reviewarticle pathomechanisms of blood-brain barrier disruption … · 2019. 7. 12. · pha g us is...

Review ArticlePathomechanisms of Blood-Brain Barrier Disruption in ALS

Nicholas Kakaroubas 12 Samuel Brennan1 Matthew Keon1 and Nitin K Saksena 1

1Neurodegenerative Disease Section Iggy Get Out 19A Boundary Street Darlinghurst NSW 2010 Sydney Australia2School of Biotechnology and Biomolecular Sciences University of New South Wales (University of NSW) Chancellery WalkKensington NSW 2033 Sydney Australia

Correspondence should be addressed to Nitin K Saksena nitiniggygetoutcom

Received 5 May 2019 Revised 18 June 2019 Accepted 25 June 2019 Published 10 July 2019

Academic Editor Mark A Cline

Copyright copy 2019 Nicholas Kakaroubas et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironmentwithin neural tissues in humansThese barriers are fundamental to all neurological processes as they provide the extremenutritionaldemands of neural tissue remove wastes and maintain immune privileged status Being a semipermeable membrane both theBBB and BSCB allow the diffusion of certain molecules whilst restricting others In amyotrophic lateral sclerosis (ALS) and otherneurodegenerative diseases these barriers become hyperpermeable allowing a wider variety of molecules to pass through leadingtomore severe andmore rapidly progressing diseaseThe intention of this review is to discuss evidence that BBB hyperpermeabilityis potentially a disease driving feature in ALS and other neurodegenerative diseases The various biochemical physiological andgenomic factors that can influence BBB permeability in ALS and other neurodegenerative diseases are also discussed in additionto novel therapeutic strategies centred upon the BBB

1 Introduction

The blood-brain barrier (BBB) is a highly selective semiper-meable complex that surrounds most of the blood vesselsin the brain [1] except for the circumventricular organs(CVOs) centred around the ventricles of the brain CVOsare characterized by their highly permeable microvascula-ture and are involved with sensory and secretory systemswithin the brain [2 3] The BBB separates the blood fromthe extracellular cerebrospinal fluid and protects the brainfrom bloodborne pathogens and toxins while allowing thediffusion of oxygen carbon dioxide and small lipophilicmoleculesethanol [4] Maintenance of the BBB is essentialfor a tight control of the chemical composition of the brainrsquosinterstitial fluid (ISF) essential for synaptic function as wellas offering a formof protection against bloodborne pathogens[1 4] Further separation of the central nervous system (CNS)from the cardiovascular system occurs via the blood-spinalcord barrier (BSCB)TheBSCB acts as a functional equivalentof the BBB by maintaining the microenvironment for thecellular constituents of the spinal cord [5] There is reasonto believe that the permeability of the BBB and BSCB differs

with evidence suggesting that the BSCB is more permeable[5] This difference in permeability has attracted motorneuron disease (MND) research with findings suggestingthat the BSCB is damaged in human and rodentALS sufferersDespite this evidence the BSCB (like the BBB) breakdown indisease pathogenesis remains unclear [6 7]

There are three cellular components that make up theBBB this includes the capillary basement membrane (BM)astrocyte end-feet ensheathing the vessels and pericytes(PCs) embedded within the BM Tight junctions (TJs) arepresent between the cerebral endothelial cells and serve thefunction of limiting the paracellular flux of molecules acrossthe BBB TJs appear as apparent sites of fusion involvingthe leaflets of plasma membrane of adjacent endothelialcells Similarly adherence junctions (AJs) are more basalthan TJs and are defined by their cytoplasmic face beinglinked to the actin cytoskeleton [8] It is currently acceptedin scientific literature that all the components of the BBBare essential for normal function and stability of the BBBDespite sharing the same principal building blocks withthe BBB there is evidence suggesting morphological andfunctional differences in the BSCB The differences between

HindawiNeuroscience JournalVolume 2019 Article ID 2537698 16 pageshttpsdoiorg10115520192537698

2 Neuroscience Journal

the two barriers include an increased permeability to trac-ers [3H]-D-mannitol and [14C]-carboxyl-inulin [9] andcytokines interferon-120572 interferon-120574 tumor necrosis factor-120572 [10] decreased Occludin and ZO-1 protein expression inTJ [11] and decreased VE-cadherin and 120573-catenin proteinexpression in AJ [11]

Neuroimaging studies have demonstrated early BBB dys-function in Alzheimer disease (AD) [12] Parkinson disease(PD) [13] Huntington disease (HD) [14] amyotrophic lateralsclerosis (ALS) [6 15 16] and multiple sclerosis (MS) [17]These demonstrations of BBB dysfunction have been con-firmedwith biofluid biomarker data andobservations of post-mortem tissue analysis [6 12ndash17] For the sake of this reviewldquohyperpermeabilityrdquo will refer to an increased state of per-meability in the otherwise semipermeable membranes BBBhyperpermeability represents a significant area of researchas despite being continuously examined in multiple motorneuron diseases (MNDs) [18] the exact biochemical pathwayof BBB breakdown is not yet known

This review aims to examine current research under-standings of BBB hyperpermeability and mechanisms ofbreakdown to identify key research targets and areas thatmayshed light on the mystery surrounding the pathophysiologyof BBB (and BSCB) breakdownThe key points of this reviewrevolve around the mechanisms involved in oxidative stresscerebrospinal microbleeds underlying genomic modalitiesand the epidemiology of ALS thereby providing insightsinto potentially valuable knowledge gaps To conclude thisreviewwill make recommendations to investigative areas thathold promise in understanding the mechanisms involved inBBB breakdown at the biological and molecular level andprovide insights into therapeutic strategies to modulate BBBpermeability

2 Oxidative Stress

Radicals are defined as a molecule species with one ormore unpaired electrons and are characterised by beinghighly reactive Reactive Oxygen Species (ROS) are a groupof oxygen centred radicals ROS can damage the bodythrough hypoxia and reoxygenation of cells Hypoxia andreoxygenation of BBB endothelial cells cause an increase inthe paracellular permeability [19 20] of the structure leadingto a state of hyperpermeability ROS may also cause changesin the localization and structure of Occludin [21] whichmay influence the regulation and assembly of tight junctionswhich are essential structures in the BBB [22]

ROS can be produced endogenously and taken intothe body exogenously Exogenous sources of ROS can beobtained from pollutants tobacco smoke xenobiotics radi-ation (ultraviolet and ionizing) ozone chemotherapeuticagents pesticides (eg Aldrindendrin [23 24]) organic sol-vents alcohol and somemetals [25 26] EndogenousROS areproduced intracellularly and extracellularly with the majorproducers being NADPH oxidase (NOX) nitrogen oxidesynthase Xanthine oxidase Heme proteins CytochromeP450

phagocytes mitochondria peroxisomes and the endo-plasmic reticulum [27ndash29]

The significance of ROS in the degradation of neuromus-cular junctions in cases of MND especially sporadic ALS(sALS) has been examined extensively within literature asa proposed mechanism of neuromuscular degeneration asper the ldquoDying Back hypothesisrdquoThe Dying Back hypothesishowever does not account for BBB or BSCB degradationROS has been demonstrated to cause BBB dysfunctionthrough alcohol induced activation of myosin light chain(MLC) kinase and phosphorylation of MLC and TJ pro-teins [30] Furthermore BBB disruption has been shownto be mediated by oxidative stress through stimulation ofinositol 145-triphosphate (IP

3R)-gated intracellular Ca2+

release resulting in a similar MLC kinase activation As suchoxidative stress remains a topic of interest in investigatingBBB hyperpermeability [31]

The effects of an abundance of ROS can be mitigated bythe metabolism of these free radicals through neutralisationvia antioxidants [32] Oxidative stress is when there is moreROS than antioxidants and can have many physiologicaleffects on the body There are enzymatic and nonenzymaticantioxidant systems in humans which appear to be keyaspects in the fight against ROS [33]

21 Enzymatic Antioxidants

211 Nrf2 Transcription Factor It is worth noting the impor-tance of the transcription factor nuclear factor erythroid2ndashrelated factor 2 (Nrf2) and its role in oxidative stress Thetranscription factor is constitutively expressed in all tissues[34] Nrf2 functions at the interface of cellular redox andintermediary metabolism reactions as the target genes areinvolved in antioxidant enzyme production [35ndash37] Nrf2 isa basic region leucine zipper transcription factor [38] thatforms heterodimers in the nucleus of cells which recognisesthe enhancer sequence known as antioxidant response ele-ment (ARE) ARE enhancer sequences are present in theregulatory regions of over 250 genes [39] Not only involvedin antioxidant production decreased Nrf2 activity decreasesthe expression of key tight junction proteins such as occludinand claudin-18 [39]

Nrf2 is activated by sulforaphane [40] an organosulfurcompound found in cruciferous vegetables eg broccoliand Brussels sprouts [41] Animal studies have shown thatsulforaphane administration after brain injury increased neu-roprotective effects of Nrf2 [42] For its role in ARE and tightjunction proteins Nrf2 represents a significant direction forALS- or neurodegenerative disease-induced BBB disruptionand hyperpermeability

Supporting this Kraft et al (2007) evaluated the endoge-nous activation of the Nrf2-ARE system during the inductionof pathology in mutant SOD mouse models and showedthat Nrf2-ARE activation appears to progress in a retrogradefashion along the motor pathway thereby implying thecontributions of the Nrf2-ARE pathway and its activationwhich can persist throughout ALS pathology and whichincreases in concert with disease severity [43]

212 SOD Protein Family The superoxide dismutase (SOD)family of enzymes function to catalyze the dismutation of

Neuroscience Journal 3

superoxide anions (O2

minus) [44 45] Mammals have threeisoforms of SOD that require metal cofactors (Cu Zn orMn) for proper activation Superoxide anions are a reactiveoxygen species and are a byproduct of the one-electronreduction of oxygen (O

2) that occurs as an antimicrobial

immune response employed by phagosomes In the pro-duction of superoxide anions the membrane associatedflavoprotein enzyme nicotinamide adenine dinucleotidephosphate (NADPH) oxidase catalyses oxygen to producesuperoxide anions and hydrogen cations [45]

NADPH + 2O2larrrarr NADP+ + 2O

2

minus +H+ (1)

The SOD family of proteins act as one of many defencemechanisms against superoxide anions The SOD proteinfamily CuZn-SODMn-SOD and EC-SOD is encoded by theSOD gene family which includes SOD1 SOD2 and SOD3respectively [27] SOD1 is located at locus 21q2211 SOD2 islocated at locus 6q253 and SOD3 is located at locus 4p152SOD1 is distributed throughout the cytoplasm and nucleuswhile SOD2 is found in the mitochondrial matrix [46 47]Interestingly SOD3 is a glycoprotein that is predominantlyexpressed in the extracellular matrix of tissues and the glyco-calyx of cell surfaces where it is anchored to heparansulfateproteoglycan SOD3 has been detected in human plasmalymph ascites and cerebrospinal fluids According to theGenotype-Tissue Expression (GTEx) project SOD3 is mostabundant in the Aorta Tibial and Coronary arteries whichcorresponds to its role as an extracellular antioxidant [48]SOD3 and its extracellular expression are noteworthy due tothe oxidative stress and subsequent paracellular permeabilitywithin the BBB (Figure 1)

The general reduction pathway for metal-coordinatedforms of SOD enzymes is the following

Cu2+-SOD +O2

minus 997888rarr Cu+-SOD +O2

(2)

(reduction of copper oxidation of superoxide)

Cu+-SOD +O2

minus + 2H+ 997888rarr Cu2+-SOD +H2O2

(3)

(oxidation of copper reduction of superoxide)where the superoxide anion is converted to two less

harmful products hydrogen peroxide (H2O2) and dioxide

(O2)While SOD2 and SOD3 have had little published link-

age to disease SOD1 has been associated with FamilialAmyotrophic Lateral Sclerosis (fALS) [49] and SOD1 isimplicated in apoptosis [50]GTEXanalysis shows high SOD1representation in the brain (Figure 1) For this reason SOD1has been the primary focus for fALS research but consideringSOD3rsquos expression and abundance in the blood stream itmaybe a potential target for future BBB permeability research

213 CAT Protein Encoded by the CAT gene catalase is atetrameric protein Each of the four subunits is 60kDa inweight and each contains a single ferriprotoporphyrin [5152] CAT is ubiquitous in living tissues that utilise oxygenUsing an iron or manganese cofactor CAT catalyses thereduction of hydrogen peroxide to form water (H

2O) and

molecular oxygen This process works in a complementaryrelationship to SOD family proteins in detoxifying the result-ing hydrogen peroxide by converting it to water and dioxide(O2) [53]

