Waste Clearance Research Articles

Identification of direct connections between the dura and the brain.

The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.

A translational approach towards understanding brain waste clearance in cerebral amyloid angiopathy.

A translational approach towards understanding brain waste clearance in cerebral amyloid angiopathy.

Hydraulic resistance of three-dimensional pial perivascular spaces in the brain

BackgroundPerivascular spaces (PVSs) carry cerebrospinal fluid (CSF) around the brain, facilitating healthy waste clearance. Measuring those flows in vivo is difficult, and often impossible, because PVSs are small, so accurate modeling is essential for understanding brain clearance. The most important parameter for modeling flow in a PVS is its hydraulic resistance, defined as the ratio of pressure drop to volume flow rate, which depends on its size and shape. In particular, the local resistance per unit length varies along a PVS and depends on variations in the local cross section.MethodsUsing segmented, three-dimensional images of pial PVSs in mice, we performed fluid dynamical simulations to calculate the resistance per unit length. We applied extended lubrication theory to elucidate the difference between the calculated resistance and the expected resistance assuming a uniform flow. We tested four different approximation methods, and a novel correction factor to determine how to accurately estimate resistance per unit length with low computational cost. To assess the impact of assuming unidirectional flow, we also considered a circular duct whose cross-sectional area varied sinusoidally along its length.ResultsWe found that modeling a PVS as a series of short ducts with uniform flow, and numerically solving for the flow in each, yields good resistance estimates at low cost. If the second derivative of area with respect to axial location is less than 2, error is typically less than 15%, and can be reduced further with our correction factor. To make estimates with even lower cost, we found that instead of solving for the resistance numerically, the well-known resistance of a circular duct could be scaled by a shape factor. As long as the aspect ratio of the cross section was less than 0.7, the additional error was less than 10%.ConclusionsNeglecting off-axis velocity components underestimates the average resistance, but the error can be reduced with a simple correction factor. These results could increase the accuracy of future models of brain-wide and local CSF flow, enabling better prediction of clearance, for example, as it varies with age, brain state, and pathological conditions.

The glymphatic system and cerebral small vessel disease

ObjectivesCerebral small vessel disease is a group of pathologies in which alterations of the brain's blood vessels contribute to stroke and neurocognitive changes. Recently, a neurotoxic waste clearance system composed of perivascular spaces abutting the brain's blood vessels, termed the glymphatic system, has been identified as a key player in brain homeostasis. Given that small vessel disease and the glymphatic system share anatomical structures, this review aims to reexamine small vessel disease in the context of the glymphatic system and highlight novel aspects of small vessel disease physiology. Materials and methodsThis review was conducted with an emphasis on studies that examined aspects of small vessel disease and on works characterizing the glymphatic system. We searched PubMed for relevant articles using the following keywords: glymphatics, cerebral small vessel disease, arterial pulsatility, hypertension, blood-brain barrier, endothelial dysfunction, stroke, diabetes. ResultsCerebral small vessel disease and glymphatic dysfunction are anatomically connected and significant risk factors are shared between the two. These include hypertension, type 2 diabetes, advanced age, poor sleep, obesity, and neuroinflammation. There is clear evidence that CSVD hinders the effective functioning of glymphatic system. ConclusionThese shared risk factors, as well as the model of cerebral amyloid angiopathy pathogenesis, hint at the possibility that glymphatic dysfunction could independently contribute to the pathogenesis of cerebral small vessel disease. However, the current evidence supports a model of cascading dysfunction, wherein concurrent small vessel and glymphatic injury hinder glymphatic-mediated recovery and promote the progression of subclinical to clinical disease.

