Clearance Of Metabolites Research Articles

Directional flow in perivascular networks: mixed finite elements for reduced-dimensional models on graphs

AbstractFlow of cerebrospinal fluid through perivascular pathways in and around the brain may play a crucial role in brain metabolite clearance. While the driving forces of such flows remain enigmatic, experiments have shown that pulsatility is central. In this work, we present a novel network model for simulating pulsatile fluid flow in perivascular networks, taking the form of a system of Stokes–Brinkman equations posed over a perivascular graph. We apply this model to study physiological questions concerning the mechanisms governing perivascular fluid flow in branching vascular networks. Notably, our findings reveal that even long wavelength arterial pulsations can induce directional flow in asymmetric, branching perivascular networks. In addition, we establish fundamental mathematical and numerical properties of these Stokes–Brinkman network models, with particular attention to increasing graph order and complexity. By introducing weighted norms, we show the well-posedness and stability of primal and dual variational formulations of these equations, and that of mixed finite element discretizations.

Immune system activation and cognitive impairment in arterial hypertension.

Chronic arterial hypertension disrupts the integrity of the cerebral microvasculature, doubling the risk of age-related dementia. Despite sufficient antihypertensive therapy, in still a significant proportion of individuals blood pressure lowering alone does not preserve cognitive health. Accumulating evidence highlights the role of inflammatory mechanisms in the pathogenesis of hypertension. In this review, we introduce a temporal framework to explore how early immune system activation and interactions at neurovascular-immune interfaces pave the way to cognitive impairment. The overall paradigm suggests that pro-hypertensive stimuli induce mechanical stress and systemic inflammatory responses that shift peripheral and meningeal immune effector mechanisms towards a pro-inflammatory state. Neurovascular-immune interfaces in the brain include a dysfunctional blood-brain barrier, crossed by peripheral immune cells; the perivascular space, in which macrophages respond to cerebrospinal fluid- and blood-derived immune regulators; and the meningeal immune reservoir, particularly T cells. Immune responses at these interfaces bridge peripheral and neurovascular unit inflammation, directly contributing to impaired brain perfusion, clearance of toxic metabolites and synaptic function. We propose that deep immunophenotyping in biofluids together with advanced neuroimaging could aid in the translational determination of sequential immune and brain endotypes specific to arterial hypertension. This could close knowledge gaps on how and when immune system activation transits into neurovascular dysfunction and cognitive impairment. In the future, targeting specific immune mechanisms could prevent and halt hypertension disease progression before clinical symptoms arise, addressing the need for new interventions against one of the leading threats to cognitive health.

Different Glymphatic Kinetics in Spontaneous Intracranial Hypotension.

The glymphatic (glia-lymphatic) system is a paravascular pathway for the clearance of waste metabolites including amyloid β from the brain. Serial T1 relaxation time measurements after the intrathecal injection of gadolinium-based contrast agents facilitate the analysis of the temporal dynamics that may be different in patients with spontaneous intracranial hypotension (SIH) and those without SIH. 3D T1-weighted magnetization-prepared 2 rapid gradient echo sequences were acquired in 4 patients with SIH with proved CSF leaks and 12 patients without SIH before, 2-4, 6-8, and 24-48 hours after intrathecal gadobutrol injection. MR scans were warped to the Montreal Neurological Institute space and serial scans were coregistered. T1 relaxation times were measured in predefined ROIs including the subarachnoid space, cortex, white matter, and cervical lymph nodes. In the subarachnoid space and cortex, T1 relaxation times decreased after 2-4 and 6-8 hours before they increased again. In contrast, in the white matter of the temporal lobe T1 relaxation time still decreased after 24-48 hours. There was a striking difference in patients with SIH who did not show a clear contrast distribution within the brain parenchyma. T1 relaxation time curves are compatible with a convective flow driven by arterial pulsations via paravascular spaces surrounding penetrating arteries into the brain's interstitial fluid in the deep white matter. Different curves in patients with SIH and those without SIH indicate that the CSF pressure also impacts the temporal kinetics of the glymphatic system.