2H2O2997888rarr 2H

2O +O

2 (4)

The biochemical mechanism of reaction of catalase is largelyspeculative however it has been proposed that it occurs intwo stages [54]

H2O2 + Fe (III) -E 997888rarr H2O +O = Fe (IV) -E

H2O2 +O = Fe (IV) -E 997888rarr H2O + Fe (III) -E(5)

(Fe-E represents the Ferriprotoporphyrin centre)CAT is located at locus 11p13 A mutation in this gene

typically results in Acatalasemia causing oral gangrene andpossibly an increase in type 2 diabetes however studying thiscondition is challenging as many cases are asymptomatic andare only diagnosed as a result of affected family membersCatalase experiences the least amount of expression in thebrain with slightly higher expression in the spinal cord(cervical c-1 Figure 2) An immunocytochemical study [55]showed higher expression of catalase (as well as SOD3)in the grey matter of human MND cervical spinal cordswhen compared to normal human cervical spinal cordsIt is not known whether the high free radical scavengingenzymes occur as a compensatory reaction to the presence ofoxidative stress Further research regarding these expressionlevel discrepancies is required

214 GPx Protein Family Glutathione peroxidase (GPx) isthe name given to a group of 8 isozymes that are present inhumans These proteins (GPx1-GPx8) have been mapped tochromosomes 3 14 5 19 6 6 1 and 5 respectively [33 56ndash58] (Table 1)

GPx catalyses the breakdown of hydrogen peroxides intowater and a lipid peroxide to corresponding alcohols [59]Glutathione (GSH) acts as the electron donor to hydrogenperoxide and is converted to glutathione disulphide (GS-SG)

2GSH +H2O2997888rarr GSndashSG + 2H

2O (6)

Due to the widespread nature of GPx enzymes their clinicalimportance has been explored with lower GPx activity beingassociated impaired antioxidant protection [59] Despiteits many forms GPx is poorly understood however it isspeculated that the GPx family (especially GPx1) is essentialto vascular oxidative stress and endothelial disfunction [59]both of which are critical components of a healthy function-ing BBB [2]

22 Nonenzymatic Antioxidants

221 Glutathione Glutathione is a tripeptide containingcysteine glycine and glutamate It is present typically inconcentrations up to 12 mM within mammalian cells [60]however it is among the most common soluble antioxidantsin the brain [61] being produced by both neurons and glial


Adrenal Gland

LiverBrain - Frontal Cortex (BA9)

Brain - Hypothalamus

Brain - Spinal cord (cervical c-1)

Brain - Substantia nigra

Artery - Aorta

Brain - Nucleus accumbens (basal ganglia)

OvaryBrain - Anterior cingulate cortex (BA24)

Brain - Cortex

Artery - Tibial

Brain - Caudate (basal ganglia)

Artery - Coronary

Brain - Cerebellar Hemisphere

Brain - Amygdala

Nerve - Tibial

Brain - Hippocampus

Brain - Cerebellum

Adipose - Subcutaneous

Pituitary

Brain - Putamen (basal ganglia)

BladderCells - Transformed fibroblasts

Cervix - Ectocervix

VaginaThyroid

Esophagus - Gastroesophageal Junction

Kidney - Cortex

Cervix - Endocervix

UterusEsophagus - Muscularis

Colon - Sigmoid

Breast - Mammary Tissue

Adipose - Visceral (Omentum)

Cells - EBV-transformed lymphocytes

ProstateFallopian Tube

Colon - Transverse

Heart - Left Ventricle

Small Intestine - Terminal Ileum

Heart - Atrial Appendage

TestisEsophagus - Mucosa

Muscle - Skeletal

LungSpleen

StomachSkin - Sun Exposed (Lower leg)

Minor Salivary Gland

Skin - Not Sun Exposed (Suprapubic)

Whole Blood

Pancreas

10

15

20

25

30

log1

0(TP

M+1

)

Gene expression for SOD1 (ENSG0000014216810)

Muscle - Skeletal



Cells - Transformed fibroblasts

LungWhole Blood

LiverAdipose - Subcutaneous


Kidney - Cortex

Fallopian Tube

Cervix - Endocervix

Cervix - Ectocervix

Adrenal Gland

Artery - Tibial

ProstateNerve - Tibial

BladderVagina

Colon - Sigmoid

Esophagus - Muscularis



UterusHeart - Left Ventricle

Artery - Coronary

Artery - Aorta

Esophagus - Mucosa

Skin - Sun Exposed (Lower leg)

ThyroidColon - Transverse


OvarySkin - Not Sun Exposed (Suprapubic)

Brain - Frontal Cortex (BA9)

SpleenBrain - Cerebellar Hemisphere


Brain - Anterior cingulate cortex (BA24)




StomachPancreas


Brain - Amygdala

Brain - Cortex

Pituitary

Brain - Cerebellum

Brain - Hippocampus


TestisCells - EBV-transformed lymphocytes

05

10

15

20

25

30

35

log1

0(TP

M+1

)


Artery - Aorta

Artery - Tibial

Artery - Coronary




Nerve - Tibial

ThyroidCervix - Ectocervix

VaginaFallopian Tube

BladderLung

Cervix - Endocervix

UterusBreast - Mammary Tissue

ProstateColon - Sigmoid


TestisSkin - Sun Exposed (Lower leg)



Kidney - Cortex

Colon - Transverse


OvaryEsophagus - Mucosa

StomachSmall Intestine - Terminal Ileum

Pancreas


SpleenCells - Transformed fibroblasts

Adrenal Gland

Pituitary

Brain - Cortex






Brain - Amygdala

Muscle - Skeletal



Brain - Hippocampus


LiverBrain - Cerebellum



Whole Blood

00

10

20

30

log1

0(TP

M+1

)


Figure 1 GTEx Analysis Release V7 Gene expression showing gene expressions of the SOD family of enzymes in TPM (Transcripts PerMillion) represented logarithmically SOD1 has high expression in regions of the brain SOD 2 is uniform amongst somatic cells and SOD3has high expression in Aorta Tibial and Coronary arteries



LiverAdipose - Visceral (Omentum)


ThyroidAdrenal Gland

BladderCervix - Endocervix

LungNerve - Tibial

Whole Blood


Cervix - Ectocervix

Fallopian Tube

SpleenKidney - Cortex


UterusColon - Transverse


Artery - Coronary



VaginaArtery - Tibial

Colon - Sigmoid


StomachProstate

Muscle - Skeletal

OvaryArtery - Aorta




Pancreas



Esophagus - Mucosa


Pituitary

Brain - Cortex

Brain - Amygdala




Brain - Hippocampus

TestisBrain - Anterior cingulate cortex (BA24)



Brain - Cerebellum


05

10

15

20

25

log1

0(TP

M+1

)Gene expression for CAT (ENSG000001216914)

Figure 2 GTEx Analysis Release V7 Gene expression showing gene expressions of CAT in TPM (Transcripts Per Million) representedlogarithmically

Table 1 Known GPx protein family and their chromosomallocation

Gene LocusGPx1 3p213GPx2 14q233GPx3 5q23GPx4 19p133GPx5 6p2132GPx6 6p211GPx7 1p323GPx8 5q112

cells with particularly high abundance in astrocytes [62ndash64] Glutathione is synthesized in vivo by the action oftwo enzymes 120574GluCys synthetase and glutathione synthetase[65] Glutathione (GSH) being a vital cellular componentacts as a redox buffer and as a cofactor for signal transductionantioxidant and electrophile defence mechanisms especiallyin the CNS Thus dysregulation of GSH homeostasis anddeactivation of GSH-dependent enzymes are believed tocontribute to initiation and progression of neurodegenera-tive diseases It is thus no surprise that the alteration anddysregulation of glutathione homeostasis in glutathione-dependent enzyme activities are implicated in the inductionand progression of neurodegenerative diseases includingAlzheimerrsquos disease Parkinsonrsquos disease Huntingtonrsquos dis-ease and amyotrophic lateral sclerosis [66]

Decreased glutathione has beendemonstrated to promoteapoptotic pathways partially contributing to motor neurondegeneration in in vivo and in vitro ALS models includingelevated cellular ROSproduction increases in oxidative stressmarker gene expression decreased cell adhesion and positiveassociation with motor neuron death and ALS-like diseaseprogression [67]

During the detoxification of ROS glutathione involvesitself in one of two ways reacting nonenzymatically withradicals such as superoxide anions nitric oxide or hydroxylor as the acting electron donor for the reduction of peroxidesin the GPx family After being catalysed by GPx glutathioneis regenerated from glutathione disulphide by the enzymeglutathione reductase (GR) [65] A disruption in any of thegenes responsible for glutathione synthesis or regenerationwould increase oxidative stress by not only the removal ofglutathione but also impairing GPx action

222 Carotenoids Carotenoids are a group of approximately700 species of lipo-soluble C-40-based isoprenoid pigmentsthat are characterised by their extended conjugated 120587-electron system [68] These pigments are only synthesized byplants and microbes and as such need to be supplementedinto the human diet [69] Of the 700 identified species only50 have been linked to play a role in the human diet [70] Asa result of their extended conjugated structure carotenoidshave a high affinity and strong role as an antioxidant tosinglet oxygen (1O

2) and peroxyl radicals [71] The reactivity

with ROS is largely dependent on the number of conjugateddouble bonds within the carotenoidrsquos structure the longerthe extension of the 120587-electron system the stronger thecarotenoidrsquos antioxidant potential [72]

Carotenoids rely on either passive process or activetransporters (scavengertransport proteins) SRBI CD36 andNPC1L1 for cellular uptake [73] Due to the dietary source forcarotenoids in humans it is of interest to note the expressionlevels of these active transport systems misfolded proteinsor mutated genes for these systems may be of interest inexplaining an abundance of ROS Sequence variations ofNPC1L1 proteins exist however these have been investigatedin relation to dietary cholesterol absorption [74] Whilenot immediately relating to MND misfolded or otherwisenonfunctional variants of CD36 and NPC1L1 remain an areaof MND and carotenoid research importance


23 Vitamins Vitamins are essential organic micronutrientsthat an organism cannot synthesise themselves VitaminsA C and E are all supplemented in human diets and actas essential antioxidants [75ndash77] Compromised nutrition isa well-documented issue within ALS patient populationsalthough most frequently this is due to difficulty eating dueto dysphagia a common symptom of ALS [78ndash80] It isnot known if this poor nutrition affects the severity of ALSdue to the absence of documented evidence for this reasonvitamins and nutritional support are best thought of as anearly adjunctive therapy rather than a late palliative therapy[81]

231 Vitamin A Often discussed alongside the structurallysimilar carotenoids is Vitamin A Vitamin A is found in thebody as retinol retinal and retinoic acid Vitamin A can actas an antioxidant via the hydrophobic chain of polyene unitsthat can decrease energy levels in singlet oxygen neutralizingthiyl radicals and combining with and stabilizing peroxylradicals [75] Vitamin A is stored in extracellular fluids andwithin cells bound to proteins such as retinyl palmitateoleate and myristate within the liver kidneys intestines andlungs [75] Disruption of the genes responsible forVitaminArsquosstorage proteins may impede its function as an antioxidant

232 Vitamin C The concentration of vitamin C in thebrain exceeds that of blood by 10-fold and in tissuesvitamin C exists primarily in the reduced form ascorbicacid Agus et al [82] showed that the oxidized form ofvitamin C dehydroascorbic acid (oxidized ascorbic acid)readily enters the brain and is retained in the brain tissuein the form of ascorbic acid Mechanistically the transportof dehydroascorbic acid into the brain was inhibited by d-glucose but not by l-glucose To support this the facili-tative glucose transporter GLUT1 which is expressed onendothelial cells at the blood-brain barrier is responsiblefor glucose entry into the brain thereby providing evidenceshowing that GLUT1 also transports dehydroascorbic acidinto the brain [82] Ascorbic acid is transported by the SVCTfamily of sodium-coupled transporters with two isoformsmolecularly cloned the transporters SVCT1 and SVCT2 thatshow different functional properties and differential cell andtissue expression With this Vitamin C moves throughoutthe body either passively or through active transportersSVCT1 and SVCT2 proteins that are encoded by the genesSlc23a1 (5q312) and Slc23a2 (20p13) respectively as well assecondary active transport of ascorbate through the sodium-dependent vitamin C transporters [76] Disruption of thegenes Slc23a1 andor Slc23a2 genes or low sodium levelswould result in Vitamin C acting less efficiently as anantioxidant As Vitamin C is a wide spectrum antioxidantessential for humans which humans are unable to synthesizeit must be obtained from dietary sources mainly fruits andvegetables [83]