The glymphatic system as a potential biomarker and therapeutic target in secondary progressive multiple sclerosis

BackgroundMultiple sclerosis (MS) is a refractory immune-mediated inflammatory disease of the central nervous system, and some cases of the major subtype, relapsing-remitting (RR), transition to secondary progressive (SP). However, the detailed pathogenesis, biomarkers, and effective treatment strategies for secondary progressive multiple sclerosis have not been established. The glymphatic system, which is responsible for waste clearance in the brain, is an intriguing avenue for investigation and is primarily studied through diffusion tensor image analysis along the perivascular space (DTI-ALPS). This study aimed to compare DTI-ALPS indices between patients with RRMS and SPMS to uncover potential differences in their pathologies and evaluate the utility of the glymphatic system as a possible biomarker. MethodsA cohort of 26 patients with MS (13 RRMS and 13 SPMS) who met specific criteria were enrolled in this prospective study. Magnetic resonance imaging (MRI), including diffusion MRI, 3D T1-weighted imaging, and relaxation time quantification, was conducted. The ALPS index, a measure of glymphatic function, was calculated using diffusion-weighted imaging data. Demographic variables, MRI metrics, and ALPS indices were compared between patients with RRMS and those with SPMS. ResultsThe ALPS index was significantly lower in the SPMS group. Patients with SPMS exhibited longer disease duration and higher Expanded Disability Status Scale (EDSS) scores than those with RRMS. Despite these differences, the correlations between the EDSS score, disease duration, and ALPS index were minimal, suggesting that the impact of these clinical variables on ALPS index variations was negligible. DiscussionOur study revealed the potential microstructural and functional differences between RRMS and SPMS related to glymphatic system impairment. Although disease severity and duration vary among subtypes, their influence on ALPS index differences appears to be limited. This highlights the stronger association between SP conversion and changes in the ALPS index. These findings align with those of previous research, indicating the involvement of the glymphatic system in the progression of MS. ConclusionAlthough the causality remains uncertain, our study suggests that a reduced ALPS index, reflecting glymphatic system dysfunction, may contribute to MS progression, particularly in SPMS. This suggests the potential of the ALPS index as a diagnostic biomarker for SPMS and underscores the potential of the glymphatic system as a therapeutic target to mitigate MS progression. Future studies with larger cohorts and pathological validation are necessary to confirm these findings. This study provides new insights into the pathogenesis of SPMS and the potential for innovative therapeutic strategies.

Therapeutic approaches to CNS diseases via the meningeal lymphatic and glymphatic system: prospects and challenges.

The brain has traditionally been considered an "immune-privileged" organ lacking a lymphatic system. However, recent studies have challenged this view by identifying the presence of the glymphatic system and meningeal lymphatic vessels (MLVs). These discoveries offer new opportunities for waste clearance and treatment of central nervous system (CNS) diseases. Various strategies have been developed based on these pathways, including modulation of glymphatic system function, enhancement of meningeal lymphatic drainage, and utilization of these routes for drug delivery. Consequently, this review explores the developmental features and physiological roles of the cerebral lymphatic system as well as its significance in various CNS disorders. Notably, strategies for ameliorating CNS diseases have been discussed with a focus on enhancing glymphatic system and MLVs functionality through modulation of physiological factors along with implementing pharmacological and physical treatments. Additionally, emphasis is placed on the potential use of the CNS lymphatic system in drug delivery while envisioning future directions in terms of mechanisms, applications, and translational research.

The effect of aquaporin-4 inhibition on cerebrospinal fluid-tissue water exchange in mouse brain detected by magnetization transfer indirect spin labeling MRI.

The fluid transport of cerebrospinal fluid (CSF) and interstitial fluid in surrounding tissues plays an important role in the drainage pathway that facilitates waste clearance from the brain. This pathway is known as the glymphatic or perivascular system, and its functions are dependent on aquaporin-4 (AQP4). Recently, magnetization transfer indirect spin labeling (MISL) magnetic resonance imaging (MRI) has been proposed as a noninvasive and noncontrast-enhanced method for detecting water exchange between CSF and brain tissue. In this study, we first optimized the MISL sequence at preclinical 3 T MRI, and then studied the correlation of MISL in CSF with magnetization transfer (MT) in brain tissue, as well as the altered water exchange under AQP4 inhibition, using C57BL/6 mice. Results showed a strong correlation of MISL signal with MT signal. With the AQP4 inhibitor, we observed a significant decrease in MISL value (P < 0.05), suggesting that the hampered AQP4 activity led to decreased water exchange between CSF and brain tissue or the impairment of the glymphatic function. Overall, our findings demonstrate the potential application of MISL in assessing brain water exchange at 3 T MRI and its potential clinical translation.

