibility in T2-weighted MRI. METHODS: MRI datasets from two earlier studies were used for motion artifact simulation and evaluating PMC, including T2-weighted NoPMC and PMC images. To simulate motion artifacts, k-space data at motion-perturbed positions were calculated from artifact-free images using nonuniform Fourier transform and misplaced onto the Cartesian grid before inverse Fourier transform. The simulation's ability to reproduce motion-induced blurring, ringing, and ghosting artifacts was evaluated using sharpness at lateral ventricle/white matter boundary, ringing artifact magnitude in the Fourier spectrum, and background noise, respectively. PVS volume fraction in white matter was employed to reflect its visibility. RESULTS: In simulation, sharpness, PVS volume fraction, and background noise exhibited significant negative correlations with motion score. Significant correlations were found in sharpness, ringing artifact magnitude, and PVS volume fraction between simulated and real NoPMC images (p ≤ 0.006). In contrast, such correlations were reduced and nonsignificant between simulated and real PMC images (p ≥ 0.48), suggesting reduction of motion effects with PMC. CONCLUSIONS: The proposed simulation approach is an effective tool to study the effects of motion and PMC on PVS visibility. PMC may reduce the systematic bias of PVS volume fraction caused by motion artifacts.

Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.

Blood-Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights.

Perivascular spaces (PVS) and blood-brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI-visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast-enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Enlarged perivascular spaces are associated with brain microangiopathy and aging in multiple sclerosis.

BACKGROUND: Growing evidence links brain-MRI enlarged perivascular spaces (EPVS) and multiple sclerosis (MS), but their role remains unclear. OBJECTIVE: This study aimed to investigate the cross-sectional associations of EPVS with several neuroinflammatory and neurodegenerative features in a large multicentric-MS cohort. METHODS: In total, 207 patients underwent 3T axial-T2-weighted brain-MRI for EPVS assessment (EPVS dichotomized into high/low according to ⩾ 2/< 2 rating categories). MRI biomarkers included brain-predicted age and brain-predicted age difference (brain-PAD), central vein sign (CVS)-positive lesion percentage (CVS%), paramagnetic rim and cortical lesions, T2-lesion load, and brain volumetry. The variable relative importance for EPVS-category prediction was explored using a classification random forest approach. RESULTS: High EPVS patients were older (49 vs 44 years, p = 0.003), had ⩾ 1 vascular risk factors (VRFs; p = 0.005), lower CVS% (67% vs 78%, p < 0.001), reduced brain volumes (whole brain: 0.63 vs 0.73, p = 0.01; gray matter: 0.36 vs 0.40; p = 0.002), and older brain-predicted age (58 vs 50 years, p < 0.001). No differences were found for neuroinflammatory markers. After adjusting for age and VFRs (multivariate analyses), the high EPVS category correlated with lower CVS% (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99; p = 0.02), lower whole brain (OR = 0.01, 95% CI = 0.0003-0.5; p = 0.02), gray matter (OR = 0.0004, 95% CI = 0.0000004-0.4; p = 0.03) volumes, and higher brain-PAD (OR = 1.05, 95% CI = 1.01-1.09; p = 0.02). Random forest identified brain-PAD as the most important predictor of high EPVS. CONCLUSION: EPVS in MS likely reflect microangiopathic disease rather than neuroinflammation, potentially contributing to accelerated neurodegeneration.

Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm.

The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-ß peptide (Aß) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer's disease (AD) defers Aß accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.

Progression of enlarged perivascular spaces contributes to occurrence of silent lacunar infarction in the elderly.

INTRODUCTION: This study aims to assess the effect of enlarged perivascular spaces (EPVS) in patients using the methods of scale score and 3D volume quantification and to determine whether EPVS progression is related to the occurrence of silent lacunar infarction (SLI). METHOD: Three hundred sixty-seven elderly patients with EPVS were screened by MRI on the day of admission and 2 years later; 295 patients were included in the final study, among which 136 patients had EPVS with SLI (EL); and 159 patients had EPVS without SLI (EOL). Both scale score and 3D volume quantification method were used to evaluate EPVS. The 295 patients were divided into three groups based on EPVS progression state: Group 1 (no progression), Group 2 (0-50% EPVS progression), and Group 3 (≥ 50% EPVS progression). Multiple logistic regression analysis was used to analyze the risk of occurrence of SLI. RESULTS: The EPVS scores and ΔEPVS scores were not significantly different between the EL and EOL groups (p > 0.05). EPVS volumes and their progression were significantly higher in EL compared with EOL (p < 0.001). The incidence of SLI was increased in Groups 2 and 3 compared with those in Group 1, and the trend test showed statistically significant (p = 0.032). Multiple logistic regression analysis showed that the risk of occurrence of SLI was significantly increased in Group 2 (OR 2.24; p = 0.024) and Group 3 (OR 3.31; p = 0.037) versus that in Group 1. CONCLUSION: 3D volume quantification allows for a more sensitive assessment of EPVS changes, and the progression of EPVS volume may contribute to the occurrence of SLI.