233 Vitamin E Vitamin E is a group of fat-solublemolecules made up of four tocopherols and four tocotrienolsThe specific function of Vitamin E is not well characterizedhowever major theories hold that Vitamin E (specifically the

isomer known as 120572-tocopherol) is a fat-soluble antioxidantthat acts primarily intercellularly in the mitochondria andendoplasmic reticulum [77] Vitamin E acts as an antioxidantthrough donation of hydrogen (H) atoms to free radicals[77] Little is known regarding the biochemical mechanismsFoods rich in Vitamin E include many fruits and vegetablesand nutsseeds

Across species vitamin E has been shown to be importantfor normal neuromuscular function owing to its potentantioxidant nature as well as its ability to modulate theexpression of certain genes that inhibit platelet aggregationthereby stabilizing plasma membranes

Animal studies have shown the importance of VitaminE in a dose-dependent manner as a protective factor forBBB permeability and have demonstrated that the dosedependence of this antioxidant in aged animals differs fromthat in younger organisms [84] In this context it is worthmentioning that previous studies have shown that the defi-ciency in vitamin E increases brain tissue oxidative stressand impairs the integrity of the blood-brain barrier whichmay have relevance to the pathogenesis of amyotrophic lateralsclerosis and other neurological diseases [85]

The underlying molecular and cellular mechanismscausing neuromuscular dysfunction as a consequence ofalpha-tocopherol deficiency remain poorly understood eventhough Vitamin E deficiency has also been linked with thepathogenesis ofmotor neurondiseaseswhere oxidative injuryplays a vital role Here it is important to mention that thefree radical damage tomotor neurons has been shown [86] inthe pathogenesis of ALS where several distinct mutations inthe copperzinc superoxide dismutase gene (SOD1) a criticalcomponent of cellular antioxidant defence mechanisms havebeen shown [50] Moreover Vitamin E supplementation hasbeen shown to slow down the progression in a transgenicmouse model of ALS [87] and more recently in a pooledanalysis from 5 prospective cohort studies where long-termvitamin E supplementation was associated with decreasedrisk of ALS [88]

3 Microbleeds

Little is known regarding the prevalence and prognosisof people with cerebrospinal microbleeds This is due tothe diagnosis requiring brain MRI (Magnetic ResonanceImaging) [89 90] and the associated costs act as a researchchallenge Microbleeds can be present in individuals with noclinical history of strokes or hypertension there is little to nounderstanding on observable symptoms Similarly to physicaltrauma possibly affecting the BBB the BSCB experiencesdisruption after spinal cord injury Secondary injury resultingfrom the physical spinal cord injury can lead to apoptosisof neurons and glia [91] Humans with ALS develop BSCBbreakdown which has been reported to cause microvascularspinal-cord lesions [7] As it stands the pathogenesis of BSCBbreakdown in ALS (and wider MNDs) remains unclear andis an area for further study

Further there is paucity of literature describing whethercerebral microbleeding leads to BBB hyperpermeability or ifBBB hyperpermeability as a result of ALS leads to cerebral


microbleeds Microbleeds are currently not known to becausative or reactionary to the conditions of ALS Studieshave linked cortical microbleeds (CMBs) with Alzheimerrsquosdisease [92 93] and shown that CMBs while rare in fron-totemporal lobar degeneration are increased in the regionsaffected by neurodegenerative lesions This suggests that theprogression of Alzheimerrsquos disease promotes CMBs Under-standing the relationship between cerebrospinal microbleedsand MND represents a significant area in understandingthe conditions and may provide a possible mechanism ofprevention

4 Immune Invasion and Hyperpermeability

Immune invasion of neural tissues is a common feature ofALS and other neurodegenerative diseases [94 95] In mousemodels of ALS expression levels of occludins and ZO-1 werecharacteristic of the disease process and were accompaniedby increased ROS levels and probable remodelling of theextracellularmatrix due toMMP-9 upregulation [96] Uptakeof Evans Blue dye by spinal regions in SOD1mice and rats hasalso been shown [97 98] and BBB hyperpermeability has alsobeen shown in human ALS patients [16]

It is known that disruption to the BBB facilitates easierleukocyte invasion into neural tissues [99] The types ofimmune cells that infiltrate areas of degenerating neuronsare also highly relevant Autopsy of human ALS patients forinstance showed infiltration of degranulating mast cells andneutrophils along the motor pathway and within degenerat-ing muscle fibres specifically at the neuromuscular junction[100] Inhibition of these cells using tyrosine kinase inhibitorsprevented infiltration of neural tissues in SOD1 rats and wasable to preserve these structures to some extent [100] T cellsare also able to infiltrate spinal tissues of ALS mouse modelsand human patients [101ndash103] and it also appears that thedifferentiation fate of T cells is biased in ALS patients asregulatory T cell numbers are decreased in ALS patientsand this decrease correlated with disease severity and rate ofprogression [104] However it is still largely unknown whatroles various infiltrating T cell populations have in humanALS patients Further experiments that aimed at determiningthe prevalence of T cell subsets in invaded neurological tissuewould greatly aid in understanding the role of these cells inBBB disruption

Current thinking suggests that disruption of the BBB isan early event in ALS pathogenesis but it remains unclear ifthis is a disease driving factor or if it is a symptom of someother ALS core pathology Another question which remainsis whether or not other protein aggregation types can leadto this disease phenotype Given that TDP-43 aggregates arepresent in approximately 97 of all ALS cases [105] this isworthy of future investigation

5 Epidemiology and Underlying Insults inthe Impairment of the BBB

51 Global Epidemiology Across the world the statistics forMND are uniform in the distribution amongst age and sex Ingeneral males are more susceptible than females with peaks

in prevalence in MND cases in people within the age rangeof roughly 50-60 years old [106] These age-related peaks inMND prevalence correspond with the morphology of agingbrains and age-associated neurodegenerative diseases suchas Alzheimerrsquos disease and dementia [107] through proposedmechanisms such as amyloid-120573 clearance [93] Studies haveshown that ldquoagricultural or manual workersrdquo in EasternIndia had a higher correlation with ALS than other MNDsthat did not discriminate [108] Similarly in a geographicalepidemiological study of MND patients in Lancashire andSouth Cumbria England there were incidences of clustersof MND patients within towns with chemical manufacturingand outlying rural areas [109] These studies reflect a generaltrend of MND clusters occurring in communities as a resultof different occupational and lifestyle exposures leadingto progressive damage resulting from toxic exposure andpotentially common genetic elements

In 2016 [106 110] the averaged worldwide all-age preva-lence of all MNDs was 45 incidences per 100 000 peopleSocio-Demographic Index (SDI) is a composite measure ofincome per capita It was found that in 2016 high SDI madeup 489 of MND cases high-middle SDI countries madeup 152 middle SDI countries made up 21sdot4 of cases low-middle SDI countries made up 11sdot8 of cases and low SDIcountries made up 26 of cases These statistics may beskewed due to different effectiveness of diagnostic informa-tion available in lower SDI countries however assuming thedata is accurate analysing lifestyles (diet industrial practiceexercise and regular activities) of individuals residing withinhigher SDI countries would be of interest to research Thehighest all-age prevalence of MND was observed in NorthAmerica Australasia and Western Europe while the lowestall-age prevalence was seen in central sub-Saharan Africaeastern sub-Saharan Africa and western sub-Saharan AfricaFrom this study half of the worldrsquos prevalent cases were incountries within the highest SDI quintile

52 Guam Studies The high rates of ALS and ALS-likeconditions in Guam are of research interest The incidenceof this condition within Guam was at one stage over onehundred times the incidence rate of ALS on the mainlandUnited States with similarly high incidence rates of a formof Parkinsonism virtually confined to the native Chamorropopulation [111] With no clear genetic pattern Chamorrolifestyle and diet were considered specifically ingestion offood products derived from the false sago palm Cycasmicronesica The toxins from this plant have been thoughtto be 120573-methylamino L-alanine (BMAA) a toxic aminoacid from the cycad nut and glycoside cycasin a knowncarcinogen within the cycad nut This mechanism acts asa ldquoslow toxinrdquo with glycoside cycasin damaging DNA invulnerable neurones with BMAA acting as a degenerativeagent [112] Despite being relatively ineffective at crossingthe BBB free BMAA has the ability to cross the BBB [113]although other proposed mechanisms include neutral aminoacid carriers [114 115] cerebral capillary transfer [116] andprotein incorporation of BMAA [117] With both neurode-generative capabilities and ability to cross the BBB BMAArepresents an interesting area of study


Despite the Chamorro population routinely treating thecycad nuts as their association with ALS is clear cases per-sisted leading to the idea that it was not direct consumptionof these cycad toxins causing ALS however consumptionof flying foxes (Pteropus tokudae and Pteropus mariannus)have bioaccumulated these cycad toxins Despite substantialobservational evidence this proposed mechanism has beenroutinely challenged [118] and the exact nature of the causeof ALS in Guam is still widely debated Investigating themechanism of BMAA perturbance is of interest to MNDresearch as the mechanism could provide insight to otherpotential mechanisms of BBB and BSCB disturbance

53 Circadian Clock The Circadian Clock is an endoge-nous oscillation of biological processes dependant on amolecular clock [119ndash121] It is thought that the mechanismsassociated with the Circadian Clock also affect permeabilityof the BBB This Circadian rhythm has been modelled inDrosophila melanogaster [121] where levels of leptin andcytokines differed at various times of the day [10 122]Humans like D melanogaster are diurnal (awake duringthe day asleep at night) and therefore would presumablydisplay similar levels of increased BBB permeability (BBBhyperpermeability) at night The advantages of this patternare two-fold During active hours in which the organismis moving around encountering many different xenobioticsthe BBB is less permeable to these insults During inactivehours however the organism has an opportunity to expelaccumulated endogenous particles (such as amyloid beta[123]) which have built up during the wakeful hours Thissuggests that increased human activity during times wherethe BBB increases permeability (eg night-shifts) or increasein the intake and production of ROS (eg smoking at nightincreasing blood carbon monoxide levels) could potentiallybe disrupting this Circadian rhythm damaging the BBBthrough oxidative stress or other means Evidence froma mouse model suggests that this is the case with REMsleep deprivation which leads to BBB hyperpermeability[124]

This research into circadian rhythms in humans hasresulted in the definition of an individualrsquos Chronotype theCircadian preference of an individual describing their pro-clivity for earlier or later sleep Chronotypes vary frompersonto personThewell documented chronotype regulatory genesinclude RGS16 PER2 PER3 PIGKAK5 INADL FBXL3HCRTR2 and HTR [125ndash127] however as of a 2019 GWASanalysis of 697 828 individuals the number of genetic lociassociated with chronotype has increased from 24 to 351[128] The information contained within these genes mayhelp identify chronotypes that confer increased susceptibilityto ALS and allow us to explore the possibility that stan-dardized working hours over vastly differing chronotypeswithin a population may help explain increasing rates ofALS It is worth examining experimentally the chronotyperegulatory genes in ALS patients and their impact on BBBintegrity expanding upon current ALS genes of interestUnderstanding individual chronotypes and how they affectBBB permeability may allow us to identify new therapeuticmechanisms and provide a new angle of research

It is of interest to note the multiple pathways that cor-respond to central nervous system and brain developmentcomponents of neuronal cells (synapses axons and den-drites) as well as neurogenesis within the identified chrono-type regulatory genes Again it is of interest to review thecorrelations between chronotype and psychiatric traits Themost substantial of these was a positive correlation betweensubjective ldquowellbeingrdquo (as a self-reported phenotype withinthe study) and being a ldquomorning personrdquo There existednegative correlations between being a morning person andschizophrenia depressive symptoms major depressive disor-der and intelligence [128]

54 Schizophrenia Schizophrenia is a mental illness thatdisrupts the functioning of the human mind with intenseepisodes of psychosis and periods of apathy followed byotherwise normal mental functioningWhile often spoken ofseparately there is biological and epidemiological evidencefor an association between those suffering motor neuron dis-ease and psychotic illness particularly Amyotrophic LateralSclerosis (ALS) and Schizophrenia A genetic correlation of143 [129] has been placed between ALS and SchizophreniaFurthermore the presence of the (apparent) monogenicC9orf72-driven overlap and polygenic overlap in the aetiol-ogy in ALS and Schizophrenia patients suggests the presenceof a common biological process [129] Interestingly therehave been propositions that prolonged use of antipsychoticmedication may prevent ALS sufferers from developingallsome clinical features of the illness [130] These antipsy-choticantidepressant medications include Chlorpromazine[131] andClozapine [132 133]While ALS cannot at this stagebe cured with antipsychoticsantidepressants there appearsto be some therapeutic relevance for their use in ALS buttheir use in ALS patients still remains controversial at best

