title: Molecular disorganization of axons adjacent to human lacunar infarcts.
abstract: Cerebral microvascular disease predominantly affects brain white matter and deep grey matter, resulting in ischaemic damage that ranges from lacunar infarcts to white matter hyperintensities seen on magnetic resonance imaging. These lesions are common and result in both clinical stroke syndromes and accumulate over time, resulting in cognitive deficits and dementia. Magnetic resonance imaging studies suggest that these lesions progress over time, accumulate adjacent to prior lesions and have a penumbral region susceptible to further injury. The pathological correlates of this adjacent injury in surviving myelinated axons have not been previously defined. In this study, we sought to determine the molecular organization of axons in tissue adjacent to lacunar infarcts and in the regions surrounding microinfarcts, by determining critical elements in axonal function: the morphology and length of node of Ranvier segments and adjacent paranodal segments. We examined post-mortem brain tissue from six patients with lacunar infarcts and tissue from two patients with autosomal dominant retinal vasculopathy and cerebral leukoencephalopathy (previously known as hereditary endotheliopathy with retinopathy, nephropathy and stroke) who accumulate progressive white matter ischaemic lesions in the form of lacunar and microinfarcts. In axons adjacent to lacunar infarcts yet extending up to 150% of the infarct diameter away, both nodal and paranodal length increase by ∼20% and 80%, respectively, reflecting a loss of normal cell-cell adhesion and signalling between axons and oligodendrocytes. Using premorbid magnetic resonance images, brain regions from patients with retinal vasculopathy and cerebral leukoencephalopathy that harboured periventricular white matter hyperintensities were selected and the molecular organization of axons was determined within these regions. As in regions adjacent to lacunar infarcts, nodal and paranodal length in white matter of these patients is increased. Myelin basic protein and neurofilament immunolabelling demonstrates that axons in these adjacent regions have preserved axonal cytoskeleton organization and are generally myelinated. This indicates that the loss of normal axonal microdomain architecture results from disrupted axoglial signalling in white matter adjacent to lacunar and microinfarcts. The loss of the normal molecular organization of nodes and paranodes is associated with axonal degeneration and may lead to impaired conduction velocity across surviving axons after stroke. These findings demonstrate that the degree of white matter injury associated with cerebral microvascular disease extends well beyond what can be identified using imaging techniques and that an improved understanding of the neurobiology in these regions can drive new therapeutic strategies for this disease entity.
authors.affiliation: 1 Departments of Neurology, David Geffen School of Medicine, University of California Los Angeles, USA jhinman@mednet.ucla.edu.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hinman
authors.affiliation: 1 Departments of Neurology, David Geffen School of Medicine, University of California Los Angeles, USA.
authors.forename: Monica D
authors.initials: MD
authors.lastname: Lee
authors.affiliation: 2 Department of Pathology and Laboratory Medicine, Section of Neuropathology, David Geffen School of Medicine, University of California Los Angeles, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Tung
authors.affiliation: 1 Departments of Neurology, David Geffen School of Medicine, University of California Los Angeles, USA 2 Department of Pathology and Laboratory Medicine, Section of Neuropathology, David Geffen School of Medicine, University of California Los Angeles, USA.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: 1 Departments of Neurology, David Geffen School of Medicine, University of California Los Angeles, USA.
authors.forename: S Thomas
authors.initials: ST
authors.lastname: Carmichael
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D020159:Citrullinemia / Q000473:pathology; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology; D013049:Spectrin / Q000378:metabolism; D059409:Stroke, Lacunar / Q000150:complications / Q000473:pathology*
chemical_list: C491323:CNTNAP1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D013049:Spectrin
keywords: ion channels; lacunar stroke; neuropathology; small vessel disease; vascular dementia