Dispersion as a waste-clearance mechanism in flow through penetrating perivascular spaces in the brain

AbstractAccumulation of metabolic wastes in the brain is correlated with several neurodegenerative disorders, including Alzheimer’s disease. Waste transport and clearance occur via dispersion, the combined effect of diffusion and advection by flow of fluid. We examine the relative contributions of diffusion and advection in the perivascular spaces (PVSs) that surround penetrating cortical blood vessels and are filled with cerebrospinal fluid (CSF). To do so, we adapt prior analytic predictions of dispersion to the context of PVSs. We also perform advection-diffusion simulations in PVS-like geometries with parameters relevant to transport of amyloid-$$\beta$$ β (associated with Alzheimer’s) in a variety of flows, motivated by in vivo measurements. Specifically, we examine solute transport in steady and unsteady Poiseuille flows in an open (not porous) concentric circular annulus. We find that a purely oscillatory flow enhances dispersion only weakly and does not produce significant transport, whereas a steady flow component, even if slow, clears waste more effectively.

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Author Correction: Dispersion as a waste-clearance mechanism in flow through penetrating perivascular spaces in the brain

Scientific Reports ◽

10.1038/s41598-021-99517-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniel E. Troyetsky ◽

Jeffrey Tithof ◽

John H. Thomas ◽

Douglas H. Kelley

Keyword(s):

Perivascular Spaces ◽

Clearance Mechanism ◽

Flow Through ◽

The Brain

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A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00669-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jie Zheng ◽

Na Tian ◽

Fei Liu ◽

Yidian Zhang ◽

Jingfen Su ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Protein Phosphatase ◽

High Efficiency ◽

Microtubule Assembly ◽

Hyperphosphorylated Tau ◽

Phosphatase 2A ◽

Dependent Learning ◽

The Brain

AbstractIntraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer’s disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

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Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain

Neurology ◽

10.1212/wnl.0000000000013077 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013077

Author(s):

Corey W Bown ◽

Roxana O Carare ◽

Matthew S Schrag ◽

Angela L Jefferson

Keyword(s):

Fluid Transport ◽

Small Vessel Disease ◽

Treatment Strategies ◽

Small Vessel ◽

Aging Brain ◽

Perivascular Spaces ◽

Vessel Disease ◽

Clinical Consequences ◽

The Brain

Perivascular spaces (PVS) are fluid filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on magnetic resonance imaging. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as two possible mechanisms that drive ePVS formation. In this review, we describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the two most prominent theoretical views and review ePVS associations with other common small vessel disease markers. As ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer’s disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

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The effects of humoral, cellular and non-specific immunity on intracerebralBordetella pertussisinfections in mice

Journal of Hygiene ◽

10.1017/s002217240004674x ◽

1975 ◽

Vol 74 (1) ◽

pp. 85-102 ◽

Cited By ~ 5

Author(s):

Jean M. Dolby ◽

D. E. Dolby ◽

Caroline J. Bronne-Shanbury

Keyword(s):

Bordetella Pertussis ◽

Cell Mass ◽

Bactericidal Effect ◽

Suppressive Effect ◽

Repeated Doses ◽

Intracerebral Infection ◽

The Brain ◽

Infecting Organisms ◽

Do So

When mice were injected intracerebrally with doses ofBordetella pertussisvaccine greater than 5 ImD50 and challenged intracerebrally 14 days later with virulentB. pertussisthere was an immediate reduction in the numbers of organisms. An analysis of thisin vivobactericidal effect has shown that large doses of an unrelated vaccine,Salmonella typhosa, equivalent in cell mass to about 50 ImD 50 ofB. pertussisvaccine can achieve this effect, so for such doses the effect must be partly non-specific. This action is not maintained and so is not ultimately protective. Local immunoglobulin was also demonstrable 14 days after 300 ImD 50 ofB. pertussisvaccine but following smaller doses of 10–20 ImD 50 it could not be found until after the mice had been infected and the blood–brain barrier impaired.A similar immediate reduction in the numbers of infecting organisms inoculated 1 day after vaccination has been shown to follow very small, non-protective doses of vaccines unrelated toB. pertussisand to be achieved with lipopolysaccharide and endotoxin isolated fromB. pertussis.Brains were not sterilized and only in mice receiving protectiveB. pertussisvaccine was the lowering of infection maintained beyond 2 days and the brains eventually sterilized.The antibody passively protecting mice against intracerebral infection was found in the 19 S and 11 S globulin fractions of the serum of once-vaccinated mice and in the 11 S and 7 S fractions of the serum of rabbits and ascitic fluid of mice receiving repeated doses of vaccine. The IgM probably eliminated infections by immediate sterilization but had to be present locally to do so since it was unable to pass from the circulation into the brain, and was therefore inactive when injected intraperitoneally. The IgA and IgG were not so restricted and both the 11 S and 7 S globulins were capable of exerting an immediate suppressive effect on infecting organisms. The 7 S globulin was also capable of a maintained or delayed suppressive effect.Lymphocytes from fully protected once-vaccinated mice, transferred 2–3 weeks after intraperitoneal vaccination, were able to confer some protection when injected intraperitoneally or intracerebrally into recipient mice infected 2 weeks after transfer. Homologous, non-concentrated antiserum from once-vaccinated mice, injected intraperitoneally 1 hr. before infection sometimes augmented the transferred immunity, whereas alone it was inactive.

