Fisher, MJ

Hainsworth, AH

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EDITORIALAtticus H. Hainsworth,PhDMark J. Fisher, MDCorrespondence toDr. Hainsworth:ahainsworth@sgul.ac.ukand Dr. Fisher:mfisher@uci.eduNeurology® 2017;88:420–421See page 426A dysfunctional blood–brain barrier andcerebral small vessel diseaseIn molecular terms, the blood–brain barrier (BBB)indicates tight junction complexes between adjacentendothelial cells that, combined with endothelialtransporters (both influx and efflux), make brainendothelia different from other endothelia. Whilehighly advantageous as a protective barrier againstcerebrovascular permeability, shielding sensitive brainelements from blood-borne agents, it also posesa problem for those who seek to develop brain ther-apeutics such as designer antibodies targeted to amy-loid deposits or tau protein derivatives.Recent evidence from human studies indicates var-iation in barrier efficacy among patient populations. Inthis issue ofNeurology®, Zhang et al.1 used quantitativeMRI measures (dynamic contrast-enhanced [DCE]–MRI) to study cerebrovascular barrier function. Theystudied 116 older people, either with clinical and MRIevidence of cerebral small vessel disease or with noovert cerebrovascular disease. They used DCE-MRI tofollow the time course of injected gadolinium-basedcontrast agent in each voxel of a brain MRI scan. Theythen used a standard analysis to derive 2 measuresrelated to BBB function. These are the rate constantfor gadolinium (Gd) transfer from blood to brain (var-iously called Ki or Ktrans) and the extent of brain tissuecontaining contrast agent (vL, the so-called fractionalvolume of leaky brain tissue), each derived for areas ofwhite matter hyperintensity, for nonhyperintensewhite matter, for cortical gray matter, and for deepgray nuclei. They observed modest permeability, re-flected in the Ki and vL values, in all brain regions(highest in cortical gray matter) and across both par-ticipant groups. They found that older people withsmall vessel disease had a greater fraction of Gd-positive tissue (observed as greater vL) relative to con-trol individuals without small vessel disease.1 This heldtrue within white matter hyperintensities, neighboringnonhyperintense white matter, and cortical gray matter(1.2- to 1.4-fold difference, depending on the tissuetype). This picture agrees—broadly—with previousstudies of older people with manifestations of smallvessel disease (lacunar stroke, white matter hyperinten-sities, or vascular cognitive impairment).2–4It may be a mistake to assume that a dysfunctionalcerebrovascular barrier indicates breach of the tightjunctions between endothelial cells. For many years,we have known about the trafficking of plasma sub-strates across the endothelial cytoplasm, known astranscytosis. Traditional emphasis on efflux transport-ers, which limit CNS concentration of penetratingdrugs, has shifted to include analyses of influx mecha-nisms capable of enhancing drug delivery.5 Interest hasrecently increased with discovery of Mfsd2a, a 60 KDatransmembrane protein greatly enriched in brain endo-thelium (.70-fold relative to peripheral endothelia).6Mice genetically engineered to have no Mfsd2a geneexhibit increased BBB permeability due to increasedtranscytosis in brain endothelia.6 This pathway may bean entry route for therapeutic antibodies recentlyshown to reduce brain amyloid load.7 The currentstudy1 leaves unclear the relative roles of paracellularvs transcellular barrier dysfunction.Then again, is the demonstrated dysfunctionalcerebrovascular barrier really an indication of endo-thelial disturbances at all? The ongoing assumptionis that the barrier changes occur at the capillary level,but this remains an assumption. Arterioles, the vesselsimmediately upstream from capillaries, have layers ofsmooth muscle cells that normally provide barrierprotection in addition to other arteriolar constituents.But