The research suggesting linkage between ALS andSchizophrenia is in its infancy and does not suggest acausative relationship between the two conditions [129] It ishowever of epidemiological interest as the linkage betweenthe conditions [134 135] may provide insight regarding theinheritance of ALS as well as widening the knowledge interms of treatment for both disorders This is particularlyurgent given that these links have not been explored since themid 1970s

55 Telomere Length Telomeres are regions of repetitivenucleotide sequences at the ends of chromosomes whichserve as a protection against chromosome shortening inchromosomal replication in cell division telomeres act as adisposable buffer such that the genetic material that is lost isnonessential [136] Telomere length is thought to be a generalfunction of age at birth telomeres are roughly 11 kB [137] longwhile in old age they can be less than 4kB [138] Generallymen have a higher average rate of decline than women [139]

To compensate for shortening telomeres the ribonucleo-protein telomerase extends the telomere ends of a chromo-some on the 31015840 end Telomerase is comprised of telomerasereverse transcriptase (TERT) telomerase RNA component(TERC) and dyskerin (DKC1) [140]There is a growing bodyof evidence suggesting that TERT deficiency potentiates BBB


dysfunction and that increased TERT expression may be aresult of oxidative stress resistance [141]This is of importanceas there is in vitro evidence suggesting that oxidative stress-mediated DNA damage is a significant aspect of telomereshortening

Telomere shortening and telomerase are of interest to thenot only links with oxidative stress but also unrepaired telom-eres and their persistent DNA damage response signallingwhich is essential to the establishment of senescence [142] Anaccumulation of senescent vascular cells is associated with acompromised BBB [143]

6 Current Concepts and Developments in GutMicrobiota and BBB Connection

The gut-brain nexus is vitally important for our general well-being There appears to be an intrinsic connection betweenthe GI tract and the brain and any impairment of theseconnections between microbiome and the gut is associatedwith the etiology of many diseases that afflict mankind andalmost all the neurodegenerative disorders [144] Notably thelongest nerve in the human body the vagus nerve whichextends from the brainstem to the lowest viscera of humanintestines maintains the communication and connectivitybetween the gut and brain There are three recognizedmechanisms involving immune activation modification ofthe autonomic and sensorimotor connections and the reg-ulation of the neuroendocrine pathway through which themicrobiome influences the gutndashbrain axis Hoyles et al [144]hypothesized that the interactions between circulating gut-derived microbial metabolites and the bloodndashbrain barrier(BBB) could contribute to the gutndashbrain axis and showed thatthe propionate produced from dietary substrates by colonicbacteria is able to stimulate intestinal gluconeogenesis andis associated with reduced stress behaviours but its potentialendocrine role remains to be addressed

The gut microbiota has been acknowledged for its impor-tance in gastrointestinal development barrier integrity andfunction metabolism immune responses and CNS devel-opment The development of the CNS includes formationof the BBB an essential component in neonates duringcritical periods of foetal brain development [145] It hasbeen shown in mouse models that the maternal gut micro-biota can influence prenatal development of the BBB bycausing hyperpermeability in foetal mice BBBs with germ-free mothers [129] It has also been shown that the lackof normal gut microbiota in germ-free mice is associatedwith a hyperpermeability of the BBB [146] Supportingthese observations studies in humans have also revealedaltered microbial profiles in children with Autism spectrumdisorders (ASD) [147 148] and oral treatment of autisticchildren with the vancomycin led to effective suppression ofsome of the gut microbiota involved in disease manifestationshowing dramatic improvement Interestingly regression toautistic symptoms was seen upon the cessation of treatmentwith vancomycin [148]

In the context of hyperpermeability of the BBB it hasbeen hypothesized that this observed increase in permeabilityof the BBB may be the consequence of disorganised tight

junctions and low expression of the transmembrane tightjunction proteins claudin 5 occludin Zo-1 Zo-2 effluxtransport (P-glycoprotein and ABCG2) nutrient transport(Glut-1 Mct-1 and Lat-1) and others (basigin and car-bonic anhydrase 4) [149] Despite observational evidencethe precise signalling mechanisms between gut microbiotaand maternal gut microbiota which modulates the BBBfunction remain poorly understood It is of interest to notethe current research efforts made in highlighting potentiallinkages between schizophreniaother psychiatric disordersand the gut oropharyngeal and mucosal microbiomesWhile this research is still in its infancy previous linkagesbetween brain development and psychiatric disordersBBBhyperpermeability may provide some insight to either of orboth conditions

61 Mechanistic Insights on BBB IntegrityPermeability fromTranscriptomics Intrinsic Role of Microbial MetabolitesRecent genomic and proteomic studies of the BBB haveidentified uniquemolecular traits of this vascular bed and theemerging concepts suggest that the BBB is heavily involvedin brain function [150] A number of animal and humanstudies support the existence of an intrinsic gut brain com-munication although the underlying mechanisms remainpoorly defined Accumulating evidence suggests that the gutmicrobiota is able to influence the integrity and permeabilityof the BBB which is supported by hyperpermeability anddysregulation of interendothelial cell tight junctions in bothantibiotic-treated and germ-free mice exhibiting consider-ably enhanced barrier permeability [151] Interestingly uponconventionalization these impairments could be reversedThe mechanism(s) by which gut microbes are able to exerttheir influence remains unclear but alterations in gut micro-biota changes that can lead to consequential changes in brainchemistry independently of vagal or sympathetic neural path-ways and in the absence of any immune response do suggesta role for soluble gut metabolites in BBB hyperpermeability[152]

The aforementioned data does highlight a likely role ofshort-chain fatty acids (SCFAs) which may be acting as keymicrobial mediators influencing the gutndashbrain axis althoughthe majority of studies looking at SCFAs for their role in thegutndashbrain axis largely focused on butyrate [153] as opposed torelatively fewer ones that investigated the role of propionatea highly potent FFAR3 agonist

It is to be noted that both butyrate and propionates showcomparable plasma concentrations and receptor affinity andincreased intestinal propionate was found to be associatedwith reduced stress behaviors in both mice and humansThus its role in endocrine mediation in the gut-brain axisremains underexplored Moreover given the presence ofFFAR3 on endothelial cells Hoyles et al [144] hypothesizedthat propionate targeting of the endothelium of the BBBwould represent an additional facet of the gutndashbrain axisand explored using transcriptomics to study the effectsof exposure to physiological levels of propionates to BBBTreatment with propionates showed significant differentialexpression of 1136 genes of which 553 were upregulated and583 were downregulated [154]


Mainly the protein processing in the endoplasmic retic-ulum and RNA transport pathways were activated uponexposure of cells to propionate in addition to gene expressionin pathways associated with nonspecific microbial infectionsthat were inhibited by propionate Other affected pathwayswere the cytosolic DNA-sensing pathway usually upregu-lated by pathogen DNA during microbial infections therebytriggering innate immune response NF120581B and the Toll-likereceptor signaling pathways Of the 19309 genes examined203 of the 224 genes were found to be associated with theBBB and 11 of these DE genes were significantly associatedwith the inflammatory response implying inflammation tobe one of the key events in BBB hyperpermeability which hasa crossover between all the known NDs Using hCMECD3cells treated with TNF120572 and IFN120574 Reijerkerk et al (2013)profiled the micro-RNAs that modulate BBB function underinflammatory conditions With a panel of miRNAs identifiedto have differential expression induced by inflammatorymediators that also displayed opposing changes after barrierinduction in the cell line the authors further examined theirexpression in brain capillaries isolated via filtration fromresected multiple sclerosis patient lesions These samplesshowed decreased expression of miR-125a-5p [155] miR-125a-5p is a key regulator of brain endothelial tightness andimmune cell efflux and these findings suggest that repairof a disturbed BBB through microRNAs may represent anovel avenue for effective treatment ofMS and can be appliedto other neurodegenerative diseases Thus finding miRNAsthat regulate the expression of genes that are unique to theBBB microvasculature may open doors to unveiling howinflammation is governed in this immune privileged site[155]

It is important to iterate that since the SCFAs are notable to fully recapitulate the BBB-restoring effects of conven-tionalization of germ-free animals as shown by Hoyles etal [144] it has been hypothesized that additional circulatinggut-derived microbial mediators are possibly contributingto the regulation of BBB function which warrants furtherinvestigation To date gt200 different microbial metabolitesare known to exist in human blood circulation [156] thusthere is clearly a great potential in studying these metabolitesfor their role in gut dysbiosis gut and brain communicationand changes in these metabolites in healthy vs diseased indi-viduals in addition to their influence on the levels of thesemetabolites on BBB integrity and hyperpermeability Thesedata will prove to be highly meaningful in understanding thedevelopment of neurological diseases as variability in BBBfunction is increasingly being recognized across all NDs andcognitive impairment Thus the knowledge of tissue-specificgene expression at the BBB and identification of genes theirexpression miRNA and proteome could provide new targetsfor drug delivery across the BBB and lead to the elucidation ofmechanisms involved in brain pathology at themicrovascularlevel In this case more human studies seem warranted

7 Conclusions

This review aimed to provide insight into the physiologicalbiochemical and novel genomic mechanisms behind BBB

hyperpermeability Not only is this topic poorly characterisedwithin literature but also there is little overarching directionbehind research efforts Many papers were omitted from thisreview due to there being a lack of wider literature support orreliance on speculative evidence A wider goal of this reviewwas not only to provide insight on but to present potentialresearch targets to fully characterise BBB hyperpermeability

Oxidative stress appears to be a prevailing idea withinliterature of BBB hyperpermeability despite the mechanismsnot being completely realized Further researches into themechanisms of hypoxia and reoxygenation are needed forthis to be a more definitive lead Furthermore researchinto not only genes responsible for encoding antioxidantsbut the mechanisms surrounding triggering events such asldquooxidative burstsrdquo which stimulate production of antioxidantswould be of importance in identifying areas for furtherresearch It would be worthwhile to conduct further researchinto storage and active transport systems of nonenzymaticantioxidants as they may also be of interest Unfortunatelyantioxidant therapies are not capable of curing or haltingALS in humans or animal models currently but they havebeen shown to increase motor performance across SOD1mutant mouse studies [157] It is currently suggested thatantioxidants be used as adjunct therapies [157] and with adeeper understanding of oxidative processes that drive BBBhyperpermeability in ALS perhaps antioxidant therapies canbe made more effective

Further investigation into cerebrospinal microbleeds isworth the effort given associations of microbleeds withBBB hyperpermeability in ALS and other neurodegenerativediseases Epidemiology of MND and the BBB is surprisinglyof little substance There is much literature on very specificaspects of MND incidences however very little correlationbetween works has been done Most epidemiological studieshave relied on hospital data in country country comparisonsof MND prevalence This is a concerning feature as manysymptoms of MND can be mistaken for others and differ-ent countries have different funding allocated to hospitalsresulting in bettermore reported cases because of superiordiagnosis

Research into Circadian rhythms in humans and theirrelation to the BBB is novel and potentially links lifestylefactors to oxidative stress for specific reasons eg all smokersmay not have an increase in the permeability of their BBBhowever night-time smokers [158] may increase oxidativestress when the brain is vulnerable [119ndash121] leading to ahyperpermeable BBB leading to MND

Telomere length is a promising area of study to lookat considering the findings in shortened telomeres almostreflect cases ofMND ie men aremore affected thanwomenand older populations are more affected than younger onesTelomeres and their roles in oxidative stress are of greatinterest to pursue

Lastly almost all neurological disorders maintain a pro-found association with the BBB and any alterations inthe microvasculature of the brain lead to inflammationand hyperpermeability Understanding the role of genesproteins and miRNA that form the BBB vasculature is vitalto understanding the processes BBB governs during disease


and will explain underlying reasons for the disruption ofthe BBB during infectious and neurodegenerative diseasesSmall molecules such as miRNA can not only lead theway in identifying novel biomarkers but may also explainhow the gene and protein expression is regulated in theBBB by miRNAs Reijerkerk et al [155] have suggested thattherapeutic application of microRNAs such as miR-125a-5pcould potentially reestablish normal functioning of the brainvasculature in endothelial cell-based neurological diseases inparticular MS and can be applied across NDs if we identifymiRNAs in BBB

Disclosure

This work did not receive any funding

Conflicts of Interest

The authors have no conflicts of interest to declare

Authorsrsquo Contributions

Matthew Keon conceived the investigation and providedfeedback on several aspects of this review NicholasKakaroubas performed all research and wrote the bulk of thereview Substantial contributions and revisions were addedby Nicholas Kakaroubas Nitin K Saksena and SamuelBrennan and both Nitin K Saksena and Samuel Brennanprovided critical input with the integration of novel conceptsrelevant to BBB All authors have approved the final paperand agree to be personally accountable for the accuracy andintegrity of the work

