Genomic Susceptibility Loci for Brain Atrophy, Ventricular Volume, and Leukoaraiosis in Hypertensive Sibships

Turner, Stephen T.; Fornage, Myriam; Jack, Clifford R.; Mosley, Thomas H.; Knopman, David S.; Kardia, Sharon L.R.; Boerwinkle, Eric; Andrade, Mariza de

doi:10.1001/archneurol.2009.110

Cited by 25 publications

(28 citation statements)

References 76 publications

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“…‡Additionally adjusted for history of hypertension, stroke, hypercholesterolemia, current smoking, family history of stroke, diabetes, height, and brachial systolic and diastolic BP. the latter hypothesis is supported by independent genetic associations with leukoaraiosis, 26 superficially similar white matter disease in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 27 and COL4A1 mutations, 28 and the demonstration of increased blood-brain barrier permeability in patients with leukoaraiosis both in lesions and in normal-appearing white matter. 5,24 However, ultimately it is likely that these 2 mechanisms are not mutually exclusive.…”

Section: Discussionmentioning

confidence: 91%

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis

Webb

Simoni²,

Mazzucco³

et al. 2012

Stroke

273

174

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Background and Purpose-Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods-Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Gosling's index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results-In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, PϽ0.0001).Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: 2 ϭ0.39, MCA-PI Pϭ0.01, aortic pulse wave velocity Pϭ0.06; age-related white matter change: 2 ϭ0.38, MCA-PI Pϭ0.015; aortic pulse wave velocity Pϭ0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r 2 ϭ0.68, PϽ0.0001), MCA-PI was independently associated with aortic pulse wave velocity (Pϭ0.016) and aortic pulse pressure (PϽ0.0001) and inversely associated with aortic diastolic blood pressure (PϽ0.0001) and MCA transit time (Pϭ0.001). Conclusions-MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis. (Stroke. 2012;43:2631-2636.)Key Words: arterial stiffness Ⅲ cerebral pulsatility Ⅲ etiology Ⅲ leukoaraiosis Ⅲ white matter disease P revention of premature leukoaraiosis by treating the underlying causes in middle age may reduce the risk of stroke 1 and dementia 2 and other consequences of cerebral small vessel disease, 3,4 but the etiology is not yet fully understood. The relative importance of hemodynamic factors as opposed to a primary microangiopathy 5 in the development of leukoaraiosis is unclear and associations with age, hypertension, and diabetes are consistent with both processes. 6 Previous studies have suggested a relationship between increased middle cerebral artery (MCA) pulsatility measured by transcranial Doppler ultrasound and leukoaraiosis or lacunar infarction in patients with hypertension 7 and diabetes, 8 although not necessarily independent of age. However, increased cerebral pulsatility has often been interpreted as a...

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Section: Discussionmentioning

confidence: 91%

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis

Webb

Simoni²,

Mazzucco³

et al. 2012

Stroke

273

174

View full text Add to dashboard Cite

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“…4,26 The candidate gene approach has supported the role of apolipoprotein E, the renin-angiotensin system, and the Notch3 signaling pathway in the development of WMH. 21 Several genome-wide linkage studies 10,[29][30][31][32] have shown linkages to chromosomes 4, 1, 5, and 11, respectively, but independent replication has not occurred. A large genome-wide association study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Figure 3.…”

Section: Strokementioning

confidence: 99%

“…21 Several genome-wide linkage studies 10,[29][30][31][32] have shown linkages to chromosomes 4, 1, 5, and 11, respectively, but independent replication has not occurred. A large genome-wide association study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) …”

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confidence: 99%

White Matter Hyperintensities Are Under Strong Genetic Influence

Sachdev

Thalamuthu

Mather

et al. 2016

Stroke

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W hite matter hyperintensities (WMH) are signal changes in the white matter seen on T2-weighted magnetic resonance imaging which are frequent incidental findings in otherwise healthy middle-aged and elderly individuals.1-3 WMH do not have a specific pathogenesis, but those seen in asymptomatic older individuals are likely to be ischemic in origin and are associated with arteriosclerosis and vascular risk factors (eg, hypertension, diabetes mellitus, coronary artery disease, high homocysteine levels). 4 These vascular risk factors, however, account for only a proportion of the variance in WMH, and studies have shown that genetic factors possibly make a major contribution. 5 Evidence for genetic contributions to WMH comes from various sources. Several gene mutations have been described leading to monogenic disorders manifesting with WMH, such as Fabry disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, 5 but these are rare. Single nucleotide polymorphisms as genetic risk markers for WMH, either directly or through their interactions with medical risk factors, have been investigated using candidate gene 5 and genome-wide association studies, 6,7 but there have been few independent replications.Considering that the genetic basis of WMH is still unclear, it is important to quantify what proportion of variance in these lesions is genetically determined. Heritability studies quantify the degree to which a trait is passed from parent to offspring and is expressed as the ratio of the additive genetic variance to the total phenotypic variance. 8 High WMH heritability was reported in a study of older male twins, comprising 74 monozygotic (MZ) and 71 dizygotic (DZ) pairs (0.73) 9 and in 2 family studies. 10,11 However, several deficiencies in the literature remain. Although the classic twin method is the best technique for examining heritability of a trait, 8 only 1 prior twin study has estimated WMH heritability but in men only. 9 In fact, there is evidence of sexual dimorphism in WMH. 12 It is arguable that WMH are not a uniform category, and at Background and Purpose-The genetic basis of white matter hyperintensities (WMH) is still unknown. This study examines the heritability of WMH in both sexes and in different brain regions, and the influence of age. Methods-Participants from the Older Australian Twins Study were recruited (n=320; 92 monozygotic and 68 dizygotic pairs) who volunteered for magnetic resonance imaging scans and medical assessments. Heritability, that is, the ratio of the additive genetic variance to the total phenotypic variance, was estimated using the twin design. Results-Heritability was high for total WMH volume (0.76), and for periventricular WMH (0.64) 13 The present study was performed to address some of these concerns. Methods ParticipantsParticipants were drawn from the Older Australian Twins Study (OATS), a study of elderly MZ-DZ twin pairs living in the 3 Eastern states of Australia and registered with the Australian Twin Registry. De...

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“…110 Finally, linkage studies have identified several chromosomes with shared loci associated with WMH volumes and also with blood pressure parameters, suggesting pleiotropic genes might exist in these locations. 111,112 New genetic technology including exome sequencing and epigenetics will probably be used in the coming years and might add new players to the field.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

Vilar-Bergua

Riba‐Llena

Nafría

et al. 2015

J Cereb Blood Flow Metab

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Vascular dementia is the second most common type of dementia after Alzheimer's disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral smallvessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.

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Genomic Susceptibility Loci for Brain Atrophy, Ventricular Volume, and Leukoaraiosis in Hypertensive Sibships

Cited by 25 publications

References 76 publications

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis

White Matter Hyperintensities Are Under Strong Genetic Influence

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

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