Population pharmacokinetic study and application of ticagrelor and AR-C124910XX after percutaneous coronary intervention in Chinese patients with acute coronary syndrome.

This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

Synaptic mitochondria glycation contributes to mitochondrial stress and cognitive dysfunction.

Mitochondrial and synaptic dysfunction are pathological features of brain aging and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigate the mechanisms of advanced glycation endproducts (AGEs)-mediated mitochondrial and synaptic stress and evaluate the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analyzed alterations in accumulation/buildup of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrate for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGEs-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in aging brain. Importantly, clearance of AGEs-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification/of AGEs, reduces synaptic mitochondrial AGEs accumulation and improves mitochondrial and cognitive function in aging and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex-vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGEs-induced synaptic plasticity and transmission by fully recovery of decline in LTP or frequency of mEPSC. These studies explore crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain aging and cognitive decline. Synaptic mitochondria are particularly susceptible to AGEs-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGEs accumulation and to improve mitochondrial function and learning and memory.

Cannabidiol Alleviates Neurological Deficits After Traumatic Brain Injury by Improving Intracranial Lymphatic Drainage.

Traumatic brain injury (TBI) persists as a substantial clinical dilemma, largely because of the absence of effective treatments. This challenge is exacerbated by the hindered clearance of intracranial metabolic byproducts and the continual accrual of deleterious proteins. The glymphatic system (GS) and meningeal lymphatic vessels (MLVs), key elements of the intracranial lymphatic network, play critical roles in the clearance of harmful substances. Cannabidiol (CBD) has shown promise in reducing metabolite overload and bolstering cognitive performance in various neurodegenerative diseases. The precise mechanisms attributing to its beneficial effects in TBI scenarios, however, are yet to be distinctly understood. Utilizing a fluid percussion injury paradigm, our research adopted a multifaceted approach, encompassing behavioral testing, immunofluorescence and immunohistochemical analyses, laser speckle imaging, western blot techniques, and bilateral cervical efferent lymphatic ligation. This methodology aimed to discern the influence of CBD on both neurological outcomes and intracranial lymphatic clearance in a murine TBI model. We observed that CBD administration notably ameliorated motor, memory, and cognitive functions, concurrently with a significant reduction in the concentration of phosphorylated tau protein and amyloid-β. In addition, CBD expedited the turnover and elimination of intracranial tracers, increased cerebral blood flow, and enhanced the efficacy of fluorescent tracer migration from MLVs to deep cervical lymph nodes (dCLNs). Remarkably, CBD treatment also induced a reversion in aquaporin-4 (AQP-4) polarization and curtailed neuroinflammatory indices. A pivotal discovery was that the surgical interruption of efferent lymphatic conduits in the neck nullified CBD's positive contributions to intracranial waste disposal and cognitive improvement, yet the anti-neuroinflammatory actions remained unaffected. These insights suggest that CBD may enhance intracranial metabolite clearance, potentially via the regulation of the intracranial lymphatic system, thereby offering neurofunctional prognostic improvement in TBI models. Our findings underscore the potential therapeutic applicability of CBD in TBI interventions, necessitating further comprehensive investigations and clinical validations to substantiate these initial conclusions.

Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice

Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease.