The influence of sleep disorders on perioperative neurocognitive disorders among the elderly: A narrative review.

This review comprehensively assesses the epidemiology, interaction, and impact on patient outcomes of perioperative sleep disorders (SD) and perioperative neurocognitive disorders (PND) in the elderly. The incidence of SD and PND during the perioperative period in older adults is alarmingly high, with SD significantly contributing to the occurrence of postoperative delirium. However, the clinical evidence linking SD to PND remains insufficient, despite substantial preclinical data. Therefore, this study focuses on the underlying mechanisms between SD and PND, underscoring that potential mechanisms driving SD-induced PND include uncontrolled central nervous inflammation, blood-brain barrier disruption, circadian rhythm disturbances, glial cell dysfunction, neuronal and synaptic abnormalities, impaired central metabolic waste clearance, gut microbiome dysbiosis, hippocampal oxidative stress, and altered brain network connectivity. Additionally, the review also evaluates the effectiveness of various sleep interventions, both pharmacological and nonpharmacological, in mitigating PND. Strategies such as earplugs, eye masks, restoring circadian rhythms, physical exercise, noninvasive brain stimulation, dexmedetomidine, and melatonin receptor agonists have shown efficacy in reducing PND incidence. The impact of other sleep-improvement drugs (e.g., orexin receptor antagonists) and methods (e.g., cognitive-behavioral therapy for insomnia) on PND is still unclear. However, certain drugs used for treating SD (e.g., antidepressants and first-generation antihistamines) may potentially aggravate PND. By providing valuable insights and references, this review aimed to enhance the understanding and management of PND in older adults based on SD.

The Effects of Sleep on Human Physiology and Its Regulation

Sleep is an essential aspect of human biology and is crucial for maintaining overall health and cognitive functioning. The significance of sleep, its effects on bodily and cognitive function, and the underlying mechanisms were covered in this essay. One of the primary functions of sleep is to facilitate physical restoration. During sleep, the body engages in critical processes such as immune system regulation, metabolic waste clearance, and cell repair. The brain also undergoes restoration during sleep, consolidates memories, enhances learning, and promotes creativity. Insufficient sleep can lead to physical symptoms such as fatigue and reduced concentration, as well as emotional instability and fluctuations in mood. The mechanisms of sleep regulation are multifaceted, incorporating both physiological and neurological processes. The body's circadian rhythm plays a crucial role in sleep regulation. Sleep quality can be influenced by various environmental and psychological factors. Exposure to artificial light, especially before bedtime, can inhibit the release of melatonin. Stress, anxiety, and depression can also disrupt sleep patterns, making it difficult to obtain restful sleep. In conclusion, sleep is a crucial aspect of human biology that impacts both physical and cognitive function. Further research into sleep regulation and its impact on academic success may provide opportunities for new therapeutic approaches for sleep-related disorders.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Is cerebral small vessel disease a central nervous system interstitial fluidopathy?

A typical anatomical congregate and functionally distinct multicellular cerebrovascular dynamic confer diverse blood-brain barrier (BBB) and microstructural permeabilities to conserve the health of brain parenchymal and its microenvironment. This equanimity presupposes the glymphatic system that governs the flow and clearance of metabolic waste and interstitial fluids (ISF) through venous circulation. Following the introduction of glymphatic system concept, various studies have been carried out on cerebrospinal fluid (CSF) and ISF dynamics. These studies reported that the onset of multiple diseases can be attributed to impairment in the glymphatic system, which is newly referred as central nervous system (CNS) interstitial fluidopathy. One such condition includes cerebral small vessel disease (CSVD) with poorly understood pathomechanisms. CSVD is an umbrella term to describe a chronic progressive disorder affecting the brain microvasculature (or microcirculation) involving small penetrating vessels that supply cerebral white and deep gray matter. This review article proposes CSVD as a form of “CNS interstitial fluidopathy”. Linking CNS interstitial fluidopathy with CSVD will open a better insight pertaining to the perivascular space fluid dynamics in CSVD pathophysiology. This may lead to the development of treatment and therapeutic strategies to ameliorate the pathology and adverse effect of CSVD.