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STIMULUS: Noninvasive Dynamic Patterns of Neurostimulation using Spatio-Temporal Interference

10.1101/216622 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jiaming Cao ◽

Pulkit Grover

Keyword(s):

Computational Model ◽

Electrode Pair ◽

Modeling Framework ◽

Model Based ◽

Spatio Temporal ◽

Spatial Interference ◽

The Brain ◽

Over Time ◽

Do So

AbstractUsing a systematic computational and modeling framework, we provide a novel Spatio-Temporal Interference-based stiMULation focUsing Strategy (STIMULUS) for high spatial precision noninvasive neurostimulation deep inside the brain. To do so, we first replicate the results of the recently proposed temporal interference (TI) stimulation (which was only tested in-vivo) in a computational model based on a Hodgkin-Huxley model for neurons and a model of current dispersion in the head. Using this computational model, we obtain a nontrivial extension of the 2-electrode-pair TI proposed originally to multielectrode TI (> 2 electrode pairs) that yields significantly higher spatial precision. To further improve precision, we develop STIMULUS techniques for generating spatial interference patterns in conjunction with temporal interference, and demonstrate strict and significant improvements over multielectrode TI. Finally, we utilize the adaptivity that is inherent in STIMULUS to create multisite neurostimulation patterns that can be dynamically steered over time.

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What Are the Molecular Mechanisms by Which Functional Bacterial Amyloids Influence Amyloid Beta Deposition and Neuroinflammation in Neurodegenerative Disorders?

International Journal of Molecular Sciences ◽

10.3390/ijms21051652 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1652 ◽

Cited By ~ 3

Author(s):

Robert P. Friedland ◽

Joseph D. McMillan ◽

Zimple Kurlawala

Keyword(s):

Amyloid Beta ◽

Neurodegenerative Disorders ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Innate Immune ◽

Know How ◽

Unique Distribution ◽

The Brain

Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.

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Autophagic Dysfunction in Dementia: Scope for Development of Potential Remedies

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666201209112256 ◽

2020 ◽

Vol 19 ◽

Author(s):

Bhumika Kumar ◽

Mukesh Pandey ◽

Ashwini Kumar Mishra ◽

Anjali Sharma ◽

Faizana Fayaz ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Social Life ◽

Daily Routine ◽

Protein Homeostasis ◽

Protein Clearance ◽

Clearance Mechanism ◽

Genetic Level ◽

The Relationship ◽

Progressive Disorder ◽

The Brain

: Dementia is a diverse category of a chronic and progressive disorder, which is commonly associated with loss of memory, difficulty in judgment, impaired language, cognitive impairment, and various other symptoms that affects a person’s daily routine life and social life. Dementia affects about 50 million people around the globe. Dementia exists in varied forms and is associated with various neurodegenerative disorders. Alzheimer's disease dementia is the most common form which accords for about 60% cases. Abnormal agglomeration of proteins in the brain has been linked to the pathogenesis of dementia. Autophagy is a necessary protein clearance mechanism, which is dependent on lysosomes. It is a basic physiological process that performs the crucial function of maintaining protein homeostasis within the cells. The autophagic dysfunction in dementia further complicates the disease by hampering the degradation and removal of abnormal pathogenic proteins. In order to understand autophagic dysfunction, it is essential to know the genetics of autophagy as well as the mutations which cause autophagic dysfunction. This understanding at the genetic level helps to define the relationship between dementia and autophagic dysfunction for developing the potential remedies for the treatment of dementia.

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PET and the multitracer concept in the study of neurodegenerative diseases

Dementia & Neuropsychologia ◽

10.1590/1980-57642015dn94000343 ◽

2015 ◽

Vol 9 (4) ◽

pp. 343-349 ◽

Cited By ~ 1

Author(s):

Henry Engler ◽

Andres Damian ◽

Cecilia Bentancourt

Keyword(s):

Positron Emission Tomography ◽

Molecular Imaging ◽

Neurodegenerative Diseases ◽

Brain Tissue ◽

Neurodegenerative Disorders ◽

Clinical Symptoms ◽

Emission Tomography ◽

Positron Emission ◽

The Brain

ABSTRACT The complexity of the pathological reactions of the brain to an aggression caused by an internal or external noxa represents a challenge for molecular imaging. Positron emission tomography (PET) can indicate in vivo,anatomopathological changes involved in the development of different clinical symptoms in patients with neurodegenerative disorders. PET and the multitracer concept can provide information from different systems in the brain tissue building an image of the whole disease. We present here the combination of 18F-flourodeoxyglucose (FDG) and N-[11C-methyl]-L-deuterodeprenyl (DED), FDG and N-[11C-methyl] 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), PIB and L-[11C]-3'4-Dihydrophenylalanine (DOPA) and finally PIB and [15O]H2O.

