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    Bo Norrving - Hypertension and Ageing Related SADB

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    In the early literature reports on SADB hypertension was considered a characteristic feature, and even considered mandatory for the development of lacunar infarcts. However, later studies have shown that the prevalence of hypertension is similar in lacunar and non-lacunar infarcts. Many patients with SADB are not hypertensive. For silent cerebral infarcts (mostly caused by SADB) and white matter hyperintensities of presumed ischemic origin, hypertension along with age have been the most consistent risk factors across studies. Recent studies using MRI have shown that high blood pressure affects brain morphometrics already in early mid-age. In most studies a simplistic definition of hypertension has been used. However, blood pressure vaiability appears to equally important as blood pressure levels in the relation to stroke. Also, the genetical co-variance between hypertension and SADB is a resaech area that is currently being explored. Whereas many pathophysiological links between hypertension and SADB remains to be further studied, the practical importance of control of hypertension in the population should be widely recognized as hypertension remains the single most important modifiable risk factor for stroke.

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    Bo Norrving - Hypertension and Ageing Related SADB

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    Fondation Singer-Polignac
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    In the early literature reports on SADB hypertension was considered a characteristic feature, and even considered mandatory for the development of lacunar infarcts. However, later studies have shown that the prevalence of hypertension is similar in lacunar and non-lacunar infarcts. Many patients with SADB are not hypertensive. For silent cerebral infarcts (mostly caused by SADB) and white matter hyperintensities of presumed ischemic origin, hypertension along with age have been the most consistent risk factors across studies. Recent studies using MRI have shown that high blood pressure affects brain morphometrics already in early mid-age. In most studies a simplistic definition of hypertension has been used. However, blood pressure vaiability appears to equally important as blood pressure levels in the relation to stroke. Also, the genetical co-variance between hypertension and SADB is a resaech area that is currently being explored. Whereas many pathophysiological links between hypertension and SADB remains to be further studied, the practical importance of control of hypertension in the population should be widely recognized as hypertension remains the single most important modifiable risk factor for stroke.

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    In the early literature reports on SADB hypertension was considered a characteristic feature, and even considered mandatory for the development of lacunar infarcts. However, later studies have shown that the prevalence of hypertension is similar in lacunar and non-lacunar infarcts. Many patients with SADB are not hypertensive. For silent cerebral infarcts (mostly caused by SADB) and white matter hyperintensities of presumed ischemic origin, hypertension along with age have been the most consistent risk factors across studies. Recent studies using MRI have shown that high blood pressure affects brain morphometrics already in early mid-age. In most studies a simplistic definition of hypertension has been used. However, blood pressure vaiability appears to equally important as blood pressure levels in the relation to stroke. Also, the genetical co-variance between hypertension and SADB is a resaech area that is currently being explored. Whereas many pathophysiological links between hypertension and SADB remains to be further studied, the practical importance of control of hypertension in the population should be widely recognized as hypertension remains the single most important modifiable risk factor for stroke.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    2K views50 pages

    Bo Norrving - Hypertension and Ageing Related SADB

    Uploaded by

    Fondation Singer-Polignac
    In the early literature reports on SADB hypertension was considered a characteristic feature, and even considered mandatory for the development of lacunar infarcts. However, later studies have shown that the prevalence of hypertension is similar in lacunar and non-lacunar infarcts. Many patients with SADB are not hypertensive. For silent cerebral infarcts (mostly caused by SADB) and white matter hyperintensities of presumed ischemic origin, hypertension along with age have been the most consistent risk factors across studies. Recent studies using MRI have shown that high blood pressure affects brain morphometrics already in early mid-age. In most studies a simplistic definition of hypertension has been used. However, blood pressure vaiability appears to equally important as blood pressure levels in the relation to stroke. Also, the genetical co-variance between hypertension and SADB is a resaech area that is currently being explored. Whereas many pathophysiological links between hypertension and SADB remains to be further studied, the practical importance of control of hypertension in the population should be widely recognized as hypertension remains the single most important modifiable risk factor for stroke.

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    Hypertension and ageing related small artery diseases of the brain (SADB)

    Bo Norrving Department of Neurology Lund University Hospital Sweden

    CADASIL symposium Paris, Sept 19-20, 2013

    Disclosure statement
    Steering and endpoint committees, DSMB: Servier, Syngis, Photothera Honoraria for presentations: Allergan, Bayer, BoehringerIngelheim
    No conflicts of interest related to this presentation

    The 2010 Global Burden of Disease Study

    Hypertension the most important risk factor globally

    Lancet Dec 15, 2012

    Global risk factor ranks 1990 and 2010


    1990 Childhood underweight Household air pollution Smoking High blood pressure Suboptimal breest feeding 2010 High blood pressure Smoking Household air pollution Low fruit Alcohol use % change 27 % 3% -32 % 29 % 32 %

    Lancet Dec 15, 2012

    Changes in life expectency 1970 to 2010

    Males: increase from 56.4 years to 67.5 years Females: increase from 61.2 years to 73.3 years