Peculiarities of metabolic and autonomic-endocrine accompaniments of urate-losing/retaining kidneys

Background. This publication initiates the project "Neuro-endocrine regulation of the clearance of nitrogenous metabolites". The first stage of project implementation is the clarification of peculiarities of metabolic and neuro-endocrine accompaniments of urate-losing and urate-retaining kidneys. Materials and Methods. The object of observations were patients with chronic pyelonephritis in the phase of remission (34 males aged 23-70 years and 10 females aged 33-76 years). Testing was performed twice - on admission and after 7-10 days of standard balneotherapy on Truskavets Spa. The battery of tests was created in line with concepts functional-metabolic continuum and NEI network. The content of nitrogenous metabolites and electrolytes was determined in daily urine and blood serum. In addition, indicators of the lipoprotein spectrum and lipids peroxidation, as well as the level of the main adaptation hormones, were determined in the blood. The state of the autonomic nervous system was assessed by the HRV method. Results. In 63.6% of cases, the renal clearance of uric acid was within the classical norm (±2σ), in 12.5% it was moderately reduced, but in the remaining cases it was increased, including drastically in 3 cases. The method of discriminant analysis revealed 20 parameters, according to the totality of which all 4 clusters of uric acid clearance clearly differ from each other (classification accuracy 100%). Conclusion. Constitutionally distinct types of uric acid metabolism (euricosis, urate-losing and urate-retaining kidneys) are characterized by specific constellations of metabolic and autonomic-endocrine parameters.

Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.

Voluntary wheel exercise improves glymphatic clearance and ameliorates colitis-associated cognitive impairment in aged mice by inhibiting TRPV4-induced astrocytic calcium activity

Background and objectivesChronic colitis exacerbates neuroinflammation, contributing to cognitive impairment during aging, but the mechanism remains unclear. The polarity distribution of astrocytic aquaporin 4 (AQP4) is crucial for the glymphatic system, which is responsible for metabolite clearance in the brain. Physical exercise (PE) improves cognition in the aged. This study aims to investigate the protective mechanism of exercise in colitis-associated cognitive impairment. MethodsTo establish a chronic colitis model, 18-month-old C57BL/6 J female mice received periodic oral administration of 1% wt/vol dextran sodium sulfate (DSS) in drinking water. The mice in the exercise group received four weeks of voluntary wheel exercise. High-throughput sequencing was conducted to screen for differentially expressed genes. Two-photon imaging was performed to investigate the function of the astrocytic calcium activity and in vivo intervention with TRPV4 inhibitor HC-067047. Further, GSK1016790A (GSK1), a TRPV4 agonist, was daily intraperitoneally injected during the exercise period to study the involvement of TRPV4 in PE protection. Colitis pathology was confirmed by histopathology. The novel object recognition (NOR) test, Morris water maze test (MWM), and open field test were performed to measure colitis-induced cognition and anxiety-like behavior. In vivo two-photon imaging and ex vivo imaging of fluorescent CSF tracers to evaluate the function of the glymphatic system. Immunofluorescence staining was used to detect the Aβ deposition, polarity distribution of astrocytic AQP4, and astrocytic phenotype. Serum and brain levels of the inflammatory cytokines were tested by Enzyme-linked immunosorbent assay (ELISA). The brain TUNEL assay was used to assess DNA damage. Expression of critical molecules was detected using Western blotting. ResultsVoluntary exercise alleviates cognitive impairment and anxiety-like behavior in aged mice with chronic colitis, providing neuroprotection against neuronal damage and apoptosis. Additionally, voluntary exercise promotes the brain clearance of Aβ via increased glymphatic clearance. Mechanistically, exercise-induced beneficial effects may be attributed, in part, to the inhibition of TRPV4 expression and TRPV4-related calcium hyperactivity, subsequent promotion of AQP4 polarization, and modulation of astrocyte phenotype. ConclusionThe present study reveals a novel role of voluntary exercise in alleviating colitis-related cognitive impairment and anxiety disorder, which is mediated by the promotion of AQP4 polarization and glymphatic clearance of Aβ via inhibition of TRPV4-induced astrocytic calcium hyperactivity.

