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Brain arterial aging and its relationship to Alzheimer dementia
Abstract
Objective:
To test the hypothesis that brain arterial aging is associated with the pathologic diagnosis of Alzheimer disease (AD).
Methods:
Brain large arteries were assessed for diameter, gaps in the internal elastic lamina (IEL), luminal stenosis, atherosclerosis, and lumen-to-wall ratio. Elastin, collagen, and amyloid were assessed with Van Gieson, trichrome, and Congo red staining intensities, and quantified automatically. Brain infarcts and AD (defined pathologically) were assessed at autopsy. We created a brain arterial aging (BAA) score with arterial characteristics associated with aging after adjusting for demographic and clinical variables using cross-sectional generalized linear models.
Results:
We studied 194 autopsied brains, 25 (13%) of which had autopsy evidence of AD. Brain arterial aging consisted of higher interadventitial and lumen diameters, thickening of the wall, increased prevalence of IEL gaps, concentric intima thickening, elastin loss, increased amyloid deposition, and a higher IEL proportion without changes in lumen-to-wall ratio. In multivariable analysis, a high IEL proportion (B = 1.96, p = 0.030), thick media (B = 3.50, p = 0.001), elastin loss (B = 6.16, p < 0.001), IEL gaps (B = 3.14, p = 0.023), and concentric intima thickening (B = 7.19, p < 0.001) were used to create the BAA score. Adjusting for demographics, vascular risk factors, atherosclerosis, and brain infarcts, the BAA score was associated with AD (B = 0.022, p = 0.002).
Conclusions:
Aging of brain large arteries is characterized by arterial dilation with a commensurate wall thickening, elastin loss, and IEL gaps. Greater intensity of arterial aging was associated with AD independently of atherosclerosis and brain infarcts. Understanding the drivers of arterial aging may advance the knowledge of the pathophysiology of AD.
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Author and article information
Contributors
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Bristol Myer Squibb, C2N, Eli Lilly, Forum, Genentech, Janssen/Johnson & Johnson, Lundbeck, Merck, Pfizer, Roche, TauRx, vTv Pharmaceutical companies.
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NIH/NIA P50AG08702, Core Leader, 2006- NIH/NIA U01AG023749, Coinvestigator, 2009- NIH/NIA U01AG016976, Coinvestigator, 2000- NIH/NINDS R01NS083976, Coinvestigator, 2014- NIH/NIA R01AG037212, Coinvestigator, 2012-
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(1) Boehringer-Ingelheim, Inc., anticoagulants and stroke (2014-2015); (2) BMS-Pfizer Partnership,anticoagulants and stroke (2014-2015); (3) Daiichi-Sankyo, anticoagulants and stroke (2013-2014); (4) Janssen Pharmaceuticals, anticoagulants and stroke (2013-2014); (5)Biogen IDEC, natalizumab and stroke (2013); (6) Biotelemetry/Cardionet, monitoring for atrial fibrillation after stroke (2014); Sanofi-Regeneron Partnership, alirocumab for atherosclerotic disease (2015)
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(1) Neurology, Resident and Fellow Section editor, published by American Academy of Neurology (2007-2015)
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UpToDate, 2015, chapters on cryptogenic stroke and hemicraniectomy for acute stroke
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(1) American Heart Association National Board of Directors (2014-2016); (2) American Heart Association Founders Affiliate Board of Directors(2008-2013); (2) American Heart Association NY City Board of Directors (2011-2015)
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(1) NIH/NINDS R37 29993, PI, 2007-2020 (2) NIH/NINDS P50 NS049060, Project 1, PI, NeuSTART, 2004- 2016
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Editorial Board, Neuropathology, 1996-present Editorial Board, Acta Neuropathologica, 2004- present Editorial Board, ASN Neuro, 2008-present Editorial Board, Frontiers in Neurogenesis, 2009-present Editorial Board, Developmental Neurobiology, 2009-present Editorial Board, Experimental Neurology, 2000-present
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Schwartz JH, Barres BA, Goldman JE: The Cells of the Nervous System. In PRINCIPALS OF NEUROSCIENCE 5th ed., Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (eds). McGraw Hill, New York, 2013, pp.71-99. Valentin J and Goldman, JE: Neuropathology, in ANATOMIC PATHOLOGY BOARD REVIEW, 2nd ed. Lefkowitch JH (ed.) Saunders Elsevier, Philadelphia, 2014,
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DOD TS110056 (David Sulzer, PI, James E. Goldman, Co-PI) ?Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder? Award Period: 07/2012 ? 06/2015 DOD TS140034 (James E. Goldman, PI) ?Molecular mechanisms underlying the epileptogenesis and seizure progression in TSC1 deficient mouse models Award Period: 07/01/15 - 06/30/18
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NMSS RG 4791A6/2 National Multiple Sclerosis Society (James E. Goldman, PI) ?HGF : c-Met signaling in oligodendrocyte development and its inhibition by CD82? Award Period: 10/01/13 ? 09/31/16