    Lancet Dec 15, 2012

    INTERSTROKE: Population-attributable risk for common risk factors


    Risk factor Populationattributable risk, % (99% CI) 34.6 (30.439.1) 18.9 (15.323.1) 26.5 (18.836.0) 18.8 (11.229.7) 28.5 (14.548.5) 5.0 (2.69.5) 3.8 (0.914.4) 6.7 (4.89.1) 24.9 (15.737.1) 4.6 (2.19.6) 5.2 (2.79.8)

    Hypertension Smoking Waist-to-hip ratio (tertile 2 vs tertile 1) Dietary risk score (tertile 2 vs tertile 1) Regular physical activity Diabetes Alcohol intake Cardiac causes Ratio of apolipoprotein B to A1 (tertile 2 vs tertile 1) Psychological factors Stress Depression

    O'Donnell MJ et al. Lancet 2010

    INTERSTROKE: major findings


    10 modifiable risk factors explain 90 % of stroke
    The population attributable risk for hypertension was almost twice higher than for coronary heart Disease (INTERHEART); 34.8 % vs 18 %

    Lacunar stroke how important is hypertension?

    Lavados et al. Lancet Neurology 2007;6:140-48

    Wu et al. Cerebrovasc Dis 2010;29:181-87

    42.3 % lacunar

    Does the risk factor profile differ between lacunar infarcts and other types of brain infarct?
    Classification bias for lacunar infarcts?
    TOAST-classification: small vessel disease category: - Lacunar syndrome - Brain imaging normal or relevant lesion <1.5 cm - A history of hypertension and diabetes supports the diagnosis - No cardiac source of embolism - No large artery stenosis >50 %

    Hypertension more common in lacunar stroke than other subtypes in studies with classification bias

    1.25 (1.21-1.28)

    Jackson and Sudlow. Are lacunar strokes really different? Stroke 2005.;36:891-904

    Only marginal excess of hypertension in studies with risk-factor free definitions

    1.11 (1.04-1.19) Jackson and Sudlow. Are lacunar strokes really different? Stroke 2005.;36:891-904

    Are lacunar syndromes specific for small vessel disease?


    Most studies on lacunar stroke are based on CT scan findings Definitions vary: only patients with a visualized infarct, or also patients with normal CT scan findings

    Associations of clinical stroke misclassifications (clinical-imaging dissociation) in acute ischemic stroke


    137 patients with a mild cortical or lacunar syndrome had an acute ischemic lesion on DWI.

    21/93 (23%) with a cortical syndrome had an acute lacunar infarct


    7/44 (16%) with a lacunar syndrome had an acute cortical infarct.
    Potter G et al. Cerebrovasc Dis 2010;29:395402

    Comparison between OCSP subtypes and dw-MRI findings


    Clinical features (and negative CT) very uncertain basis for diagnosis of lacunar infarct.
    Positive predictive value for lacunar infarct from LACI subtype only 40-60 %

    Asdaghi et al. Stroke 2011;42:2143-48

    Acute small subcortical infarctions on diffusion weighted MRI: clinical presentation and aetiology.
    93 patients with subcortical or brainstem DWI lesions <1.5 cm in diameter <7 days from the onset of stroke symptoms. Only 41 (44.1%) patients presented clinically with a lacunar syndrome according to OCSP criteria.

    Seifert et al. J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1520-4.

    Lancet Aug 10 2013

    Silent cerebral infarcts

    Prevalence of silent cerebral infarcts in the population: overview of studies

    Vermeer et al. Lancet Neurology 2007;6:611-619

    19 out of 20 silent infarcts are subcortical

    Vermeer et al. Stroke 2002;33:21-25

    Silent cerebral infarct: risk factors

    Vermeer et al. Lancet Neurology 2007;6:611-619

    Is a lacune always the result of an old infarct?

    Moreau et al. Stroke 2012;43:1837-42

    A differential diagnosis: perivascular (Virchow-Robin) spaces

    Wardlaw J et al. Lancet Neurology 2013;12:483-97

    Characteristics of SVD-related MR imaging findings

    Recent small subcortical infarct Usual diameter1 Comment < 20 mm best identified on DWI h

    White matter hyperintensity variable located in white matter 1

    Lacune 3 -15 mm usually have hyperintense rim 1 /(i)

    Perivascular space < 2mm usually linear without hyperintense rim 1

    Cerebral microbleeds < 10 mm detected on GRE seq., round or ovoid, blooming 1

    DWI

    FLAIR
    T2 T1 T2* / GRE

    h
    h i 1

    h
    h 1 /(i) h

    i
    h i 1 (i if hemorrage)

    i
    h i 1

    i
    i 1 ii

    The Centers of Excellece in Neurodegeneration Vascular Imaging Standards Working Group. Lancet Neurology 2013

    Do all symptomatic lacunar infarcts cavitate?

