Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA)

Two of the key functions of arteries in the brain are (1) the well‐recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri‐arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

[1]  L. Schneider Developing appropriate methodologies for effective clinical trial engagement in vascular cognitive impairment and dementia (VCID) , 2020 .

[2]  Andreas A. Linninger,et al.  In Vivo Intrathecal Tracer Dispersion in Cynomolgus Monkey Validates Wide Biodistribution Along Neuraxis , 2020, IEEE Transactions on Biomedical Engineering.

[3]  T. Wisniewski,et al.  Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis) , 2020, Frontiers in Aging Neuroscience.

[4]  A. Tannenbaum,et al.  Perivascular spaces in the brain: anatomy, physiology and pathology , 2020, Nature Reviews Neurology.

[5]  A. Ljubimov,et al.  Identification of early pericyte loss and vascular amyloidosis in Alzheimer’s disease retina , 2020, Acta Neuropathologica.

[6]  R. Carare,et al.  Vasomotion Drives Periarterial Drainage of Aβ from the Brain , 2020, Neuron.

[7]  David A Hartmann,et al.  Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ+/− mice , 2020, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  P. Eide,et al.  Cerebrospinal fluid tracer efflux to parasagittal dura in humans , 2020, Nature Communications.

[9]  P. Mozley,et al.  Intrathecal 99mTc‐DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans , 2020, Alzheimer's & dementia.

[10]  R. Sperling,et al.  Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways , 2019, Nature Reviews Neurology.

[11]  M. Frosch,et al.  Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain , 2019, Neuron.

[12]  Mohammed Q. Qutaish,et al.  Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. , 2019, JCI insight.

[13]  C. Supuran,et al.  A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease , 2019, International journal of molecular sciences.

[14]  A. Dorrance,et al.  Locus Coeruleus Degeneration Induces Forebrain Vascular Pathology in a Transgenic Rat Model of Alzheimer's Disease. , 2019, Journal of Alzheimer's disease : JAD.

[15]  C. Holmes,et al.  Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease , 2019, Brain : a journal of neurology.

[16]  L. Beckett,et al.  White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities , 2019, Alzheimer's & dementia.

[17]  C. Berka,et al.  Transcranial Impedance Changes during Sleep: A Rheoencephalography Study , 2019, IEEE Journal of Translational Engineering in Health and Medicine.

[18]  R. Carare,et al.  Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain , 2019, Front. Aging Neurosci..

[19]  Eric E. Smith,et al.  Vascular dysfunction—The disregarded partner of Alzheimer's disease , 2019, Alzheimer's & Dementia.

[20]  Scott T. Acton,et al.  Functional aspects of meningeal lymphatics in aging and Alzheimer’s disease , 2018, Nature.

[21]  M. D. de Leon,et al.  Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity , 2018, Aging cell.

[22]  Roxana O. Carare,et al.  Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways , 2018, Acta Neuropathologica.

[23]  G. Bu,et al.  ApoE4 Accelerates Early Seeding of Amyloid Pathology , 2017, Neuron.

[24]  D. Werring,et al.  Animal models of cerebral amyloid angiopathy. , 2017, Clinical science.

[25]  R. Carare,et al.  LOSS OF CLUSTERIN SHIFTS AMYLOID DEPOSITION TO THE CEREBROVASCULATURE VIA DISRUPTION OF PERIVASCULAR DRAINAGE PATHWAYS , 2017, Alzheimer's & Dementia.

[26]  E. Ólafsson,et al.  Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy , 2017, Laboratory Investigation.

[27]  H. Rusinek,et al.  Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET , 2017, The Journal of Nuclear Medicine.

[28]  David A Hartmann,et al.  Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex , 2017, bioRxiv.

[29]  A. Zoubeidi,et al.  Clusterin as a therapeutic target , 2017, Expert opinion on therapeutic targets.

[30]  D. Wilcock,et al.  Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). , 2016, Biochimica et biophysica acta.