References

[1] N J Abbott and A Friedman ldquoOverview and introduction theblood-brain barrier in health and diseaserdquo Epilepsia vol 53supplement 6 pp 1ndash6 2012

[2] P M Gross ldquoCircumventricular organ capillariesrdquo Progress inBrain Research vol 91 pp 219ndash233 1992

[3] P M Gross Weindl A and K M Weindl ldquoPeering throughthe windows of the brainrdquo Journal of Cerebral Blood Flow ampMetabolism vol 7 no 6 pp 663ndash672 1987

[4] P Ballabh A Braun and M Nedergaard ldquoThe blood-brainbarrier an overview Structure regulation and clinical impli-cationsrdquo Neurobiology of Disease vol 16 no 1 pp 1ndash13 2004

[5] V Bartanusz D Jezova B Alajajian andM Digicaylioglu ldquoTheblood-spinal cord barrier morphology and clinical implica-tionsrdquo Annals of Neurology vol 70 no 2 pp 194ndash206 2011

[6] E A Winkler J D Sengillo J S Sullivan J S HenkelS H Appel and B V Zlokovic ldquoBlood-spinal cord barrierbreakdown and pericyte reductions in amyotrophic lateralsclerosisrdquo Acta Neuropathologica vol 125 no 1 pp 111ndash1202013

[7] E A Winkler J D Sengillo A P Sagare et al ldquoBlood-spinalcord barrier disruption contributes to early motor-neurondegeneration in ALS-model micerdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 111 no11 pp E1035ndashE1042 2014

[8] Y Serlin I Shelef B Knyazer and A Friedman ldquoAnatomyand physiology of the blood-brain barrierrdquo Seminars in Cell ampDevelopmental Biology vol 38 pp 2ndash6 2015

[9] L D Prockop K A Naidu J E Binard and J Ranso-hoff ldquoSelective permeability of [3H]-D-mannitol and [14C]-carboxyl-inulin across the blood-brain barrier and blood-spinalcord barrier in the rabbitrdquoThe Journal of Spinal Cord Medicinevol 18 no 4 pp 221ndash226 1995

[10] W Pan W A Banks and A J Kastin ldquoPermeability of theblood-brain and blood-spinal cord barriers to interferonsrdquoJournal of Neuroimmunology vol 76 no 1-2 pp 105ndash111 1997

[11] S Ge and J S Pachter ldquoIsolation and culture of microvascularendothelial cells from murine spinal cordrdquo Journal of Neuroim-munology vol 177 no 1-2 pp 209ndash214 2006

[12] T Lashley et al ldquoMolecular biomarkers of Alzheimerrsquos diseaseprogress and prospectsrdquo Disease Models amp Mechanisms vol 11p 5 2018

[13] I Cova and A Priori ldquoDiagnostic biomarkers for Parkinsonrsquosdisease at a glance where are werdquo Journal of Neural Transmis-sion vol 125 no 10 pp 1417ndash1432 2018

[14] C A Ross E H Aylward E J Wild et al ldquoHuntington diseasenatural history biomarkers and prospects for therapeuticsrdquoNature Reviews Neurology vol 10 no 4 pp 204ndash216 2014

[15] L T Vu and R Bowser ldquoFluid-based biomarkers for amy-otrophic lateral sclerosisrdquo Neurotherapeutics vol 14 no 1 pp119ndash134 2017

[16] S Garbuzova-Davis and P R Sanberg ldquoBlood-CNS barrierimpairment in ALS patients versus an animal modelrdquo Frontiersin Cellular Neuroscience vol 8 p 21 2014

[17] I Dujmovic ldquoCerebrospinal fluid and blood biomarkers ofneuroaxonal damage in multiple sclerosisrdquo Multiple SclerosisInternational vol 2011 Article ID 767083 18 pages 2011

[18] M D Sweeney A P Sagare and B V Zlokovic ldquoBlood-brainbarrier breakdown inAlzheimer disease and other neurodegen-erative disordersrdquo Nature Reviews Neurology vol 14 no 3 pp133ndash150 2018

[19] K A Witt K S Mark S Hom and T P Davis ldquoEffects ofhypoxia-reoxygenation on rat blood-brain barrier permeabilityand tight junctional protein expressionrdquo American Journal ofPhysiology-Heart and Circulatory Physiology vol 285 no 6 ppH2820ndashH2831 2003

[20] K A Witt K S Mark K E Sandoval and T P Davis ldquoReoxy-genation stress on blood-brain barrier paracellular permeabilityand edema in the ratrdquoMicrovascular Research vol 75 no 1 pp91ndash96 2008

[21] J J Lochhead G McCaffrey C E Quigley et al ldquoOxidativestress increases blood-brain barrier permeability and inducesalterations in occludin during hypoxia-reoxygenationrdquo Journalof Cerebral Blood Flow and Metabolism vol 30 no 9 pp 1625ndash1636 2010

[22] S M Stamatovic A M Johnson R F Keep and A VAndjelkovic ldquoJunctional proteins of the blood-brain barrierNew insights into function and dysfunctionrdquo Tissue Barriers pe1154641 2016

[23] H Mao X Fang K M Floyd J E Polcz P Zhang and B LiuldquoInduction of microglial reactive oxygen species production bythe organochlorinated pesticide dieldrinrdquo Brain Research vol1186 pp 267ndash274 2007

[24] M T Baltazar R J Dinis-Oliveira M D L Bastos A MTsatsakis J A Duarte and F Carvalho ldquoPesticides exposure as


etiological factors of Parkinsonrsquos disease and other neurodegen-erative diseasesmdasha mechanistic approachrdquo Toxicology Lettersvol 230 pp 85ndash103 2014

[25] A Churg ldquoInteractions of exogenous or evoked agents andparticles the role of reactive oxygen speciesrdquo Free RadicalBiology amp Medicine vol 34 no 10 pp 1230ndash1235 2003

[26] J Vaage M Antonelli M Bufi et al ldquoExogenous ReactiveOxygen Species Deplete the Isolated RatHeart of AntioxidantsrdquoFree Radical Biology ampMedicine vol 22 no 1-2 pp 85ndash92 1997

[27] F Muller ldquoThe nature and mechanism of superoxide produc-tion by the electron transport chain Its relevance to agingrdquoJournal of theAmericanAgingAssociation vol 23 no 4 pp 227ndash253 2000

[28] D Han E Williams and E Cadenas ldquoMitochondrial respira-tory chain-dependent generation of superoxide anion and itsrelease into the intermembrane spacerdquo Biochemical Journal vol353 no 2 pp 411ndash416 2001

[29] X Li P Fang J Mai E T Choi H Wang and X F YangldquoTargeting mitochondrial reactive oxygen species as noveltherapy for inflammatory diseases and cancersrdquo Journal ofHematology amp Oncology vol 6 p 19 2013

[30] J Haorah B Knipe J Leibhart A Ghorpade and Y PersidskyldquoAlcohol-induced oxidative stress in brain endothelial cellscauses blood-brain barrier dysfunctionrdquo Journal of LeukocyteBiology vol 78 no 6 pp 1223ndash1232 2005

[31] J Haorah B Knipe S Gorantla J Zheng and Y PersidskyldquoAlcohol-induced blood-brain barrier dysfunction is mediatedvia inositol 145-triphosphate receptor (IP3R)-gated intracellu-lar calcium releaserdquo Journal of Neurochemistry vol 100 no 2pp 324ndash336 2007

[32] P Saikumar Z Dong J M Weinberg and M A Venkat-achalam ldquoMechanisms of cell death in hypoxiareoxygenationinjuryrdquo Oncogene vol 17 no 25 pp 3341ndash3349 1998

[33] O M Ighodaro and O A Akinloye ldquoFirst line defenceantioxidants-superoxide dismutase (SOD) catalase (CAT) andglutathione peroxidase (GPX) Their fundamental role in theentire antioxidant defence gridrdquoAlexandria Journal ofMedicinevol 54 no 4 pp 287ndash293 2018

[34] P Moi K Chan I Asunis A Cao and Y W Kan ldquoIsolation ofNF-E2-related factor 2 (Nrf2) a NF-E2-like basic leucine zippertranscriptional activator that binds to the tandem NF-E2AP1repeat of the beta-globin locus control regionrdquo Proceedings ofthe National Acadamy of Sciences of the United States of Americavol 91 no 21 p 9926 1994

[35] K Park S E Lee K-O Shin and Y Uchida ldquoInsights intothe role of endoplasmic reticulum stress in skin function andassociated diseasesrdquoThe FEBS Journal vol 286 no 2 pp 413ndash425 2019

[36] N Esteras A T Dinkova-Kostova and A Y Abramov ldquoNrf2activation in the treatment of neurodegenerative diseases Afocus on its role in mitochondrial bioenergetics and functionrdquoBiological Chemistry p 383 2016

[37] F Sivandzade S Prasad A Bhalerao and L Cucullo ldquoNRF2and NF-kappaB interplay in cerebrovascular and neurodegen-erative disorders Molecular mechanisms and possible thera-peutic approachesrdquo Redox Biology vol 21 Article ID 1010592019

[38] Q Ma ldquoRole of Nrf2 in oxidative stress and toxicityrdquo AnnualReview of Pharmacology and Toxicology vol 53 pp 401ndash4262013

[39] A Cuadrado G Manda A Hassan et al ldquoTranscription FactorNRF2 as a Therapeutic Target for Chronic Diseases A Systems

Medicine Approachrdquo Pharmacological Reviews vol 70 no 2pp 348ndash383 2018

[40] C AHoughton R G Fassett and J S Coombes ldquoSulforaphaneand other nutrigenomic Nrf2 activators can the clinicianrsquosexpectation be matched by the realityrdquoOxidative Medicine andCellular Longevity vol 2016 Article ID 7857186 17 pages 2016

[41] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013

[42] P K Dash J Zhao S A Orsi M Zhang and A NMoore ldquoSul-foraphane improves cognitive function administered followingtraumatic brain injuryrdquoNeuroscience Letters vol 460 no 2 pp103ndash107 2009

[43] A D Kraft J M Resch D A Johnson and J A JohnsonldquoActivation of the Nrf2-ARE pathway in muscle and spinal cordduring ALS-like pathology in mice expressing mutant SOD1rdquoExperimental Neurology vol 207 no 1 pp 107ndash117 2007

[44] P Back F Matthijssens C Vlaeminck B P Braeckman andJ R Vanfleteren ldquoEffects of sod gene overexpression anddeletion mutation on the expression profiles of reporter genesof major detoxification pathways in Caenorhabditis elegansrdquoExperimental Gerontology vol 45 no 7-8 pp 603ndash610 2010

[45] T Offer A Russo and A Samuni ldquoThe pro-oxidative activityof SOD and nitroxide SODmimicsrdquoThe FASEB Journal vol 14no 9 pp 1215ndash1223 2000

[46] I N Zelko T J Mariani and R J Folz ldquoSuperoxide dismutasemultigene family a comparison of the CuZnndashSOD (SOD1)Mn-SOD (SOD2) and EC-SOD (SOD3) gene structures evolu-tion and expressionrdquo Free Radical Biology amp Medicine vol 33no 3 pp 337ndash349 2002

[47] S L Marklund ldquoExpression of extracellular superoxide dismu-tase by human cell linesrdquo Biochemical Journal vol 266 no 1 pp213ndash219 1990

[48] R J Folz and J D Crapo ldquoExtracellular superoxide dismutase(SOD3) tissue-specific expression genomic characterizationand computer-assisted sequence analysis of the human EC SODgenerdquo Genomics vol 22 no 1 pp 162ndash171 1994

[49] P Milani S Gagliardi E Cova and C Cereda ldquoSOD1 Tran-scriptional and Posttranscriptional Regulation and Its PotentialImplications in ALSrdquo Neurology Research International vol2011 Article ID 458427 9 pages 2011

[50] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993

[51] P Chelikani I Fita and P C Loewen ldquoDiversity of structuresand properties among catalasesrdquo Cellular and Molecular LifeSciences vol 61 no 2 pp 192ndash208 2004

[52] C D Putnam A S Arvai Y Bourne and J A Tainer ldquoActiveand inhibited human catalase structures ligand and NADPHbinding and catalytic mechanismrdquo Journal of Molecular Biologyvol 296 no 1 pp 295ndash309 2000

[53] D Martins and A M English ldquoCatalase activity is stimulatedby H

2O2in rich culture medium and is required for H

2O2

resistance and adaptation in yeastrdquo Redox Biology vol 2 no 1pp 308ndash313 2014

[54] A L Dounce ldquoA proposedmechanism for the catalatic action ofcatalaserdquo Journal of Theoretical Biology vol 105 no 4 pp 553ndash567 1983