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Cerebrospinal Fluid Efflux Through Dynamic Paracellular Pores on Venule as a Missing Piece for the Image of Brain Drainage System

10.21203/rs.3.rs-941995/v1 ◽

2021 ◽

Author(s):

Yaqiong Dong ◽

Ting Xu ◽

Lan Yuan ◽

Yahan Wang ◽

Siwang Yu ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Laser Scanning ◽

Vascular Endothelial Cells ◽

Drainage System ◽

Fluorescein Isothiocyanate ◽

Blood Pool ◽

Confocal Laser ◽

Perivascular Spaces ◽

The Brain

Abstract Background: The glymphatic system has been considered to contribute to a larger portion of parenchyma waste clearance and related to pathogenesis of many neural degenerative diseases such as the Alzheimer’s disease (AD). However, up to date, the key route for the efflux from perivascular spaces to the blood pool remains a mystery.Methods: BBB-impermeable fluorescent lanthanide probes of different size were first applied as cerebrospinal fluid (CSF)/interstitial fluid (ISF) tracers to quantitatively clarify the relative importance of different pathways to drain CSF/ISF solutes. The in vivo dynamic flows of subarachnoid CSF labeled with fluorescein isothiocyanate-dextran (4 kDa) tracers along brain blood vessels were observed under a two-photon confocal laser scanning microscope. Results: Three phasic process for the brain drainage was observed, in which the rapid efflux of ISF solutes with a time constant close to the CSF oscillation during sleep appeals for new routes from perivenuous spaces to the blood pool. Careful observation on the dynamic efflux in vivo revealed a novel drainage pathway in which CSF molecules converge into the bloodstream directly through dynamic trumpet-like pores (basolateral f＜8 μm; apical f＜2 μm) on the wall of brain venule in mice. Zn2+, an inducer of reconstruction of the tight junctions (TJs) in vascular endothelial cells, could facilitate the brain clearance of macromolecular ISF solutes. Deficit clearance of Aβ through the asymmetric pores on venule potentially causing perivascular space dilation was observed on the AD model mice.Conclusions: The novel asymmetric pore path through reconstruction of endothelial TJs on the wall of venule shall provide a key piece for ISF solutes to drainage from brain in very rapid pathway. The update image would help to understand the structure and the regulation of glymphatic clearance of brain metabolites such as Aβ in search for the solutions of neurodegenerative diseases.

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Hydraulic resistance of perivascular spaces in the brain

10.1101/522409 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jeffrey Tithof ◽

Douglas H. Kelley ◽

Humberto Mestre ◽

Maiken Nedergaard ◽

John H. Thomas

Keyword(s):

Cerebrospinal Fluid ◽

Blood Vessels ◽

Hydraulic Resistance ◽

Perivascular Spaces ◽

Navier Stokes Equation ◽

Pial Arteries ◽

Cross Sectional ◽

Annular Channels ◽

The Brain

AbstractBackgroundPerivascular spaces (PVSs) are annular channels that surround blood vessels and carry cerebrospinal fluid through the brain, sweeping away metabolic waste. In vivo observations reveal that they are not concentric, circular annuli, however: the outer boundaries are often oblate, and the blood vessels that form the inner boundaries are often offset from the central axis.MethodsWe model PVS cross-sections as circles surrounded by ellipses and vary the radii of the circles, major and minor axes of the ellipses, and two-dimensional eccentricities of the circles with respect to the ellipses. For each shape, we solve the governing Navier-Stokes equation to determine the velocity profile for steady laminar flow and then compute the corresponding hydraulic resistance.ResultsWe find that the observed shapes of PVSs have lower hydraulic resistance than concentric, circular annuli of the same size, and therefore allow faster, more efficient flow of cerebrospinal fluid. We find that the minimum hydraulic resistance (and therefore maximum flow rate) for a given PVS cross-sectional area occurs when the ellipse is elongated and intersects the circle, dividing the PVS into two lobes, as is common around pial arteries. We also find that if both the inner and outer boundaries are nearly circular, the minimum hydraulic resistance occurs when the eccentricity is large, as is common around penetrating arteries.ConclusionsThe concentric circular annulus assumed in recent studies is not a good model of the shape of actual PVSs observed in vivo, and it greatly overestimates the hydraulic resistance of the PVS. Our parameterization can be used to incorporate more realistic resistances into hydraulic network models of flow of cerebrospinal fluid in the brain. Our results demonstrate that actual shapes observed in vivo are nearly optimal, in the sense of offering the least hydraulic resistance. This optimization may well represent an evolutionary adaptation that maximizes clearance of metabolic waste from the brain.

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