Automated workflow to study microsomal clearance and analysis of metabolites using collision-induced dissociation and electron-activated dissociation MS/MS data

Automated workflow to study microsomal clearance and analysis of metabolites using collision-induced dissociation and electron-activated dissociation MS/MS data

Association of body-mass index with physiological brain pulsations across adulthood – a fast fMRI study

Background/objectiveObesity is a risk factor for several brain-related health issues, and high body-mass index (BMI) is associated with an increased risk for several neurological conditions, including cognitive decline and dementia. Cardiovascular, respiratory, and vasomotor brain pulsations have each been shown to drive intracranial cerebrovascular fluid (CSF) flow, which is linked to the brain metabolite efflux that sustains homeostasis. While these three physiological pulsations are demonstrably altered in numerous brain diseases, there is no previous investigation of the association between physiological brain pulsations and BMI.Subjects/methodsWe measured the amplitudes of the physiological brain pulsations using amplitude of low frequency fluctation (ALFF) based method with resting-state functional magnetic resonance imaging via high temporal resolution whole-brain magnetic resonance encephalography (MREG) in 115 healthy subjects. We next undertook multiple linear regression to model the BMI effect voxel-wise whole-brain on very low frequency (VLF), respiration, cardiovascular, and respiratory induced modulation of cardiovascular pulsation amplitudes with age, pulse pressure, and gender as nuisance variables.ResultsIn our study population, BMI was positively associated with the amplitudes of vasomotor, respiratory, and respiratory induced modulations of cardiovascular pulsations (p < 0.05), while negatively associated with the amplitudes of cardiovascular pulsations (p < 0.05).ConclusionsThe findings suggest that BMI is a significant factor in alterations of cardiovascular pulsation of neurofluids. As physiological pulsations are the drivers of CSF flow and subsequent metabolite clearance, these results emphasize the need for further research into the mechanisms through which obesity affects brain clearance.

Perioperative regional anaesthesia in kidney transplantation

Background. Postoperative analgesia in kidney transplant recipients is challenging due to potential nephrotoxicity of nonsteroidal anti-inflammatory drugs and the reduced clearance of opioid metabolites during transient renal impairment. Opioid-sparing multimodal postoperative analgesia using regional analgesia methods could provide better pain control and early activation after kidney transplantation.Aim. To evaluate the clinical results of treatment using regional pain management methods in kidney transplant recipients.Material and methods. A single-center study was conducted at Republican Research Center of Emergency Medicine from 2020 to 2022. The study included 97 patients who underwent heterotopic kidney transplantation from a living related donor. Patients were divided into 3 groups. In group 1 (31 patients), general anesthesia was used. For postoperative analgesia opioid analgesics in combination with metamizole 1000 mg were used. In group 2 (33 recipient patients), a combination of general anesthesia and open transversus abdominis plane block was used. In group 3 (33 recipient patients), a combination of general anesthesia and erector spine plane block was performed. Opioid analgesics were used as a "rescue analgesia" when necessary. The primary study end points were the pain intensity assessed by a visual analogue scale and opioid consumption on the first day after surgery. Secondary endpoints were the time of intestinal motility recovery, the presence of nausea and vomiting, the Intensive Care Unit length of stay and the hospital length of stay.Results. Pain intensity 6 hours after surgery in patients of group 1 was 13.5% and 24.6% higher than in patients of group 2 and 3, respectively. In group 2, pain intensity was 12.8% higher compared to group 3 (p=0.0017). At 12 hours after surgery, the pain intensity was 42% higher in group 1 compared to group 2 and group 3 (p&lt;0.0001). After 18 hours, the pain score in group 3 was 48.5% and 35.7% lower compared to groups 1 and 2, respectively (p&lt;0.0001 and p=0.0016). 24 hours after surgery, the sensation of pain was 18.6% and 65.3% higher in group 1 compared to groups 2 and 3 (p&lt;0.0001). The mean dose of narcotic analgesic equivalent to morphine in group 1 was 22.6±8.6 mg, which was 18.5% higher than in group 2 patients. In group 3, it was 12.0±4.3 mg and was 47% lower compared to group 1 (p&lt;0.0001) and 34.7% lower compared to group 2 (p&lt;0.0001) (all comparisons are statistically significant). The adequacy of analgesia and less opioid consumption contributed to the absence of postoperative nausea and vomiting in 75% of cases, early restoration of intestinal motility in 63% compared with the group of patients where opioid analgesics were used for postoperative pain relief.Conclusion. The combined use of general anesthesia and erector spine plane block may be recommended as a method of effective perioperative analgesia in kidney transplantation.

Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.

Choroid Plexus Volume, Amyloid Burden, and Cognition in the Alzheimer's Disease Continuum.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-β (Aβ) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aβ burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aβ deposition (β = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (β = 0.85, P = 0.034) and lower composite scores for memory (β = -0.68, P = 0.002) and frontal/executive function domains (β = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (β = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aβ deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Whole-Brain Electrophysiology and Calcium Imaging in Drosophila during Sleep and Wake.

Sleep is likely a whole-brain phenomenon, with most of the brain probably benefiting from this state of decreased arousal. Recent advances in our understanding of some potential sleep functions, such as metabolite clearance and synaptic homeostasis, make it evident why the whole brain is likely impacted by sleep: All neurons have synapses, and all neurons produce waste metabolites. Sleep experiments in the fly Drosophila melanogaster suggest that diverse sleep functions appear to be conserved across all animals. Studies of brain activity during sleep in humans typically involve multidimensional data sets, such as those acquired by electroencephalograms (EEGs) or functional magnetic resonance imaging (fMRI), and these whole-brain read-outs often reveal important qualities of different sleep stages, such as changes in frequency dynamics or connectivity. Recently, various techniques have been developed that allow for the recording of neural activity simultaneously across multiple regions of the fly brain. These whole-brain-recording approaches will be important for better understanding sleep physiology and function, as they provide a more comprehensive view of neural dynamics during sleep and wake in a relevant model system. Here, we present a brief summary of some of the findings derived from sleep activity recording studies in sleeping Drosophila flies and discuss the value of electrophysiological versus calcium imaging techniques. Although these involve very different preparations, they both highlight the value of multidimensional data for studying sleep in this model system, like the use of both EEG and fMRI in humans.

Glymphatic dysfunction in the pathogenesis of neurodegenerative diseases and pathological aging

Recently, the concept of the glymphatic system as a highly organized perivascular network has been formed, which by hydrodynamic approach, with the key participation of aquaporin-4 as a central molecule, connects the cerebrospinal fluid with the lymphatic vessels of the meninges through the brain interstitium. The latest scientific works demonstrates the potential role of glymphatic dysfunction in the development of neurodegeneration and pathological aging. Although the precise molecular mechanisms of glymphatic pathway function have not yet been fully characterized, the critical processes underlying cerebral solute transport and clearance of amyloid and metabolites have been largely elucidated. The complex interaction between a number of age-associated factors, including cellular aging, disturbances in the sleep-wake cycle with changes in sleep architecture and quality, low-grade systemic inflammation, and the development of concomitant diseases, determines not only life expectancy in general, but also forms the basis of healthy and unhealthy aging the brain in particular. Imbalances in homeostatic functions, changes in the activity of glymphatic clearance and the blood-brain barrier that support the exchange of fluid and solutes in cerebral tissue, which can be observed both normally with physiological aging and with the development of neuropathology, have longitudinal consequences ranging from disruption of synaptic signal transmission to onset of neurodegenerative processes. This review analyzes the current scientific information in this area of research, details the features of the perivascular glial-mediated transport system, and discusses how its dysfunction plays a fundamental role in the pathological accumulation of metabolites during aging, the development of age-associated changes in the brain, and the progression of neurodegenerative diseases.

Acoustic stimulation during sleep predicts long-lasting increases in memory performance and beneficial amyloid response in older adults.

