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