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D. Active Support 5 R01 MH64168-10 (Dwork) NIMH 08/01/01 - 03/31/15 (NCE) Golgi Studies of Schizophrenia Role: Principal Investigator Uses Golgi stains to examine the structure of dendrites and spines in archival brain specimens from schizophrenia and nonpsychiatric cases. Also supports collection and analysis of brains and clinical histories from the Republic of Macedonia for use in NIMH-supported post mortem studies of psychiatric disorders. 2 R01 MH083862-06A1 (Boldrini) NIMH 05/23/14 - 04/30/19 Adult hippocampal neuroplasticity and depression Role: Co-Investigator Characterizes human adult neurogenesis in normal subjects and individuals with mood disorders and suicide and the effects of antidepressants treatment on human adult neurogenesis. 5 P50 MH090964-02 (Mann) 07/19/13 - 06/30/18 NIMH Role on Project: Co-Investigator Conte Center: Neurobiological and Developmental Antecedents to Suicidal Behavior The Conte Center will employ a multidisciplinary approach to study how reported childhood adversity can mold the diathesis for suicidal behavior. These projects will help elucidate how early adverse experiences affect gene expression and brain biology to increase risk of suicidal behavior later in life. 5 R01 MH094774-04 (Haghighi) NIMH 09/15/11 - 06/30/16 Neurodevelopmental Profiling of the Epigenome in Human and Rhesus Role: Co-Investigator Characterizes whole-genome DNA and histone methylation marks within brains of human and rhesus macaque, using state of the art ultra-high throughput sequencing technology. 5 R01 MH083990-05 (Perera) NIMH 01/06/10 - 11/30/15 (NCE) Necessity of Neurogenesis for Antidepressant Efficacy Role: Co-Investigator Study of the necessity of hippocampal neurogenesis for efficacy of the antidepressant, fluoxetine, in nonhuman primates models of depression. Exploring groups of depressed vs non-depressed animals, drug treatment vs. placebo, and irradiated (to ablate development of new neurons in the hippocampus) vs. non-irradiated animals. 5 R01 MH098786-03 (Dwork/Rosoklija; Multi-PI) NIMH/Fogarty 09/18/12 - 06/30/17 Building Schizophrenia Research in Macedonia Role: Principal Investigator This is a collaboration between scientists in Macedonia and the US to train and equip Macedonian scientists and institutions for state-of-the-art use of electron microscopy, stereology, image analysis, RNA-seq, and label-free proteomics in the context of continuing studies of white matter in schizophrenia. Major Equipment Grant (Hen) NYSTEM 04/01/14 - 03/31/18 Imaging stem cells in the brain for studying neuropsychiatric disorders Role: Major User Equipment grant for transparent brain imaging. 5 R01 MH080116-05 (Gingrich) NIMH 0 4/01/08 - 11/30/13 Serotonin and the Modulation of Brain Development Role: Co-Investigator Five year project that will increase our understanding of which developmental periods are sensitive to SERT inhibition and advance understanding of the mechanisms that might explain this phenomenon. Young Investigator Award (Aly) NARSAD 08/01/11 - 07/31/13 Seizures and synaptogenesis: Mechanisms and safety of convulsive therapy Role: Mentor Brain sections from nonhuman primates subjected to electrically- or magnetically-induced seizures will be studied for synaptic density, microglial activation, and thrombospondins. 5 R01 MH40210-26 (Arango) NIMH 02/01/90 - 04/30/12 Postmortem Neurochemical Studies in Suicide Role: Co-Investigator Aims to determine: 1) whether alterations in the serotonergic system in violent suicide victims are localized to specific brain regions beyond the prefrontal cortex; 2) the biochemical specificity of alterations in the serotonergic system; 3) neurochemical differences attributable to suicide versus major depression; and 4) molecular underpinnings of serotonin dysfunction. 5 R01 MH060877-13 (Dwork) NIMH 09/30/91 - 08/31/12 Myelin Pathology in Schizophrenia Role: Principal Investigator This study seeks to identify stereological, biochemical and histological abnormalities of white matter in prefrontal and cingulate regions in schizophrenia and to determine whether these parameters are related to cognitive function in this disease.
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American Foundation for Suicide Prevention. Grant# SRG-0- 129-12. (Boldrini).10/01/13 - 09/30/15.Hippocampal Neurogenesis in Suicide.Role: Co-Investigator. This study attempts to distinguish between the associations of depression and suicide with depressed or enhanced neurogenesis. American Foundation for Suicide Prevention. Grant# DIG-0- 041-13. (Dwork).10/01/14 - 09/30/16. Autopsy Studies of Potential Targets of In Vivo Imaging for Suicide Risk. Role: Principal Investigator. Immunohistochemical and receptor autoradiography studies of microglia and macrophages in prefrontal white matter of individuals who died by suicide, compared with individuals with and without psychiatric disease who died in a different manner. American Heart Association.Grant#13CRP14800040. (Gutierrez).07/01/13 - 06/30/14. Contribution of HIV Infection to Intracranial Vascular Remodeling: A Case Control Study Role: Mentor This study compares the morphology of HIV-induced changes in cerebral blood vessels with those induced by other causes. National Alliance for Schizophrenia and Depression. Grant# none. Independent Investigator Award. (Dwork).03/15/09 - 03/14/12 Subicular Region Association Fibers in Development and Schizophrenia. Role: Principal Investigator.Examine hippocampal myelination in autopsy subjects with and without schizophrenia.
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Not-for-profit; Advisory Board member, Temple University Comprehensive NeuroAIDS Center (CNAC)
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Journal of Neurovirology, editorial board, 2001 to present, no compensation received
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NIH: R24MH59724, U01MH083501, U24MH100931, PI, 1998-present R25MH080663, PI, 2007-present R01MH107345, Subsite PI, 2015-present R01DA037611, Subsite PI, 2014-present R21NR015009, Subsite PI, 2015-present
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Assorted Grand Rounds talks sponsored by the academic institution, topics of stroke treatment and stroke recovery, (no corporate sponsorship), 2000-present
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(1) JAMANeurology, Editorial Board, 2013 - present (2) Stroke, Editorial Board, 2012, 2012 - present (3) Neurology Editorial Board, 2014-present (4) Annals of Neurology Editorial Board, 2013-present
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NINDS 1R01NS076277 2012-2017 Co-PI NINDS 1U10 NS086728 2013-2018 PI NINDS 1U01 NS086872 2013-2018 Co-I NINDS 1R01 NS080168 2014-2020 Site PI
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Affiliations
Author notes
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 article.