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• W4225621567 abstract "HomeCirculationVol. 145, No. 14What Turns the White Matter White? Metabolomic Clues to the Origin of Age-Related Cerebral White Matter Hyperintensities Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWhat Turns the White Matter White? Metabolomic Clues to the Origin of Age-Related Cerebral White Matter Hyperintensities Eric E. Smith, MD, MPH Eric E. SmithEric E. Smith Correspondence to: Eric E. Smith, MD, MPH, Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3956-1668 Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. Search for more papers by this author Originally published4 Apr 2022https://doi.org/10.1161/CIRCULATIONAHA.122.059281Circulation. 2022;145:1053–1055This article is a commentary on the followingCirculating Metabolome and White Matter Hyperintensities in Women and MenWhat are white matter hyperintensities (WMHs), visible on brain magnetic resonance imaging, made of?1 In this issue of the journal, Sliz and colleagues2 use advanced methods to identify circulating metabolites that provide clues to the pathogenesis of these common age-related brain lesions. WMHs are regions of bright signal on T2-weighted magnetic resonance imaging sequences, reflecting increased water concentration in the tissue. Larger regions of WMH are also visible on computed tomography as areas of hypodensity. Histopathologically, they correspond to areas of demyelination, axonal loss, and microinfarction and are presumed to be caused by vascular dysfunction and disease.Article, see p 1040The volume of WMH increases with aging; however, it can vary substantially between individuals of the same age. Determining the prevalence of high WMH burden is challenging because of variation in WMH measurement methods and reporting, but data from cohort studies suggest that high burden, clinically defined as confluent or beginning confluent changes, can be seen in as many as 30% of persons >75 years old.3 Independent of age, high WMH burden is associated with vascular risk factors and with genetic forms of cerebral small vessel disease such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and hereditary cerebral amyloid angiopathy. High burden of WMH is associated with 2.45-fold higher risk for future stroke, 1.84-fold higher risk for future dementia, and 2.00-fold higher risk for death, controlling for age and vascular risk factors.4 WMH may be discovered on brain imaging for stroke or cognitive symptoms, but because it can be covert (that is, clinically unrecognized), it is frequently detected incidentally on brain imaging done for other reasons such as headache or dizziness.Because they are associated with vascular disease and can be measured easily, WMHs are the most commonly studied biomarker of cerebral small vessel disease and related vascular cognitive impairment and dementia. However, it goes mostly unrecognized that vascular risk factors such as hypertension explain only a small part of the variation in WMH. In the study by Sliz et al, individual vascular risk factors such as hypertension explained 1% or less of the variance of WMH in each of their cohorts.2 Analysis of other cohorts has also found that conventional vascular risk factors explain 2% or less of the variation in WMH.5 In contrast, conventional vascular risk factors and age account for more than half of the variance in carotid atherosclerotic plaque.5,6 Clearly, we understand much less about the pathogenesis of WMH than we do about atherosclerosis.In the study by Sliz et al, a working group from NeuroCHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) used the emerging techniques of metabolomics to seek new biomarkers of WMH.2 In metabolomics, methods such as mass spectrometry and high-performance liquid chromatography are used to measure hundreds, or even thousands, of products of metabolism from biological samples such as serum or saliva.7 Using these methods, they were able to test 2217 metabolites and lipoproteins in serum from participants in 8 community-based cohort studies.2 Accounting for multiple hypothesis testing using the false discovery rate method, they found associations between WMH and hydroxyphenylpyruvate (an amino acid metabolite), glucose metabolism products, lipids, cell membrane components (lysophosphatidylcholines), and myelin components (hydroxysphingomyelins). It is interesting, but of unclear significance, that they also found evidence of modification by sex, with most associations significant in men only.Previous work on WMH using -omics technologies has mostly focused on genetics in large populations. Genetics may explain up to half the variation in WMH between individuals.8 Genome-wide association studies in the general population have identified 36 loci associated with higher WMH volume with genome-wide significance.9 The biological mechanisms linking these genetic variations to higher WMH are still being investigated. Preliminary evidence points to associations with genes involved in sphingolipid metabolism, myelination, blood-brain barrier integrity, neurodevelopment, and Wnt signaling.9There are few previous studies of WMH and the metabolome. A study of patients diagnosed clinically with cerebral small vessel disease, found that several sphingolipids, glycerophospholipids, and amino acids were associated with higher WMH.10 Another study of participants from the general population, targeting 6 plasma phospholipids and sphingolipids previously associated with cognitive impairment, found that phosphatidylcholine aa C36:5 was associated with higher WMH.11Collectively, these different lines of evidence suggest multiple steps in the pathogenesis of WMH, including endothelial dysfunction, loss of blood-brain barrier integrity, and dysmyelination. They suggest that the oligodendrocyte is one of the key cells in the pathogenesis of WMH. Oligodendrocytes synthesize the myelin sheaths that surround axons, enabling more rapid propagation of axon potentials and supporting the health of the axon. Loss of myelin is the most widely seen neuropathological correlate of WMH, more so than axonal loss or