Brain Pathology ISSN 1015-6305
MINI-SYMPOSIUM: Pathology of Genetics of (non-CAA) Cerebral Microvascular Disease – Introduction
Hereditary and Sporadic Cerebral Microvascular Diseases Harry V. Vinters Departments of Pathology & Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA.
Corresponding author: Harry V. Vinters, MD, Departments of Pathology & Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA 90095-1732 (E-mail: [email protected]) Received 10 July 2014 Accepted 10 July 2014 doi:10.1111/bpa.12176
INTRODUCTION Cerebral microvascular disease (MVD), its pathogenesis and consequences for the brain, have been a career-long obsession and remain a major interest of my laboratory. The “interest” began when one of my residency mentors in London, Ontario, Dr. Joseph Gilbert, suggested we review a substantial number of spontaneous brain parenchymal hemorrhages— examined at necropsy—that we had encountered (in the late 1970s and early 1980s), and apparently originating from cerebral amyloid angiopathy (CAA). He proposed that an interesting companion study would be to examine the topography of CAA within the aging brain. The gold standard for detecting CAA in those “ancient times” was either the Congo red stain and polarization microscopy or a thioflavin stain with fluorescence microscopy; the A4ABeta/beta-amyloid peptide had yet to be discovered in 1984 (1, 4). The results of both investigations were published as back-to-back papers in Stroke, in 1983 (2, 5). We now know that meningocortical CAA is also associated with cerebral microinfarcts (3); severe CAA may result from mutations in the amyloid precursor protein gene (1). The genetics of (beta-amyloid) CAA are almost inseparable from the genetics of Alzheimer’s disease itself. By intent, the following mini-symposium deals with cerebral MVDs other than CAA, because the latter entity has been the subject of many detailed and extensive reviews in recent years— including some in the pages of Brain Pathology. It originates from the Saul Korey Lecture I was asked to present at the 2013 meeting of the American Association of Neuropathologists, entitled “Gain and pain from cerebral microvessels; adventures in vascular neuropathology.” With the discovery of genetically determined forms of non-CAA cerebral MVD such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke
494
(HERNS) and cerebroretinal vasculopathies—discussed at length in this issue—molecular genetics is beginning to inform our understanding of the cellular pathogenesis of sporadic MVD, the most common form of which is arteriolosclerosis (lipohyalinosis). Unfortunately arteriolosclerosis/lipoyhalinosis is “multifactorial” in origin, although this sporadic entity has similarities to several of the hereditary cerebral microangiopathies. Modern neuroimaging techniques have revolutionized our understanding of the consequences of cerebral MVD for brain parenchyma, even if small arteries, arterioles, venules and (certainly) capillaries are difficult or impossible to visualize, even using high-resolution radiographic techniques. Both hereditary and sporadic forms of cerebral MVD can now be studied using sophisticated quantitative immunohistochemical and morphometric techniques, applied to either autopsyor biopsy-derived human tissues. This mini-symposium will attempt to present and integrate our current state of understanding of this complex group of entities— how they contribute to stroke, “sub-infarctive” cerebral ischemic disease and cognitive impairment.
REFERENCES 1. Ellison D, Love S, Chimelli L, Harding BN, Lowe JS, Vinters HV et al (2013) Neuropathology. A Reference Text of CNS Pathology, 3rd edn. Mosby Elsevier: Edinburgh-London-New York, pp. 196–232. 2. Gilbert JJ, Vinters HV (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. I. Cerebral hemorrhage. Stroke 14:915–923. 3. Soontornniyomkij V, Lynch MD, Mermash S, Pomakian J, Badkoobehi H, Clare R, Vinters HV (2010) Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 20:459–467. 4. Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324. 5. Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:925–928.
Brain Pathology 24 (2014) 494 © 2014 International Society of Neuropathology
MINI-SYMPOSIUM: Pathology of Genetics of (non-CAA) Cerebral Microvascular Disease – Introduction
Hereditary and Sporadic Cerebral Microvascular Diseases Harry V. Vinters Departments of Pathology & Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA.
Corresponding author: Harry V. Vinters, MD, Departments of Pathology & Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA 90095-1732 (E-mail: [email protected]) Received 10 July 2014 Accepted 10 July 2014 doi:10.1111/bpa.12176
INTRODUCTION Cerebral microvascular disease (MVD), its pathogenesis and consequences for the brain, have been a career-long obsession and remain a major interest of my laboratory. The “interest” began when one of my residency mentors in London, Ontario, Dr. Joseph Gilbert, suggested we review a substantial number of spontaneous brain parenchymal hemorrhages— examined at necropsy—that we had encountered (in the late 1970s and early 1980s), and apparently originating from cerebral amyloid angiopathy (CAA). He proposed that an interesting companion study would be to examine the topography of CAA within the aging brain. The gold standard for detecting CAA in those “ancient times” was either the Congo red stain and polarization microscopy or a thioflavin stain with fluorescence microscopy; the A4ABeta/beta-amyloid peptide had yet to be discovered in 1984 (1, 4). The results of both investigations were published as back-to-back papers in Stroke, in 1983 (2, 5). We now know that meningocortical CAA is also associated with cerebral microinfarcts (3); severe CAA may result from mutations in the amyloid precursor protein gene (1). The genetics of (beta-amyloid) CAA are almost inseparable from the genetics of Alzheimer’s disease itself. By intent, the following mini-symposium deals with cerebral MVDs other than CAA, because the latter entity has been the subject of many detailed and extensive reviews in recent years— including some in the pages of Brain Pathology. It originates from the Saul Korey Lecture I was asked to present at the 2013 meeting of the American Association of Neuropathologists, entitled “Gain and pain from cerebral microvessels; adventures in vascular neuropathology.” With the discovery of genetically determined forms of non-CAA cerebral MVD such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke
494
(HERNS) and cerebroretinal vasculopathies—discussed at length in this issue—molecular genetics is beginning to inform our understanding of the cellular pathogenesis of sporadic MVD, the most common form of which is arteriolosclerosis (lipohyalinosis). Unfortunately arteriolosclerosis/lipoyhalinosis is “multifactorial” in origin, although this sporadic entity has similarities to several of the hereditary cerebral microangiopathies. Modern neuroimaging techniques have revolutionized our understanding of the consequences of cerebral MVD for brain parenchyma, even if small arteries, arterioles, venules and (certainly) capillaries are difficult or impossible to visualize, even using high-resolution radiographic techniques. Both hereditary and sporadic forms of cerebral MVD can now be studied using sophisticated quantitative immunohistochemical and morphometric techniques, applied to either autopsyor biopsy-derived human tissues. This mini-symposium will attempt to present and integrate our current state of understanding of this complex group of entities— how they contribute to stroke, “sub-infarctive” cerebral ischemic disease and cognitive impairment.
REFERENCES 1. Ellison D, Love S, Chimelli L, Harding BN, Lowe JS, Vinters HV et al (2013) Neuropathology. A Reference Text of CNS Pathology, 3rd edn. Mosby Elsevier: Edinburgh-London-New York, pp. 196–232. 2. Gilbert JJ, Vinters HV (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. I. Cerebral hemorrhage. Stroke 14:915–923. 3. Soontornniyomkij V, Lynch MD, Mermash S, Pomakian J, Badkoobehi H, Clare R, Vinters HV (2010) Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 20:459–467. 4. Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324. 5. Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:925–928.
Brain Pathology 24 (2014) 494 © 2014 International Society of Neuropathology