Four-dimensional flow MRI for quantitative assessment of cerebrospinal fluid dynamics: Status and opportunities.

Neurological disorders can manifest with altered neurofluid dynamics in different compartments of the central nervous system. These include alterations in cerebral blood flow, cerebrospinal fluid (CSF) flow, and tissue biomechanics. Noninvasive quantitative assessment of neurofluid flow and tissue motion is feasible with phase contrast magnetic resonance imaging (PC MRI). While two-dimensional (2D) PC MRI is routinely utilized in research and clinical settings to assess flow dynamics through a single imaging slice, comprehensive neurofluid dynamic assessment can be limited or impractical. Recently, four-dimensional (4D) flow MRI (or time-resolved three-dimensional PC with three-directional velocity encoding) has emerged as a powerful extension of 2D PC, allowing for large volumetric coverage of fluid velocities at high spatiotemporal resolution within clinically reasonable scan times. Yet, most 4D flow studies have focused on blood flow imaging. Characterizing CSF flow dynamics with 4D flow (i.e., 4D CSF flow) is of high interest to understand normal brain and spine physiology, but also to study neurological disorders such as dysfunctional brain metabolite waste clearance, where CSF dynamics appear to play an important role. However, 4D CSF flow imaging is challenged by the long T1 time of CSF and slower velocities compared with blood flow, which can result in longer scan times from low flip angles and extended motion-sensitive gradients, hindering clinical adoption. In this work, we review the state of 4D CSF flow MRI including challenges, novel solutions from current research and ongoing needs, examples of clinical and research applications, and discuss an outlook on the future of 4D CSF flow.

Automatic Quantification of Enlarged Perivascular Space in Patients With Traumatic Brain Injury Using Super-Resolution of T2-Weighted Images.

The perivascular space (PVS) is important to brain waste clearance and brain metabolic homeostasis. Enlarged PVS (ePVS) becomes visible on magnetic resonance imaging (MRI) and is best appreciated on T2-weighted (T2w) images. However, quantification of ePVS is challenging because standard-of-care T1-weighted (T1w) and T2w images are often obtained via two-dimensional (2D) acquisition, whereas accurate quantification of ePVS normally requires high-resolution volumetric three-dimensional (3D) T1w and T2w images. The purpose of this study was to investigate the use of a deep-learning-based super-resolution (SR) technique to improve ePVS quantification from 2D T2w images for application in patients with traumatic brain injury (TBI). We prospectively recruited 26 volunteers (age: 31 ± 12 years, 12 male/14 female) where both 2D T2w and 3D T2w images were acquired along with 3D T1w images to validate the ePVS quantification using SR T2w images. We then applied the SR method to retrospectively acquired 2D T2w images in 41 patients with chronic TBI (age: 41 ± 16 years, 32 male/9 female). ePVS volumes were automatically quantified within the whole-brain white matter and major brain lobes (temporal, parietal, frontal, occipital) in all subjects. Pittsburgh Sleep Quality Index (PSQI) scores were obtained on all patients with TBI. Compared with the silver standard (3D T2w), in the validation study, the SR T2w provided similar whole-brain white matter ePVS volume (r = 0.98, p < 0.0001), and similar age-related ePVS burden increase (r = 0.80, p < 0.0001). In the patient study, patients with TBI with poor sleep showed a higher age-related ePVS burden increase than those with good sleep. Sleep status is a significant interaction factor in the whole brain (p = 0.047) and the frontal lobe (p = 0.027). We demonstrate that images produced by SR of 2D T2w images can be automatically analyzed to produce results comparable to those obtained by 3D T2 volumes. Reliable age-related ePVS burden across the whole-brain white matter was observed in all subjects. Poor sleep, affecting the glymphatic function, may contribute to the accelerated increase of ePVS burden following TBI.