microinfarction, which also occur but to a lesser degree.12 Genetic and metabolic influences on the susceptibility of the oligodendrocyte to hypoxic injury, or response to injury by repair, may underlie some of the variation in WMH between individuals, potentially explaining why some patients with hypertension and other vascular risk factors have more WMH than others.Still, many questions remain unanswered. The precise links between vascular disease and oligodendrocyte function are not clear. However, the mediators between ischemia and oligodendrocyte survival and function are beginning to be explored in model systems.13 It remains difficult to assess gene expression in the living brain. Clues from the blood, like the metabolite differences in the study by the NeuroCHARGE group, are important but may not reflect what is happening in the brain, which is kept biochemically distinct from the blood by the blood-brain barrier. Analysis of cerebrospinal fluid may provide a better view of the brain metabolic environment, but because lumbar puncture is required to obtain cerebrospinal fluid, it is not feasible at the same scale as blood sampling. Additional experimentation will be needed to determine which metabolites are related to the causal pathway to WMH, which are related to the effects of WMH on function and nutrition, and which are related to confounding factors such as vascular risk–reducing medicines (eg, statins). Metabolomic profiling can be vulnerable to error from multiple hypothesis testing, and this potential vulnerability will only increase as advances in chemistry allow detection of more classes of metabolites. This multiple-hypothesis testing error can be addressed by analyzing metabolite pathways instead of individual metabolites and, with aggregation of sufficiently large datasets, testing for metabolome-wide significance using conservative methods like Bonferroni correction. The comparability of chemical methods across different laboratories must be established.Although the molecular pathogenesis of WMH remains incompletely defined, advances in high-throughput technologies will undoubtedly continue to provide more clues. These technologies will include metabolomics, genomics, proteomics, and, potentially, microbiomics.14 Ultimately, a molecular signature could be developed to identify persons at risk for white matter degeneration, obviating the need for expensive magnetic resonance imaging scans to identify WMH. However, much more extensive validation, standardization, and commercialization are needed before these technologies can be applied routinely in the clinic for diagnostic or prognostic purposes. Instead, the most promising application of these technologies may be to discover new pathways to WMH that could be targeted with drugs. Currently, the only therapy with moderate evidence to reduce progression of WMH is lowering blood pressure.15 However, additional preventive strategies would be welcome to reduce the substantial risk of stroke and cognitive decline in older persons with high WMH burden.Article InformationSources of FundingNone.Disclosures The author reports grant funding from the Canadian Institutes of Health Research and Weston Brain Institute; research services contracts to the University of Calgary from McMaster University, Ottawa Heart Institute, and Sense Diagnostics; and personal consulting for Bayer, Biogen, and Cyclerion.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1054.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Eric E. Smith, MD, MPH, Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada. Email [email protected]caReferences1. Wardlaw JM, Valdés Hernández MC, Muñoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment.J Am Heart Assoc. 2015; 4:001140. doi: 10.1161/JAHA.114.001140LinkGoogle Scholar2. Sliz E, Shin J, Ahmad S, Williams DM, Frenzel S, Gauß F, Harris SE, Henning A-K, Valdes Hernandez M, Hu Y-H. Circulating metabolome and white matter hyperintensities in women and men.Circulation. 2022;145:1040–1052. doi: 10.1161/CIRCULATIONAHA.121.056892LinkGoogle Scholar3. Smith EE, Saposnik G, Biessels GJ, Doubal FN, Fornage M, Gorelick PB, Greenberg SM, Higashida RT, Kasner SE, Seshadri S; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Council on Hypertension. 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Extremes of unexplained variation as a phenotype: an efficient approach for genome-wide association studies of cardiovascular disease.Circ Cardiovasc Genet. 2010; 3:215–221. doi: 10.1161/CIRCGENETICS.109.934505LinkGoogle Scholar7. Wishart DS. Metabolomics for investigating physiological and pathophysiological processes.Physiol Rev. 2019; 99:1819–1875. doi: 10.1152/physrev.00035.2018CrossrefMedlineGoogle Scholar8. Atwood LD, Wolf PA, Heard-Costa NL, Massaro JM, Beiser A, D’Agostino RB, DeCarli C. Genetic variation in white matter hyperintensity volume in the Framingham Study.Stroke. 2004; 35:1609–1613. doi: 10.1161/01.STR.0000129643.77045.10LinkGoogle Scholar9. Bordes C, Sargurupremraj M, Mishra A, Debette S. Genetics of common cerebral small vessel disease.Nat Rev Neurol. 2022; 18:84–101. doi: 10.1038/s41582-021-00592-8CrossrefMedlineGoogle Scholar10. Harshfield EL, Sands CJ, Tuladhar AM, de Leeuw FE, Lewis MR, Markus HS. 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Association of intensive vs standard blood pressure control with cerebral white matter lesions.JAMA. 2019; 322:524–534. doi: 10.1001/jama.2019.10551CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCirculating Metabolome and White Matter Hyperintensities in Women and MenLenore Launer, et al. Circulation. 2022;145:1040-1052 April 5, 2022Vol 145, Issue 14 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.059281PMID: 35377744 Originally publishedApril 4, 2022 KeywordsEditorialsmetabolomeleukoaraiosisPDF download Advertisement SubjectsCerebrovascular Disease/Stroke" @default.
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• W4225621567 title "What Turns the White Matter White? Metabolomic Clues to the Origin of Age-Related Cerebral White Matter Hyperintensities" @default.
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