[55] P J Shaw RM Chinnery HThagesen GM Borthwick and PG Ince ldquoImmunocytochemical study of the distribution of the


free radical scavenging enzymes CUZN superoxide dismutase(SOD1) MN superoxide dismutase (MN SOD) and catalase inthe normal human spinal cord and in motor neuron diseaserdquoJournal of the Neurological Sciences vol 147 no 2 pp 115ndash1251997

[56] F L Muller M S Lustgarten Y Jang A Richardson and Hvan Remmen ldquoTrends in oxidative aging theoriesrdquo Free RadicalBiology amp Medicine vol 43 no 4 pp 477ndash503 2007

[57] K Socha J Kochanowicz E Karpinska et al ldquoDietary habitsand selenium glutathione peroxidase and total antioxidantstatus in the serumof patients with relapsing-remittingmultiplesclerosisrdquo Nutrition Journal vol 13 p 62 2014

[58] R Brigelius-Flohe andMMaiorino ldquoGlutathione peroxidasesrdquoBiochimica et Biophysica Acta vol 1830 no 5 pp 3289ndash33032013

[59] S Zulaikhah Anies and A Suwondo ldquoEffect of TenderCoconut Water on Antioxidant Enzymatic Superoxida Dismu-tase (SOD) Catalase (CAT) Glutathione Peroxidase (GPx) andLipid Peroxidation in Mercury ExposureWorkersrdquo pp 517-5242015

[60] R Dringen ldquoMetabolism and functions of glutathione in brainrdquoProgress in Neurobiology vol 62 no 6 pp 649ndash671 2000

[61] C Mytilineou B C Kramer and J A Yabut ldquoGlutathionedepletion and oxidative stressrdquo Parkinsonism amp Related Disor-ders vol 8 no 6 pp 385ndash387 2002

[62] E Pileblad P S Eriksson and E Hansson ldquoThe presence ofglutathione in primary neuronal and astroglial cultures from ratcerebral cortex and brain stemrdquo Journal of Neural Transmissionvol 86 no 1 pp 43ndash49 1991

[63] J Sagara K Miura and S Bannai ldquoMaintenance of NeuronalGlutathione by Glial Cellsrdquo Journal of Neurochemistry vol 61no 5 pp 1672ndash1676 1993

[64] A Slivka C Mytilineou and G Cohen ldquoHistochemical evalu-ation of glutathione in brainrdquo Brain Research vol 409 no 2 pp275ndash284 1987

[65] M Smeyne and R J Smeynen ldquoGlutathione metabolism andParkinsonrsquos diseaserdquo Free Radical Biology amp Medicine vol 62pp 13ndash25 2013

[66] W M Johnson A L Wilson-Delfosse and J J Mieyal ldquoDys-regulation of glutathione homeostasis in neurodegenerativediseasesrdquo Nutrients vol 4 no 10 pp 1399ndash1440 2012

[67] L Chi Y Ke C LuoDGozal andR Liu ldquoDepletion of reducedglutathione enhances motor neuron degeneration in vitro andin vivordquo Neuroscience vol 144 no 3 pp 991ndash1003 2007

[68] A Kaulmann and T Bohn ldquoCarotenoids inflammation andoxidative stress-implications of cellular signaling pathways andrelation to chronic disease preventionrdquo Nutrition Research vol34 no 11 pp 907ndash929 2014

[69] T Bohn ldquoBioavailability of Non-Provitamin A CarotenoidsrdquoCurrent Nutrition and Food Science vol 4 no 4 pp 240ndash2582008

[70] L Mueller and V Boehm ldquoAntioxidant activity of 120573-carotenecompounds in different in vitro assaysrdquoMolecules vol 16 no 2pp 1055ndash1069 2011

[71] K-J Yeum G Aldini R M Russell and N I Krin-sky ldquoAntioxidantPro-oxidant Actions of Carotenoidsrdquo inCarotenoids Volume 5 Nutrition and Health G Britton HPfander and S Liaaen-Jensen Eds pp 235ndash268 BirkhauserBasel Switzerland 2009

[72] W Stahl and H Sies ldquoAntioxidant activity of carotenoidsrdquoMolecular Aspects of Medicine vol 24 no 6 pp 345ndash351 2003

[73] R S Parker ldquoAbsorption metabolism and transport ofcarotenoidsrdquo The FASEB Journal vol 10 no 5 pp 542ndash5511996

[74] L Wang J Wang N Li L Ge B Li and B Song ldquoMolec-ular Characterization of the NPC1L1 Variants Identified fromCholesterol Low Absorbersrdquo The Journal of Biological Chem-istry vol 286 no 9 pp 7397ndash7408 2011

[75] V P Palace N Khaper Q Qin and P K Singal ldquoAntioxidantpotentials of vitamin A and carotenoids and their relevance toheart diseaserdquo Free Radical Biology ampMedicine vol 26 no 5-6pp 746ndash761 1999

[76] S J Padayatty A Katz Y Wang et al ldquoVitamin C as anantioxidant evaluation of its role in disease preventionrdquo Journalof the American College of Nutrition vol 22 no 1 pp 18ndash352003

[77] J X Wilson ldquoRegulation of vitamin C transportrdquo AnnualReview of Nutrition vol 25 pp 105ndash125 2005

[78] J C Desport P M Preux T C Truong J M Vallat DSautereau and P Couratier ldquoNutritional status is a prognosticfactor for survival in ALS patientsrdquoNeurology vol 53 no 5 pp1059-1059 1999

[79] O Hardiman ldquoSymptomatic treatment of respiratory andnutritional failure in amyotrophic lateral sclerosisrdquo Journal ofNeurology vol 247 no 4 pp 245ndash251 2000

[80] L Mazzini T Corra M Zaccala G Mora M Del Piano andM Galante ldquoPercutaneous endoscopic gastrostomy and enteralnutrition in amyotrophic lateral sclerosisrdquo Journal of Neurologyvol 242 no 10 pp 695ndash698 1995

[81] J Rosenfeld and A Ellis ldquoNutrition and dietary supplementsin motor neuron diseaserdquo Physical Medicine and RehabilitationClinics of North America vol 19 no 3 pp 573ndash589 2008

[82] D B Agus S S Gambhir W M Pardridge et al ldquoVitamin Ccrosses the blood-brain barrier in the oxidized form throughthe glucose transportersrdquo The Journal of Clinical Investigationvol 100 no 11 pp 2842ndash2848 1997

[83] C I Rivas F A Zuniga A Salas-Burgos L Mardones VOrmazabal and J C Vera ldquoVitamin C transportersrdquo Journal ofPhysiology and Biochemistry vol 64 no 4 pp 357ndash375 2008

[84] H Yorulmaz F B Seker and B Oztas ldquoEffect of vitamin E onblood-brain barrier permeability in aged ratswith PTZ-inducedconvulsionsrdquo pp 349-353 2011

[85] H O Mohammed S R Starkey K Stipetic T J Divers B ASummers and A de Lahunta ldquoThe Role of Dietary AntioxidantInsufficiency on the Permeability of the Blood-Brain BarrierrdquoJournal of Neuropathology amp Experimental Neurology vol 67no 12 pp 1187ndash1193 2008

[86] D P R Muller ldquoVitamin E and neurological functionrdquoMolecu-lar Nutrition amp Food Research vol 54 no 5 pp 710ndash718 2010

[87] M E Gurney F B Cutting P Zhai P K Andrus and E DHall ldquoPathogenic mechanisms in familial amyotrophic lateralsclerosis due to mutation of Cu Zn superoxide dismutaserdquoPathologie Biologie vol 44 no 1 pp 51ndash56 1996

[88] HWang E J OrsquoReilly M GWeisskopf et al ldquoVitamin e intakeand risk of amyotrophic lateral sclerosis A pooled analysis ofdata from 5 prospective cohort studiesrdquo American Journal ofEpidemiology vol 173 no 6 pp 595ndash602 2011

[89] P M Thompson and H V Vinters ldquoPathologic lesions inneurodegenerative diseasesrdquo Progress in Molecular Biology andTranslational Science vol 107 pp 1ndash40 2012

[90] S Martinez-Ramirez S M Greenberg and A Viswanathanldquoerebral microbleeds overview and implications in cognitive


impairmentrdquo Alzheimerrsquos Research amp Therapy vol 6 no 3 p33 2014

[91] J Y Lee H Y Choi W H Na B G Ju and T Y Yune ldquoGhrelininhibits BSCB disruptionhemorrhage by attenuating MMP-9and SUR1TrpM4 expression and activation after spinal cordinjuryrdquo Biochimica et Biophysica Acta (BBA) - Molecular Basisof Disease vol 1842 no 12 pp 2403ndash2412 2014

[92] J De Reuck F Auger N Durieux et al ldquoThe topography ofcortical microbleeds in frontotemporal lobar degeneration apost-mortem 70-tesla magnetic resonance studyrdquo Folia Neu-ropathologica vol 54 no 2 pp 149ndash155 2016

[93] A R Nelson M D Sweeney A P Sagare and B V ZlokovicldquoNeurovascular dysfunction and neurodegeneration in demen-tia and Alzheimerrsquos diseaserdquo Biochimica et Biophysica Acta(BBA) - Molecular Basis of Disease vol 1862 no 5 pp 887ndash9002016

[94] L L Muldoon J I Alvarez D J Begley et al ldquoImmunologicPrivilege in the Central Nervous System and the BloodndashBrainBarrierrdquo Journal of Cerebral Blood Flow amp Metabolism vol 33no 1 pp 13ndash21 2013

[95] B Obermeier R Daneman and R M Ransohoff ldquoDevelop-ment maintenance and disruption of the blood-brain barrierrdquoNature Medicine vol 19 no 12 pp 1584ndash1596 2013

[96] K Miyazaki Y Ohta M Nagai et al ldquoDisruption of neurovas-cular unit prior to motor neuron degeneration in amyotrophiclateral sclerosisrdquo Journal of Neuroscience Research vol 89 no 5pp 718ndash728 2011

[97] S Garbuzova-Davis S Saporta E Haller et al ldquoEvidence ofCompromised Blood-Spinal Cord Barrier in Early and LateSymptomatic SOD1Mice Modeling ALSrdquo PLoS ONE vol 2 no11 Article ID e1205 2007

[98] C Nicaise D Mitrecic P Demetter et al ldquoImpaired blood-brain and blood-spinal cord barriers in mutant SOD1-linkedALS ratrdquo Brain Research vol 1301 pp 152ndash162 2009

[99] J Maiuolo M Gliozzi V Musolino et al ldquoThe ldquoFrailrdquo BrainBloodBarrier inNeurodegenerativeDiseases Role of EarlyDis-ruption of Endothelial Cell-to-Cell Connectionsrdquo InternationalJournal of Molecular Sciences vol 19 no 9 p 2693 2018

[100] E Trias P H King and Y Si ldquoMast cells and neutrophilsmediate peripheral motor pathway degeneration in ALSrdquo JCIInsight vol 3 no 19 2018

[101] J I Engelhardt J Tajti and SHAppel ldquoLymphocytic infiltratesin the spinal cord in amyotrophic lateral sclerosisrdquo Archives ofNeurology vol 50 no 1 pp 30ndash36 1993

[102] T Holmoslashy ldquoT cells in amyotrophic lateral sclerosisrdquo EuropeanJournal of Neurology vol 15 no 4 pp 360ndash366 2008

[103] G Nardo M C Trolese M Verderio et al ldquoCounteractingroles of MHCI and CD8+ T cells in the peripheral andcentral nervous system of ALS SOD1G93A micerdquo MolecularNeurodegeneration vol 13 no 1 p 42 2018

[104] D R Beers W Zhao J Wang et al ldquoALS patientsrsquo regulatoryT lymphocytes are dysfunctional and correlate with diseaseprogression rate and severityrdquo JCI Insight vol 2 no 5 2017

[105] E L Scotter H-J Chen and C E Shaw ldquoTDP-43 Pro-teinopathy and ALS Insights into Disease Mechanisms andTherapeutic Targetsrdquo Neurotherapeutics vol 12 no 2 pp 352ndash363 2015

[106] E McCann K Williams J Fifita et al ldquoThe genotype-phenotype landscape of familial amyotrophic lateral sclerosis inAustraliardquo Clinical Genetics vol 92 no 3 pp 259ndash266 2017

[107] F Erdo L Denes and E de Lange ldquoAge-associated physio-logical and pathological changes at the bloodndashbrain barrier Areviewrdquo Journal of Cerebral Blood Flow amp Metabolism vol 37no 1 pp 4ndash24 2016