A machine learning method to explore the glymphatic system via poroelastodynamics

Until recently, scientists thought that waste was cleared from the central nervous system primarily by diffusion, with waste slowly moving from the brain tissue toward the blood vessels. However, scientists have discovered a dedicated macroscopic waste clearance system, called glymphatic system, that performs efficient waste elimination through a unique system of perivascular channels formed by astrocytes, a type of glia. To better understand the complex dynamics of fluid movements in the glymphatic system, we implemented a four-compartmental poroelasticity model of the cerebral environment and used the model in a systematic and efficient parametric study aided by machine learning, a physiologically inspired perceptron method, to explore the functional impact of water transfer coefficients. The results suggested that the model captured the transport phenomenon of human brain. Moreover, within a specific distribution range of water transfer coefficients, the model indirectly predicts the existence of the glymphatic system, providing theoretical support to the glymphatic theory. Our study also demonstrates the feasibility of discovering physiological properties of complex biological systems through computer-aided modeling. Meanwhile, the presented novel method shown its potential for parametric study.

Interplay between the glymphatic system and neurotoxic proteins in Parkinson's disease and related disorders: current knowledge and future directions.

Parkinson's disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-β, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson's disease, expands the disease landscape within the continuum of Parkinson's disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson's disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson's disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson's disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy.

Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.

Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain's extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being.

Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors.

Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death. We show that both apoptotic pathways are activated in BVSMCs by oligomeric Aβ42 and Aβ40-Q22 (AβQ22) and mitochondrial respiration is severely impaired. Importantly, the CAIs methazolamide (MTZ) and acetazolamide (ATZ) prevent the pro-apoptotic effects in BVSMCs, while reducing caspase 3 activation and Aβ deposition in the arterial walls of TgSwDI animals, a murine model of cerebral amyloid angiopathy (CAA). This study reveals new molecular targets and a promising therapeutic strategy against BVSMC dysfunction in AD, CAA, and ARIA (amyloid-related imaging abnormalities) complications of recently FDA-approved anti-Aβ antibodies.

Interorgan communication with the liver: novel mechanisms and therapeutic targets.

The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.

Analysis of blood and cerebrospinal fluid flows in preclinical AD. Preliminary results from ALFA+ cohort

AbstractBackgroundIntracranial cerebrospinal fluid (CSF) motion is driven by the wave pressure associated with arterial blood flow into the skull (Figure 1). Since one of the roles of CSF is the clearance of neural waste, it was investigated the relationship between blood and CSF flow parameters (as measured by magnetic resonance imaging [MRI]) and CSF Ab42/40 and ptau‐181 levels in the preclinical stages of Alzheimer’s disease (AD).MethodThree hundred sixty‐five subjects from the ALFA+ cohort underwent two MRI phase‐encoded velocity sequences (30 frames per cardiac cycle) to measure (1) blood flow in carotids below carotid bifurcation and (2) CSF flow through foramen magnum. The scanner’s Q‐flow tool was used to quantify stroke volume (volume per cardiac cycle), percent of vessel’s area increase and flow velocity increase, as a proxy for vessel elasticity and flow pulsatility, respectively. Associations between flow parameters and age, CSF Ab42/40 and ptau‐181 concentrations were sought, correcting for sex, age and time between lumbar puncture and MRI (P&lt;0.05).ResultOne hundred thirty‐two subjects were excluded because the scanning session was not completed, showed missing or outlier values or did not pass quality control (artifacts or unbalanced outwards‐inwards CSF flow measures), resulting in a final sample size of 233 participants (mean age [SD]: 60.8±4.5 years; male: n = 73 [31.3%]). Figure 2 shows the plots with the most significant relationships between flow parameters, CSF biomarkers, CSF volume and age. It was observed that a higher stroke volume in CSF flow was associated with lower Ab42/40 and higher ptau‐181 concentrations in CSF.ConclusionThese results indicate that, despite the role of CSF in waste clearance, the accumulation of amyloid and tau in the brain might be neither caused nor enhanced by a global deficit in CSF circulation. We hypothesize that a higher volume of CSF associated with age and high ptau‐181 levels and/or the loss of parenchyma elasticity might reduce the global intracranial compressibility, resulting in an enhanced response to pressure increase due to blood flow into the skull, which could explain the observed increase in CSF flow associated with the early stages of AD.