Sleep and neurodegeneration are assumed to be locked in a bi-directional vicious cycle. Improving sleep could break this cycle and help to prevent neurodegeneration. We tested multi-night phase-locked acoustic stimulation (PLAS) during slow wave sleep (SWS) as a non-invasive method to improve SWS, memory performance and plasma amyloid levels. 32 healthy older adults (agemean: 68.9) completed a between-subject sham-controlled three-night intervention, preceded by a sham-PLAS baseline night. PLAS induced increases in sleep-associated spectral-power bands as well as a 24% increase in slow wave-coupled spindles, known to support memory consolidation. There was no significant group-difference in memory performance or amyloid-beta between the intervention and control group. However, the magnitude of PLAS-induced physiological responses were associated with memory performance up to 3 months post intervention and beneficial changes in plasma amyloid. Results were exclusive to the intervention group. Multi-night PLAS is associated with long-lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool to build upon and develop long-term protocols for the prevention of cognitive decline.

Medicinal Chemistry and NMR Driven Discovery of Novel UDP-glucuronosyltransferase 1A Inhibitors That Overcome Therapeutic Resistance in Cells

The UDP glucuronosyltransferases (UGT) deactivate many therapeutics via glucuronidation while being required for clearance of normal metabolites and xenobiotics. There are 19 UGT enzymes categorized into UGT1A and UGT2B families based on sequence conservation. This presents a challenge in terms of targeting specific UGTs to overcome drug resistance without eliciting overt toxicity. Here, we identified for the first time that UGT1A4 is highly elevated in acute myeloid leukemia (AML) patients and its reduction corresponded to objective clinical responses. To develop inhibitors to UGT1A4, we leveraged previous NMR-based fragment screening data against the C-terminal domain of UGT1A (UGT1A-C). NMR and medicinal chemistry strategies identified novel chemical matter based on fragment compounds with the capacity to bind ∼20 fold more tightly to UGT1A-C (Kd ∼ 600 μM vs ∼30 μM). Some compounds differentially inhibited UGT1A4 versus UGT1A1 enzyme activity and restored drug sensitivity in resistant human cancer cells. NMR-based NOE experiments revealed these novel compounds recognised a region distal to the catalytic site suggestive of allosteric regulation. This binding region is poorly conserved between UGT1A and UGT2B C-terminal sequences, which otherwise exhibit high similarity. Consistently, these compounds did not bind to the C-terminal domain of UGT2B7 nor a triple mutant of UGT1A-C replaced with UGT2B7 residues in this region. Overall, we discovered a site on UGTs that can be leveraged to differentially target UGT1As and UGT2Bs, identified UGT1A4 as a therapeutic target, and found new chemical matter that binds the UGT1A C-terminus, inhibits glucuronidation and restores drug sensitivity.

Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system

AbstractThe glymphatic system plays a key role in the clearance of waste from the parenchyma, and its dysfunction has been associated with the pathogenesis of Alzheimer's disease (AD). However, questions remain regarding its complete mechanisms. Here, we report that efflux of cerebrospinal fluid (CSF)/interstitial fluid (ISF) solutes occurs through a triphasic process that cannot be explained by the current model, but rather hints at the possibility of other, previously undiscovered routes from paravenous spaces to the blood. Using real‐time, in vivo observation of efflux, a novel drainage pathway was discovered, in which CSF molecules enter the bloodstream directly through dynamically assembled, trumpet‐shaped pores (basolateral ϕ&lt;8 μm; apical ϕ &lt; 2 μm) on the walls of brain venules. As Zn2+ could facilitate the brain clearance of macromolecular ISF solutes, Zn2+‐induced reconstruction of the tight junctions (TJs) in vascular endothelial cells may participate in pore formation. Thus, an updated model for glymphatic clearance of brain metabolites and potential regulation is postulated. In addition, deficient clearance of Aβ through these asymmetric venule pores was observed in AD model mice, supporting the notion that impaired brain drainage function contributes to Aβ accumulation and pathogenic dilation of the perivascular space in AD.