[108] S P Saha S K Das P K Gangopadhyay T N Roy and BMaiti ldquoPattern of motor neurone disease in eastern Indiardquo ActaNeurologica Scandinavica vol 96 no 1 pp 14ndash21 1997

[109] J D Mitchell A C Gatrell A Al-Hamad R B Davies and GBatterby ldquoGeographical epidemiology of residence of patientswith Motor Neuron Disease in Lancashire and south CumbriardquoJournal of Neurology Neurosurgery amp Psychiatry vol 65 no 6pp 842ndash847 1998

[110] G Logroscino B Marin M Piccininni et al ldquoGlobal regionaland national burden of motor neuron diseases 1990-2016 asystematic analysis for the Global Burden of Disease Study2016rdquoThe Lancet Neurology vol 17 no 12 pp 1083ndash1097 2018

[111] A Hirano L T Kurland R S Krooth and S LessellldquoParkinsonism-dementia complex an endemic disease on theisland of Guam I Clinical featuresrdquo Brain vol 84 no 4 pp642ndash661 1961

[112] M Orsini et al ldquoFrontotemporal dementia in amyotrophiclateral sclerosis from rarity to realityrdquoNeurology Internationalvol 8 no 2 pp 6534-6534 2016

[113] L Berntzon L O Ronnevi B Bergman and J ErikssonldquoDetection of BMAA in the human central nervous systemrdquoNeuroscience vol 292 pp 137ndash147 2015

[114] MW Duncan N E Villacreses P G Pearson et al ldquo2-Amino-3-(methylamino)-propanoic acid (BMAA) pharmacokineticsand blood-brain barrier permeability in the ratrdquoThe Journal ofPharmacology and ExperimentalTherapeutics vol 258 no 1 pp27ndash35 1991

[115] Q R Smith H Nagura Y Takada and M W DuncanldquoFacilitated transport of the neurotoxin 120573-N-Methylamino-L-alanine across the blood-brain barrierrdquo Journal of Neurochem-istry vol 58 no 4 pp 1330ndash1337 1992

[116] X Xie M Basile and D C Mash ldquoCerebral uptake and proteinincorporation of cyanobacterial toxin 120573-N-methylamino-L-alaninerdquo NeuroReport vol 24 no 14 pp 779ndash784 2013

[117] O Karlsson L Jiang M Andersson L L Ilag and E BBrittebo ldquoProtein association of the neurotoxin and non-protein amino acid BMAA (120573-N-methylamino-l-alanine) inthe liver and brain following neonatal administration in ratsrdquoToxicology Letters vol 226 no 1 pp 1ndash5 2014

[118] J C Steele and P LMcGeer ldquoTheALSPDC syndrome ofGuamand the cycad hypothesisrdquo Neurology vol 70 no 21 pp 1984ndash1990 2008

[119] D R Weaver ldquoIntroduction to circadian rhythms and mech-anisms of circadian oscillationsrdquo in Circadian Clocks Role inHealth and Disease M L Gumz Ed pp 1ndash55 Springer NewYork NY USA 2016

[120] R M Kelly U Healy S Sreenan J H McDermott and A NCoogan ldquoClocks in the clinic circadian rhythms in health anddiseaserdquo Postgraduate Medical Journal vol 94 no 1117 p 6532018

[121] Anonymous Circadian Clocks Role in Health and Disease vol378 Springer New York NY USA 2016

[122] W Pan G Cornelissen F Halberg and A J Kastin ldquoSelectedcontribution circadian rhythm of tumor necrosis factor-alphauptake into mouse spinal cordrdquo Journal of Applied Physiologyvol 92 no 3 pp 1357ndash1362 2002 discussion 1356


[123] C Wu ldquoBeyond abeta neuronal toxicity of the beta c-terminalfragment of amyloid precursor proteinrdquo Alzheimerrsquos amp Demen-tia The Journal of the Alzheimerrsquos Association vol 12 no 7 p386 2016

[124] B Gomez-Gonzalez G Hurtado-Alvarado E Esqueda-LeonR Santana-Miranda J A Rojas-Zamorano and J Velazquez-Moctezuma ldquoREM sleep loss and recovery regulates blood-brain barrier functionrdquoCurrent Neurovascular Research vol 10no 3 pp 197ndash207 2013

[125] Y Hu A Shmygelska D Tran N Eriksson J Y Tung andD AHinds ldquoGWAS of 89283 individuals identifies genetic variantsassociated with self-reporting of being a morning personrdquoNature Communications vol 7 p 10448 2016

[126] J M Lane I Vlasac S G Anderson et al ldquoGenome-wide asso-ciation analysis identifies novel loci for chronotype in 100420individuals from the UK Biobankrdquo Nature Communicationsvol 7 p 10889 2016

[127] S E Jones J Tyrrell A R Wood et al ldquoGenome-WideAssociation Analyses in 128266 Individuals Identifies NewMorningness and Sleep Duration Locirdquo PLOS Genetics vol 12no 8 Article ID e1006125 2016

[128] S E Jones J M Lane andM NWeedon ldquoGenome-wide asso-ciation analyses of chronotype in 697828 individuals providesinsights into circadian rhythmsrdquo Nature Communications vol10 no 1 p 343 2019

[129] R L McLaughlin D Schijven W van Rheenen et alldquoGenetic correlation between amyotrophic lateral sclerosis andschizophreniardquo Nature Communications vol 8 p 14774 2017

[130] E W Stommel D Graber J Montanye J A Cohen and BT Harris ldquoDoes treating schizophrenia reduce the chances ofdeveloping amyotrophic lateral sclerosisrdquoMedical Hypothesesvol 69 no 5 pp 1021ndash1028 2007

[131] M Mengozzi G Fantuzzi R Faggioni et al ldquoChlorpromazinespecifically inhibits peripheral and brain TNF production andup-regulates IL-10 production in micerdquo Immunology vol 82no 2 pp 207ndash210 1994

[132] A Dalla Libera G Scutari R Boscolo M P Rigobello andA Bindoli ldquoAntioxidant properties of clozapine and relatedneurolepticsrdquo Free Radical Research vol 29 no 2 pp 151ndash1571998

[133] B J Turner A Rembach R Spark E C Lopes and S SCheema ldquoOpposing Effects of Low and High-Dose Clozapineon Survival of Transgenic Amyotrophic Lateral Sclerosis MicerdquoJournal of Neuroscience Research vol 74 no 4 pp 605ndash6132003

[134] Y Yase N Matsumoto K Azuma Y Nakai and H ShirakildquoAmyotrophic lateral sclerosis Association with schizophrenicsymptoms and showing Alzheimerrsquos tanglesrdquo Archives of Neu-rology vol 27 no 2 pp 118ndash128 1972

[135] F A Mettler and A Crandell ldquoNeurologic disorders in psychi-atric institutionsrdquo The Journal of Nervous and Mental Diseasevol 128 no 2 pp 148ndash159 1959

[136] E H Blackburn ldquoStructure and function of telomeresrdquo Naturevol 350 no 6319 pp 569ndash573 1991

[137] K Okuda A Bardeguez J P Gardner et al ldquoTelomere lengthin the newbornrdquo Pediatric Research vol 52 no 3 pp 377ndash3812002

[138] Y Arai C M Martin-Ruiz M Takayama et al ldquoInflammationbut not telomere length predicts successful ageing at extremeold age a longitudinal study of semi-supercentenariansrdquoEBioMedicine vol 2 no 10 pp 1549ndash1558 2015

[139] C Dalgard A Benetos S Verhulst et al ldquoLeukocyte telomerelength dynamics in women andmen menopause vs age effectsrdquoInternational Journal of Epidemiology vol 44 no 5 pp 1688ndash1695 2015

[140] M I Zvereva D M Shcherbakova and O A DontsovaldquoTelomerase Structure functions and activity regulationrdquoBiochemistry vol 75 no 13 pp 1563ndash1583 2010

[141] T Richter and T V Zglinicki ldquoA continuous correlationbetween oxidative stress and telomere shortening in fibroblastsrdquoExperimental Gerontology vol 42 no 11 pp 1039ndash1042 2007

[142] J W Shay and W E Wright ldquoSenescence and immortalizationrole of telomeres and telomeraserdquo Carcinogenesis vol 26 no 5pp 867ndash874 2005

[143] Y Yamazaki D J Baker M Tachibana et al ldquoVascular CellSenescence Contributes to BloodndashBrain Barrier BreakdownrdquoStroke vol 47 no 4 pp 1068ndash1077 2016

[144] L Hoyles T Snelling U-K Umlai et al ldquoMicrobiomendashhostsystems interactions Protective effects of propionate upon thebloodndashbrain barrierrdquoMicrobiome vol 6 no 1 p 55 2018

[145] K Goasdoue S M Miller P B Colditz and S T BjorkmanldquoReview The blood-brain barrier protecting the developingfetal brainrdquo Placenta vol 54 pp 111ndash116 2017

[146] V Braniste M Al-Asmakh C Kowal et al ldquoThe gut microbiotainfluences blood-brain barrier permeability in micerdquo ScienceTranslational Medicine vol 6 no 263 p 263ra158 2014

[147] SM Finegold S EDowdVGontcharova et al ldquoPyrosequenc-ing study of fecal microflora of autistic and control childrenrdquoAnaerobe vol 16 no 4 pp 444ndash453 2010

[148] S M Finegold J Downes and P H Summanen ldquoMicrobiologyof regressive autismrdquoAnaerobe vol 18 no 2 pp 260ndash262 2012

[149] M A Huntley N Bien-Ly R Daneman and R J Watts ldquoDis-secting gene expression at the blood-brain barrierrdquo Frontiers inNeuroscience vol 8 p 355 2014

[150] J Y Li R J Boado and W M Pardridge ldquoBlood-brain barriergenomicsrdquo Journal of Cerebral Blood FlowampMetabolism vol 21no 1 pp 61ndash68 2001

[151] E E Frohlich A Farzi R Mayerhofer et al ldquoCognitiveimpairment by antibiotic-induced gut dysbiosis Analysis ofgut microbiota-brain communicationrdquo Brain Behavior andImmunity vol 56 pp 140ndash155 2016

[152] P Bercik E Denou J Collins et al ldquoThe intestinal microbiotaaffect central levels of brain-derived neurotropic factor andbehavior in micerdquo Gastroenterology vol 141 no 2 pp 599ndash609e3 2011

[153] M van de Wouw M Boehme J M Lyte et al ldquoShort-chainfatty acids microbial metabolites that alleviate stress-inducedbrainndashgut axis alterationsrdquo The Journal of Physiology vol 596no 20 pp 4923ndash4944 2018

[154] M V Kuleshov M R Jones A D Rouillard et al ldquoEnrichra comprehensive gene set enrichment analysis web server 2016updaterdquo Nucleic Acids Research vol 44 no W1 pp W90ndashW972016

[155] A Reijerkerk M A Lopez-Ramirez B van het Hof et alldquoMicroRNAs Regulate Human Brain Endothelial Cell-BarrierFunction in Inflammation Implications for Multiple SclerosisrdquoThe Journal of Neuroscience vol 33 no 16 pp 6857ndash6863 2013

[156] X Zheng G Xie A Zhao et al ldquoThe Footprints of GutMicrobialndashMammalian Co-Metabolismrdquo Journal of ProteomeResearch vol 10 no 12 pp 5512ndash5522 2011

[157] L Bond K Bernhardt P Madria K Sorrentino H Scelsiand C S Mitchell ldquoA metadata analysis of oxidative stress


etiology in preclinical Amyotrophic Lateral Sclerosis Benefitsof antioxidant therapyrdquo Frontiers in Neuroscience vol 12 no 102018

[158] M Hossain T Sathe V Fazio et al ldquoTobacco smoke A criticaletiological factor for vascular impairment at the bloodndashbrainbarrierrdquo Brain Research vol 1287 pp 192ndash205 2009

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAutismDepression Research

and TreatmentHindawiwwwhindawicom Volume 2018

Neurology Research International


Alzheimerrsquos DiseaseHindawiwwwhindawicom Volume 2018

International Journal of


BioMed Research International


Research and TreatmentSchizophrenia

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018Hindawiwwwhindawicom Volume 2018

Neural PlasticityScienticaHindawiwwwhindawicom Volume 2018


Parkinsonrsquos Disease

Sleep DisordersHindawiwwwhindawicom Volume 2018


Neuroscience Journal

MedicineAdvances in



Psychiatry Journal


Computational and Mathematical Methods in Medicine

Multiple Sclerosis InternationalHindawiwwwhindawicom Volume 2018

StrokeResearch and TreatmentHindawiwwwhindawicom Volume 2018


Behavioural Neurology


Case Reports in Neurological Medicine

Submit your manuscripts atwwwhindawicom


the two barriers include an increased permeability to trac-ers [3H]-D-mannitol and [14C]-carboxyl-inulin [9] andcytokines interferon-120572 interferon-120574 tumor necrosis factor-120572 [10] decreased Occludin and ZO-1 protein expression inTJ [11] and decreased VE-cadherin and 120573-catenin proteinexpression in AJ [11]