small vessel disease, either hereditary or sporadic,is typically characterized by substantial loss of smoothmuscle cells.8 Given that smooth muscle cells of arte-rioles may be no more than one layer thick,9 somearterioles in small vessel disease could contribute toloss of cerebrovascular barrier protection, a subject forfurther investigation.The nature of the relationship between a dysfunc-tional cerebrovascular barrier and the pathogenesis ofcerebral small vessel disease remains the critical ques-tion. The possible relationships, especially cause vsconsequence, are complex and largely speculative atthis point. Any unified model or fully developed theorylinking white matter hyperintensities, microinfarcts,and cerebral microbleeds10 will need to incorporateconceptually a dysfunctional BBB.From the Molecular and Clinical Sciences Research Institute (A.H.H.), St Georges University of London; Neurology (A.H.H.), St George’sUniversity Hospitals NHS Foundation Trust, London, UK; and Departments of Neurology, Anatomy & Neurobiology, and Pathology &Laboratory Medicine (M.J.F.), University of California, Irvine.Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.420 © 2016 American Academy of Neurologyª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.STUDY FUNDINGNo targeted funding reported.DISCLOSUREWork in Dr. Hainsworth’s laboratory receives financial support from Alz-heimer’s Society (UK) (PG146/151), Alzheimer’s Drug Discovery Founda-tion (Grant Ref 20140901), and Alzheimer’s Research UK (PPG2014A-8).Dr. Hainsworth acknowledges honoraria from Eli Lilly, Dementia Discov-ery Fund, and National Institute on Aging. Dr. Hainsworth served on theVascular Contributions to Cognitive Impairment and Dementia panel forthe Alzheimer’s Disease Related Dementias Summit, NIH, March 2016.Dr. Fisher is supported by NIH RO1 NS20989 (Dr. Fisher). Dr. Fisheralso has research grants from Otsuka Pharmaceutical Company andBoehringer-Ingelheim, and serves on clinical event committees for Covi-dien. Go to Neurology.org for full disclosures.REFERENCES1. Zhang CE, Wong SM, van de Haar HJ, et al. Blood–brainbarrier leakage is more widespread in patients with cerebralsmall vessel disease. Neurology 2017;88:426–432.2. Huisa BN, Caprihan A, Thompson J, Prestopnik J, QuallsCR, Rosenberg GA. Long-term blood-brain barrier permeabil-ity changes in Binswanger disease. Stroke 2015;46:2413–2418.3. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased in normal-appearingwhite matter in patients with lacunar stroke and leucoar-aiosis. J Neurol Neurosurg Psychiatry 2010;81:192–197.4. Wardlaw JM, Doubal F, Armitage P, et al. Lacunar strokeis associated with diffuse blood-brain barrier dysfunction.Ann Neurol 2009;65:194–202.5. Sanchez-Covarrubias L, Slosky LM, Thompson BJ, DavisTP, Ronaldson PT. Transporters at CNS barrier sites:obstacles or opportunities for drug delivery? Curr PharmDes 2014;20:1422–1449.6. Ben-Zvi A, Lacoste B, Kur E, et al. Mfsd2a is critical forthe formation and function of the blood-brain barrier.Nature 2014;509:507–511.7. Sevigny J, Chiao P, Bussiere T, et al. The antibody adu-canumab reduces Abeta plaques in Alzheimer’s disease.Nature 2016;537:50–56.8. Craggs LJL, Yamamoto Y, Deramecourt V, Kalaria RN.Microvascular pathology and morphometrics of sporadicand hereditary small vessel diseases of the brain. BrainPathol 2014; 24:495–509.9. Martinez-Lemus LA. The dynamic structure of arterioles.Basic Clin Pharmacol Toxicol 2011;110:5–11.10. Fisher M. Cerebral microbleeds and thrombolysis: clinicalconsequences and mechanistic implications. JAMA Neurol2016;73:632–635.Neurology 88 January 31, 2017 421ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

A dysfunctional blood-brain barrier and cerebral small vessel disease.

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A dysfunctional blood-brain barrier and cerebral small vessel disease.

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