Association between Perivascular Spaces Burden and Future Stroke Risk in Ischemic Stroke and Transient Ischemic Attack: A Systematic Review and Meta-Analysis.

INTRODUCTION: This meta-analysis aimed to explore the association of perivascular spaces (PVS) burden with the risks of future stroke events and mortality in patients with ischemic stroke and transient ischemic attack (TIA). METHODS: We systematically searched PubMed, Embase, and Cochrane database from inception to December 31, 2023. We included eligible studies that reported adjusted estimated effects for future intracranial hemorrhage (ICH), ischemic stroke, and mortality with baseline PVS burden in patients with ischemic stroke and TIA. Data were pooled using an inverse-variance method for the fixed effects (FE) model and a restricted maximum likelihood method for the random effects (RE) model. RESULTS: Thirteen observational studies (5 prospective, 8 retrospective) were included, comprising 20,256 patients. Compared to 0-10 PVS at basal ganglia (BG-PVS), a higher burden (>10) of BG-PVS was significantly associated with an increased risk of future ICH (adjusted hazards ratio [aHR] 2.79, 95% confidence interval [CI]: 1.16-6.73, RE model; aHR 2.14, 95% CI: 1.34-3.41, FE model; I2 = 64%, n = 17,084 from four studies) followed up for at least 1 year. There was no significant association between >10 BG-PVS and ICH within 7 days after reperfusion therapy (adjusted odds ratio [aOR] 1.69, 95% CI: 0.74-3.88, RE model; aOR 1.43, 95% CI: 0.89-2.88, FE model; I2 = 67%, n = 1,176 from four studies). We did not detect a significant association of recurrent ischemic stroke, mortality, or disability with BG-PVS burden. Neither >10 PVS at centrum semiovale (CSO-PVS) nor increasing CSO-PVS burden was significantly associated with the risk of future intracranial hemorrhage or ischemic stroke recurrence. CONCLUSIONS: Current evidence suggests that a higher BG-PVS burden may be associated with an increased risk of future ICH in patients with ischemic stroke and TIA.

Giant tumefactive mesencephalothalamic Virchow-Robin space with triventricular hydrocephalus: a case-based systematic literature review.

BACKGROUND: The perivascular spaces of the brain are also known as Virchow-Robin spaces (VRSs). Dilated Virchow-Robin spaces in the brainstem are rare and mainly cause symptoms due to obstructive hydrocephalus, less frequently because of their size, mass effect, and impact on eloquent structures. CASE ILLUSTRATION: We present a patient with giant tumefactive VRS with hydrocephalus and neurological symptoms who was treated with endoscopic third ventriculostomy (ETV) followed by microscopic cyst fenestration. On the basis of this observation, we performed a thorough review of the literature to evaluate different treatment options. RESULTS: An 11-year-old girl presented with a headache for 3 months. The patient had a giant tumefactive mesencephalothalamic VRS with triventricular hydrocephalus. She was initially treated with endoscopic third ventriculostomy and multiple cyst fenestration. Symptomatic cyst regrowth required multiple cyst fenestrations via transcallosal transchoroidal (N = 2) and subtemporal approaches (N = 1) at the 2- and 4-year follow-ups. A literature review of these conditions allowed the detection of 12 cases (including our index case), and only 25% (3/12) of the patients underwent cyst fenestration 16.7% (2/12) required endoscopic fenestration and 8.3% (1/12) required microscopic fenestration. CONCLUSION: Giant mesencephalothalamic dVRSs are rare in the pediatric population. These patients are usually symptomatic due to obstructive hydrocephalus. Surgical options are endoscopic third ventriculostomy, ventricular shunt procedures, or direct cyst fenestration (microscopic or endoscopic). Close follow-up is mandatory owing to the risk of progression of the disease. Cyst fenestration resolves symptoms immediately, as it addresses both hydrocephalus and mass effects due to the cystic lesion in the same setting.