Neuroimaging studies have demonstrated early BBB dys-function in Alzheimer disease (AD) [12] Parkinson disease(PD) [13] Huntington disease (HD) [14] amyotrophic lateralsclerosis (ALS) [6 15 16] and multiple sclerosis (MS) [17]These demonstrations of BBB dysfunction have been con-firmedwith biofluid biomarker data andobservations of post-mortem tissue analysis [6 12ndash17] For the sake of this reviewldquohyperpermeabilityrdquo will refer to an increased state of per-meability in the otherwise semipermeable membranes BBBhyperpermeability represents a significant area of researchas despite being continuously examined in multiple motorneuron diseases (MNDs) [18] the exact biochemical pathwayof BBB breakdown is not yet known

This review aims to examine current research under-standings of BBB hyperpermeability and mechanisms ofbreakdown to identify key research targets and areas thatmayshed light on the mystery surrounding the pathophysiologyof BBB (and BSCB) breakdownThe key points of this reviewrevolve around the mechanisms involved in oxidative stresscerebrospinal microbleeds underlying genomic modalitiesand the epidemiology of ALS thereby providing insightsinto potentially valuable knowledge gaps To conclude thisreviewwill make recommendations to investigative areas thathold promise in understanding the mechanisms involved inBBB breakdown at the biological and molecular level andprovide insights into therapeutic strategies to modulate BBBpermeability

2 Oxidative Stress

Radicals are defined as a molecule species with one ormore unpaired electrons and are characterised by beinghighly reactive Reactive Oxygen Species (ROS) are a groupof oxygen centred radicals ROS can damage the bodythrough hypoxia and reoxygenation of cells Hypoxia andreoxygenation of BBB endothelial cells cause an increase inthe paracellular permeability [19 20] of the structure leadingto a state of hyperpermeability ROS may also cause changesin the localization and structure of Occludin [21] whichmay influence the regulation and assembly of tight junctionswhich are essential structures in the BBB [22]

ROS can be produced endogenously and taken intothe body exogenously Exogenous sources of ROS can beobtained from pollutants tobacco smoke xenobiotics radi-ation (ultraviolet and ionizing) ozone chemotherapeuticagents pesticides (eg Aldrindendrin [23 24]) organic sol-vents alcohol and somemetals [25 26] EndogenousROS areproduced intracellularly and extracellularly with the majorproducers being NADPH oxidase (NOX) nitrogen oxidesynthase Xanthine oxidase Heme proteins CytochromeP450

phagocytes mitochondria peroxisomes and the endo-plasmic reticulum [27ndash29]

The significance of ROS in the degradation of neuromus-cular junctions in cases of MND especially sporadic ALS(sALS) has been examined extensively within literature asa proposed mechanism of neuromuscular degeneration asper the ldquoDying Back hypothesisrdquoThe Dying Back hypothesishowever does not account for BBB or BSCB degradationROS has been demonstrated to cause BBB dysfunctionthrough alcohol induced activation of myosin light chain(MLC) kinase and phosphorylation of MLC and TJ pro-teins [30] Furthermore BBB disruption has been shownto be mediated by oxidative stress through stimulation ofinositol 145-triphosphate (IP

3R)-gated intracellular Ca2+

release resulting in a similar MLC kinase activation As suchoxidative stress remains a topic of interest in investigatingBBB hyperpermeability [31]

The effects of an abundance of ROS can be mitigated bythe metabolism of these free radicals through neutralisationvia antioxidants [32] Oxidative stress is when there is moreROS than antioxidants and can have many physiologicaleffects on the body There are enzymatic and nonenzymaticantioxidant systems in humans which appear to be keyaspects in the fight against ROS [33]

21 Enzymatic Antioxidants

211 Nrf2 Transcription Factor It is worth noting the impor-tance of the transcription factor nuclear factor erythroid2ndashrelated factor 2 (Nrf2) and its role in oxidative stress Thetranscription factor is constitutively expressed in all tissues[34] Nrf2 functions at the interface of cellular redox andintermediary metabolism reactions as the target genes areinvolved in antioxidant enzyme production [35ndash37] Nrf2 isa basic region leucine zipper transcription factor [38] thatforms heterodimers in the nucleus of cells which recognisesthe enhancer sequence known as antioxidant response ele-ment (ARE) ARE enhancer sequences are present in theregulatory regions of over 250 genes [39] Not only involvedin antioxidant production decreased Nrf2 activity decreasesthe expression of key tight junction proteins such as occludinand claudin-18 [39]

Nrf2 is activated by sulforaphane [40] an organosulfurcompound found in cruciferous vegetables eg broccoliand Brussels sprouts [41] Animal studies have shown thatsulforaphane administration after brain injury increased neu-roprotective effects of Nrf2 [42] For its role in ARE and tightjunction proteins Nrf2 represents a significant direction forALS- or neurodegenerative disease-induced BBB disruptionand hyperpermeability

Supporting this Kraft et al (2007) evaluated the endoge-nous activation of the Nrf2-ARE system during the inductionof pathology in mutant SOD mouse models and showedthat Nrf2-ARE activation appears to progress in a retrogradefashion along the motor pathway thereby implying thecontributions of the Nrf2-ARE pathway and its activationwhich can persist throughout ALS pathology and whichincreases in concert with disease severity [43]

212 SOD Protein Family The superoxide dismutase (SOD)family of enzymes function to catalyze the dismutation of







2

minus +H+ (1)



Cu2+-SOD +O2


(2)


Cu+-SOD +O2


(3)






2O) and


2H2O2997888rarr 2H

2O +O

2 (4)









2O (6)





Adrenal Gland





Artery - Aorta



Brain - Cortex

Artery - Tibial


Artery - Coronary


Brain - Amygdala

Nerve - Tibial

Brain - Hippocampus

Brain - Cerebellum


Pituitary



Cervix - Ectocervix

VaginaThyroid


Kidney - Cortex

Cervix - Endocervix


Colon - Sigmoid





Colon - Transverse





Muscle - Skeletal

LungSpleen




Whole Blood

Pancreas

10

15

20

25

30

log1

0(TP

M+1

)


Muscle - Skeletal




LungWhole Blood



Kidney - Cortex

Fallopian Tube

Cervix - Endocervix

Cervix - Ectocervix

Adrenal Gland

Artery - Tibial


BladderVagina

Colon - Sigmoid





Artery - Coronary

Artery - Aorta

Esophagus - Mucosa












StomachPancreas


Brain - Amygdala

Brain - Cortex

Pituitary

Brain - Cerebellum

Brain - Hippocampus



05

10

15

20

25

30

35

log1

0(TP

M+1

)


Artery - Aorta

Artery - Tibial

Artery - Coronary




Nerve - Tibial



BladderLung

Cervix - Endocervix







Kidney - Cortex

Colon - Transverse




Pancreas



Adrenal Gland

Pituitary

Brain - Cortex






Brain - Amygdala

Muscle - Skeletal



Brain - Hippocampus





Whole Blood

00

10

20

30

log1

0(TP

M+1

)









LungNerve - Tibial

Whole Blood


Cervix - Ectocervix

Fallopian Tube





Artery - Coronary




Colon - Sigmoid


StomachProstate

Muscle - Skeletal

OvaryArtery - Aorta




Pancreas



Esophagus - Mucosa


Pituitary

Brain - Cortex

Brain - Amygdala




Brain - Hippocampus




Brain - Cerebellum


05

10

15

20

25

log1

0(TP

M+1





















3 Microbleeds





































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal
















2

minus +H+ (1)



Cu2+-SOD +O2


(2)


Cu+-SOD +O2


(3)






2O) and


2H2O2997888rarr 2H

2O +O

2 (4)









2O (6)





Adrenal Gland





Artery - Aorta



Brain - Cortex

Artery - Tibial


Artery - Coronary


Brain - Amygdala

Nerve - Tibial

Brain - Hippocampus

Brain - Cerebellum


Pituitary



Cervix - Ectocervix

VaginaThyroid


Kidney - Cortex

Cervix - Endocervix


Colon - Sigmoid





Colon - Transverse





Muscle - Skeletal

LungSpleen




Whole Blood

Pancreas

10

15

20

25

30

log1

0(TP

M+1

)


Muscle - Skeletal




LungWhole Blood



Kidney - Cortex

Fallopian Tube

Cervix - Endocervix

Cervix - Ectocervix

Adrenal Gland

Artery - Tibial


BladderVagina

Colon - Sigmoid





Artery - Coronary

Artery - Aorta

Esophagus - Mucosa












StomachPancreas


Brain - Amygdala

Brain - Cortex

Pituitary

Brain - Cerebellum

Brain - Hippocampus



05

10

15

20

25

30

35

log1

0(TP

M+1

)


Artery - Aorta

Artery - Tibial

Artery - Coronary




Nerve - Tibial



BladderLung

Cervix - Endocervix







Kidney - Cortex

Colon - Transverse




Pancreas



Adrenal Gland

Pituitary

Brain - Cortex






Brain - Amygdala

Muscle - Skeletal



Brain - Hippocampus





Whole Blood

00

10

20

30

log1

0(TP

M+1

)









LungNerve - Tibial

Whole Blood


Cervix - Ectocervix

Fallopian Tube





Artery - Coronary




Colon - Sigmoid


StomachProstate

Muscle - Skeletal

OvaryArtery - Aorta




Pancreas



Esophagus - Mucosa


Pituitary

Brain - Cortex

Brain - Amygdala




Brain - Hippocampus




Brain - Cerebellum


05

10

15

20

25

log1

0(TP

M+1





















3 Microbleeds





































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal











Adrenal Gland





Artery - Aorta



Brain - Cortex

Artery - Tibial


Artery - Coronary


Brain - Amygdala

Nerve - Tibial

Brain - Hippocampus

Brain - Cerebellum


Pituitary



Cervix - Ectocervix

VaginaThyroid


Kidney - Cortex

Cervix - Endocervix


Colon - Sigmoid





Colon - Transverse





Muscle - Skeletal

LungSpleen




Whole Blood

Pancreas

10

15

20

25

30

log1

0(TP

M+1

)


Muscle - Skeletal




LungWhole Blood



Kidney - Cortex

Fallopian Tube

Cervix - Endocervix

Cervix - Ectocervix

Adrenal Gland

Artery - Tibial


BladderVagina

Colon - Sigmoid





Artery - Coronary

Artery - Aorta

Esophagus - Mucosa












StomachPancreas


Brain - Amygdala

Brain - Cortex

Pituitary

Brain - Cerebellum

Brain - Hippocampus



05

10

15

20

25

30

35

log1

0(TP

M+1

)


Artery - Aorta

Artery - Tibial

Artery - Coronary




Nerve - Tibial



BladderLung

Cervix - Endocervix







Kidney - Cortex

Colon - Transverse




Pancreas



Adrenal Gland

Pituitary

Brain - Cortex






Brain - Amygdala

Muscle - Skeletal



Brain - Hippocampus





Whole Blood

00

10

20

30

log1

0(TP

M+1

)









LungNerve - Tibial

Whole Blood


Cervix - Ectocervix

Fallopian Tube





Artery - Coronary




Colon - Sigmoid


StomachProstate

Muscle - Skeletal

OvaryArtery - Aorta




Pancreas



Esophagus - Mucosa


Pituitary

Brain - Cortex

Brain - Amygdala




Brain - Hippocampus




Brain - Cerebellum


05

10

15

20

25

log1

0(TP

M+1





















3 Microbleeds





































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal
















LungNerve - Tibial

Whole Blood


Cervix - Ectocervix

Fallopian Tube





Artery - Coronary




Colon - Sigmoid


StomachProstate

Muscle - Skeletal

OvaryArtery - Aorta




Pancreas



Esophagus - Mucosa


Pituitary

Brain - Cortex

Brain - Amygdala




Brain - Hippocampus




Brain - Cerebellum


05

10

15

20

25

log1

0(TP

M+1





















3 Microbleeds





































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal



















3 Microbleeds





































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal












































7 Conclusions










Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal












Disclosure






References


























































2O2






































































































































MedicineAdvances in



Psychiatry Journal











































2O2






































































































































MedicineAdvances in



Psychiatry Journal












































































































































MedicineAdvances in



Psychiatry Journal










reviewarticle pathomechanisms of blood-brain barrier disruption … · 2019. 7. 12. · pha g us is...

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