[31]  D. Holtzman,et al.  Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease , 2016, Science Translational Medicine.

[32]  D. Wilcock,et al.  Animal Models of Vascular Cognitive Impairment and Dementia (VCID) , 2016, Cellular and Molecular Neurobiology.

[33]  R. Carare,et al.  Vascular basement membranes as pathways for the passage of fluid into and out of the brain , 2016, Acta Neuropathologica.

[34]  J. Ghiso,et al.  The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain , 2016, Neurobiology of Disease.

[35]  Per Kristian Eide,et al.  MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain , 2015, Acta radiologica open.

[36]  M. Ihara,et al.  New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy , 2014, Front. Aging Neurosci..

[37]  R. Carare,et al.  Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid , 2014, Annals of clinical and translational neurology.

[38]  E. Ólafsson,et al.  Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis , 2013, Brain Research.

[39]  R O Weller,et al.  Review: Cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy , 2013, Neuropathology and applied neurobiology.

[40]  V. Perry,et al.  Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer’s disease , 2013, Acta neuropathologica communications.

[41]  Brian J. Bacskai,et al.  Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models , 2013, Acta Neuropathologica.

[42]  R. Carare,et al.  Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain , 2013, Aging cell.

[43]  Antonio Colombo,et al.  Anti–amyloid β autoantibodies in cerebral amyloid angiopathy–related inflammation: Implications for amyloid‐modifying therapies , 2013, Annals of neurology.

[44]  R. Carare,et al.  Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele , 2012, PloS one.

[45]  Nick C Fox,et al.  Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis , 2012, The Lancet Neurology.

[46]  Keith L. Black,et al.  Alzheimer’s Disease in the Retina: Imaging Retinal Aβ Plaques for Early Diagnosis and Therapy Assessment , 2012, Neurodegenerative Diseases.

[47]  R. Kalaria,et al.  Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts , 2011, Acta Neuropathologica.

[48]  Clifford R. Jack,et al.  Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup , 2011, Alzheimer's & Dementia.

[49]  Daniel L. Farkas,et al.  Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model , 2011, NeuroImage.

[50]  G. Halliday,et al.  Oligomeric Aβ40 species accumulate in the toxic plaques in Alzheimer's disease , 2009, Alzheimer's & Dementia.

[51]  J. McLaurin,et al.  Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy , 2009, Proceedings of the National Academy of Sciences.

[52]  Katie Hamm,et al.  apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. , 2008, The Journal of clinical investigation.

[53]  R O Weller,et al.  Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. , 2008, Brain : a journal of neurology.

[54]  T. Révész,et al.  Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene‐related dementias: a morphological study , 2006, Neuropathology and applied neurobiology.

[55]  D. Wilcock,et al.  Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration , 2004, Neurobiology of Disease.

[56]  U. Dirnagl,et al.  Immune surveillance of mouse brain perivascular spaces by blood‐borne macrophages , 2001, The European journal of neuroscience.

[57]  E. Matsubara,et al.  Isoform‐Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood‐Brain Barrier Transport of Circulating Alzheimer's Amyloid β , 1997, Journal of neurochemistry.

[58]  R O Weller,et al.  Pathways of Fluid Drainage from the Brain ‐ Morphological Aspects and Immunological Significance in Rat and Man , 1992, Brain pathology.

[59]  R O Weller,et al.  Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. , 1990, Journal of anatomy.

[60]  H. Soininen,et al.  Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus. , 2019, Journal of Alzheimer's disease : JAD.

[61]  B. Winblad,et al.  Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease: Need for Prognostic Biomarkers? , 2016, Journal of Alzheimer's disease : JAD.

[62]  D. Wilcock,et al.  β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice , 2014, Alzheimer's Research & Therapy.

[63]  E. Zhang,et al.  Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain , 2004, Acta Neuropathologica.

[64]  D. Wilcock,et al.  Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. , 2004, Neurobiology of disease.