    28-94 % of symptomatic lacunar infarcts cavitate: definition, time interval, location, MRI sequence
    Potter et al. Stroke 2010;41:267272 Moreau F et al. Stroke 2012;43:1837-42

    Common late sequelae of acute small deep infarcts

    Disappeared

    Turned into WMH

    Cavitated (lacune)

    Wardlaw J et al. Lancet Neurology 2013;12:483-97

    acute

    stroke symptoms, no visible lesion

    small subcortical infarct

    large subcortical infarct (e.g. striatocapsular)

    other lesion (e.g. small deep ICH, inflammatory lesion)

    time

    chronic

    lacune

    white matter hyperintensity

    normal or nearly normal MRI

    The Centers of Excellece in Neurodegeneration Vascular Imaging Standards Working Group. Lancet Neurology 2013

    Silent subcortical infarcts and white matter disease often coexist

    Kuller et al. Stroke 2004;35:1821-25

    Part of WMD is due to old infarcts .

    Silent cerebral infarcts

    White Matter Hyperintensities

    Clinical caveats in silent brain infarcts


    May have been truly silent i e did not cause acute neurological dysfunction
    But - symptoms may have been forgotten - infarct may have been minimally symptomatic - may have been a TIA - ischemic event during sleep

    What makes small deep infarcts symptomatic?

    Localization is the key: involvement of motor and sensory long tracts subcortically

    Symptomatic and silent small deep infarcts; is it the same disease?

    Brain Pathology 2012;22:583-91

    ICD 11 Cerebrovascular Diseases single block In the Diseases of the Nervous System chapter
    Cerebrovascular disease with no acute cerebral symptoms
    Silent cerebral infarct Definition: Cerebral infarct that has not caused acute focal dysfunction of the brain Silent cerebral microbleed Definition: Small bleeding in the brain parenchyma that has not caused acute focal dysfunction of the brain Silent white matter abnormalities associated with vascular disease Definition: Abnormalities in the cerebral white matter of proven or assumed vascular origin

    Silent cerebral microbleeds 1(2)


    4 population based studies
    N 280 472 1962 1062 Mean age 60 64.4 76 69.6 Prevalence 6.4 % 4.7 11.1 23.5

    Austrian Stroke Prevention Study Framingham Study AGES-Reykjavik study Rotterdam Scan Study

    ASPS: hypertension a RF Rotterdam: hypertension a RF for deep microbleeds

    Age groups included MR equipment Study power for RF and subgroup analyses

    Silent cerebral microbleeds 2(2)


    Patients with lacunar stroke1
    Several blood pressure indices associated with microbleeds (in particular deep microbleeds)

    Patients with CADASIL2


    Hba1c, LDL, and systolic blood pressure associated with higher probability of any microbleed Systolic P and hypertension associated with multiple CMBs

    1 Staals

    et al, Stroke 2009;40:3264-8 2 Viswanathan et al. Brain 2006;129:2375-83

    Genetics related to

    - stroke subtype (small vessel stroke)


    - intermediate fenotype (hypertension)

    Metastroke

    Traylor et al. Lancet Neurol 2012;11:951-962. See also Bellenguez et al. Nat Gen 2012;44:328-333.

    Chromosome 6p21.1

    LAA

    Holliday et al. Nature Genetics 2012;44:1147-1151.

    AB0 locus on chromosome 9


    Known that non-0 bloodgroups are related to stroke risk
    Genomewide significance, related to coagulation/fibrin phenotypes

    Rs505922 (vWF in ABO-gene), related to Stroke, p=0.023

    Williams et al. Ann Neurol 2013;73:16-31.

    Rs505922, chromosome 9 related to: Ischemic stroke p=0.001 CE p=0.0002 LAA p=0.001 SVD p=ns

    Modified, from: Bevan et al. Curr Atheroscler Rep 2013,15:342

    GCTA Genomewide complex trait analysis


    Allows estimation of heritability by assessing all SNPs in the model

    For all stroke 37.9% heritability


    Bevan et al. Stroke 2012;43;3161-3167.

    Intermediate phenotype: Hypertension


    Risk score of 29 variants related to hypertension was related to stroke

    Ehret et al. Nature 2011.

    Blood pressure variability

    Rothwell PM. Lancet 2010;375:938-48.

    Does lowering blood pressure help?

    Substudies of PROGRESS CT substudy: no significant effect of BP lowering on rate of silent cerebral infarcts over 3.9 yearsHasegawa et al 2004 MRI substudy: BP-lowering stopped or delayed progression of white matter lesionsDufouil et al 2005

    Lancet Aug 10 2013

    Lancet Aug 10 2013

    Endothelial dysfunction in small vessel disease Synergism with hypertension?

    Wardlaw J, Smith C, Dichgans M. Lancet Neurology 2013; 12:483-97

    CONCLUSIONS
    Hypertension and age are core risk factors for all common forms of small vessel disease of the brain

    Small vessel ischemic phenotypes are never pure: clinical and imaging caveats
    Dichotomized definition of hypertension oversimplified: blood pressure variability appears at least as important as blood pressure levels Genetic component of lacunar stroke appears smaller than for other stroke subtypes Hypertension plays a key role in all aspects of small vessel disease of the brain

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