Association Between Enlarged Perivascular Spaces and Early Acute Ischemic Stroke with Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND: Enlarged perivascular spaces (EPVSs) are commonly detected via magnetic resonance imaging. It is unclear whether EPVSs are associated with cognitive impairment within one month after an acute ischemic stroke (AIS) (i.e., early AIS with cognitive impairment (EAIS-CI)). This study explored the severity and location of EPVSs and their association with EAIS-CI severity and provides clinicians with early warning indicators before the onset of typical clinical symptoms in the Chinese population. METHODS: The clinical data of 208 patients (176 AIS patients and 32 controls) were prospectively analyzed using the Montreal Cognitive Assessment Beijing version (MoCA-BJ) score as the primary group criterion and the Mini-Mental State Examination (MMSE) score as a supplementary criterion. When EPVS I as the main EPVS type detected by imaging, the basal ganglia (BG) is the area most severely affected. Statistical analysis was conducted on the relevant clinical data. RESULTS: AIS patients were grouped based on MoCA-BJ scores. Age (p < 0.01), education level (p = 0.02), EPVS I as the main EPVS type (p < 0.01), the number of right-sided BG-EPVSs (p = 0.04), white matter hyperintensities (WMHs) (Fazekas scores: p = 0.02), brain atrophy (global cortical atrophy scores: p < 0.01, Koedam posterior atrophy visual scale scores: p = 0.01, medial temporal lobe atrophy scores: p < 0.01) and AIS lesion volume (p = 0.01) were significantly greater in the EAIS-CI group than in the EAIS without cognitive impairment group. The cognitive domains of attention (p = 0.04) and orientation (p < 0.01) were more closely associated with EPVS I as the main EPVS type. However, multivariate regression analysis did not identify EPVS I as the main EPVS type as the main risk factor for EAIS-CI (p = 0.098). Grouping by MMSE scores revealed that EPVS I as the main EPVS type was linked to low education level (p < 0.01) and was significantly associated with EAIS in individuals with cognitive dementia (p < 0.01). CONCLUSIONS: As a result of multiple factors, EAIS-CI is significantly associated with a low education level, BG-EPVS, WMHs, and worsening brain atrophy severity. Imaging markers, such as the severity of BG-EPVS, can assist in the early diagnosis and assessment of EAIS-CI. CLINICAL TRIAL REGISTRATION: The study was registered with the China Clinical Trial Registry (https://www.chictr.org.cn/), registration number: ChiCTR2000038819.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Non-hemorrhagic imaging markers of cerebral amyloid angiopathy in memory clinic patients.

INTRODUCTION: The Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) incorporated non-hemorrhagic imaging markers. Their prevalence and significance in patients with cognitive impairment remain uncertain. METHODS: We studied 622 memory clinic patients with available magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers. Two raters assessed non-hemorrhagic markers, and we explored their association with clinical characteristics through multivariate analyses. RESULTS: Most patients had mild cognitive impairment; median age was 71 years and 50% were female. Using the v2.0 criteria, possible or probable CAA increased from 75 to 383 patients. Sixty-eight percent of the sample had non-hemorrhagic CAA markers, which were independently associated with age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07), female sex (OR = 1.68, 95% CI = 1.11-2.54), and hemorrhagic CAA markers (OR = 2.11, 95% CI = 1.02-4.35). DISCUSSION: Two-thirds of patients from a memory clinic cohort had non-hemorrhagic CAA markers, increasing the number of patients meeting the v2.0 CAA criteria. Longitudinal approaches should explore the implications of these markers, particularly the hemorrhagic risk in this population. HIGHLIGHTS: The updated Boston criteria for cerebral amyloid angiopathy (CAA) now include non-hemorrhagic markers. The prevalence of non-hemorrhagic CAA markers in memory clinic patients is unknown. Two-thirds of patients in our memory clinic presented non-hemorrhagic CAA markers. The presence of these markers was associated with age, female sex, and hemorrhagic CAA markers. The hemorrhagic risk of patients presenting these type of markers remains unclear.