Small vessel disease and post stroke cognitive impairment

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1 Small vessel disease and post stroke cognitive impairment Dr Fergus Doubal Stroke Association Clinical Senior Lecturer Consultant Stroke Physician and Geriatrician Royal Infirmary of Edinburgh

2 Outline What is small vessel disease? Why does it happen? Why does it matter including links between stroke and dementia? How should I manage patients with SVD?

3 Cerebral Small Vessel Disease

DWI FLAIR FLAIR T2 T2*/GRE 25% of stroke Age Hypertension Disability

4 stroke Recent small subcortical infarct Lacune Small Vessel Disease: lesions White matter lesions silent Perivascular Spaces Microbleeds DWI FLAIR FLAIR T2 T2*/GRE 25% of stroke Age Hypertension Disability Cognitive impairment Dementia Stroke risk depression inflammation amyloid

5 Largely Variable Terminology Slide courtesy J. Wardlaw

6 Radiological features of Silent CVD Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. The Lancet Neurology 2013;12:

7 Radiological changes of non silent SVD Lacunar stroke ICH Microinfarcts Will better technology find more markers?

8 Features also visible on CT lacune R old infarct atrophy L WMH

9 Small vessel disease: effects are diffuse and dynamic WMH can: increase shrink, white matter atrophy cortical atrophy. Lacunes and microbleeds also appear and disappear; Wallerian degeneration Thinning of overlying cortex Acute small subcortical infarct may: cavitate disappear stay a WMH expand affect the cortex affect the brainstem and spinal cord. Normal white matter is diffusely abnormal: closer to lesions; as lesions increase. Reasons for variability, reversibility, incompletely understood Wardlaw JAHA 2015; METACOHORTS Alz Dem 2016

10 Small vessel disease links stroke and dementia? Imaging defines SVD Dementia Stroke

11 Unknown causes SVD? Endothelial Damage Inflammation Impaired Glymphatic Drainage Vessel Stiffening Vessel Occlusion

Small Vessel Disease matters to patients (JLA) Lacunar Stroke 20-25% 3 million per year worldwide 35,000 per year in the UK Few die, A fifth are left dependent A third have cognitive

12 Small Vessel Disease matters to patients (JLA) Lacunar Stroke 20-25% 3 million per year worldwide 35,000 per year in the UK Few die, A fifth are left dependent A third have cognitive impairment Vascular Dementia 25-45% Up to 16 million dementias worldwide Poor blood vessels worse Alzheimer s Balance and walking problems Mood common cause of depression at older ages

13 Stroke Cognitive impairment Stroke leads to dementia: 7-30% in 1 st year after stroke, severity, pre-existing cognitive decline

14 Prediction of dementia is difficult Dementia tests focus on memory other abilities are more affected Tests often too long and tiring Patients may not be able to do some tests after stroke Don t account for previous cognitive ability, but this is the strongest predictor of cognitive problems after stroke

REGARDS cohort in US 24000 pts >45yrs, f/u from 2003 for 6 yrs Investigated acute and chronic cognition post

15 REGARDS cohort in US pts >45yrs, f/u from 2003 for 6 yrs Investigated acute and chronic cognition post stroke Global cognition SIS (six item screener) Executive functioning and memory 500 patients had stroke JAMA 2015

16 Results Acute significant decline in global cognition and memory Incident stroke Accelerated decline in global cognition and executive function

17 Cognitive decline predicts Stroke Cognitive decline predicts stroke: 930 men in Sweden without stroke 13 years follow-up Worse performance on a join the dots test predicted stroke slowest fastest

18 Cognitive decline predicts stroke Leiden 85+ Study, 480 subjects, 85 years, In the very elderly, cognition predicts stroke better than vascular risk factors: Vascular risk score Memory test Sabayan B et al. Stroke. 2013;44:

Cognition impaired after even minor stroke Patients, n=135, 1 year after with minor stroke, median age 66 (IQR 56-75),

0001 Aver (National Rarefy Adult Reading Test) Bouquet Abstemious Rarefy WMH score 1.58 0.

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19 Cognition impaired after even minor stroke Patients, n=135, 1 year after with minor stroke, median age 66 (IQR 56-75), 17% ACE-R <82 ( dementia ): R p Age Pre-morbid Chord IQ : Sidereal 0.92 Quadruped < Aver (National Rarefy Adult Reading Test) Bouquet Abstemious Rarefy WMH score Not NIHSS, old stroke, lesion location, lacunar vs non-lacunar, etc Makin et al 2014 Idyll Zealot Gist Superfluous Simile Deny Ache Banal Naïve Depot Beatify Facade Catacomb Equivocal Gauche Placebo Détente Heir Aeon Puerperal Topiary Radix Debt Assignate Capon Thyme Drachma Sidereal Topiary Prelate Demesne Syncope Labile Procreate Subtle Gaoled Courteous Gouge Hiatus Psalm Campanile Leviathan Aisle Cellist

20 White matter hyperintensities mild risk of dementia severe Age 50-69: 7% : 17% + Debette BMJ 2010

Total SVD burden and cognition Simple sum score or more complex latent variable model Higher SVD burden associated with: Poorer general cognitive ability: Full score

21 Total SVD burden and cognition Simple sum score or more complex latent variable model Higher SVD burden associated with: Poorer general cognitive ability: Full score β -0.08, p=0.02 Without WMH β -0.1, p=0.4 Staals et al Neurology 2014; NBA 2015 Staals Neurology 2014; +Neurology Patient page; Staals NBA 2015; Karema Mol Psych 2015

22 Working party consensus Recommends cognitive screening Examples are MOCA or the Oxford Cognitive Screen RCP 2016

23 SVD Treatment options consider aim No specific SVD treatments Case 1 Asymptomatic Case 2 Lacunar stroke Case 3 Co-incidental SVD

Smith EE, Saposnik G, Biessels GJ, et al.

24 Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: A Scientific Statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2017;48:e44-e71.

25 Case 1 Asymptomatic patient 70 yr old man golfer (18 holes) Well Headache/head injury Incidental finding Is this really silent? Revert to primary prevention risk factor control

26 Treatment and prevention Treat vascular risk factors? High blood pressure ++ Diabetes + High cholesterol + Smoking ++ But! Impact may differ at different ages eg BP may be more important in 40s 60s than 70s 90s But! All common vascular risk factors combined only explain a small proportion of the burden of brain vascular disease, and so far trials of risk factor reduction have been disappointing

27 Case 2 Lacunar stroke patient 65 yr old female Left sided weakness Is there enough evidence to manage her differently from other ischaemic strokes? Many studies included lacunar stroke patients but did not adequately report subtype findings Few studies in lacunar stroke

Benavente NEJM 2012, Benavente Lancet Neurol 2013 SPS3 trial N=3000 patients with lacunar stroke and baseline MRI scans Intensive blood pressure control no

28 Benavente NEJM 2012, Benavente Lancet Neurol 2013 SPS3 trial N=3000 patients with lacunar stroke and baseline MRI scans Intensive blood pressure control no significant benefit on stroke/mortality (but fewer ICH) Dual antiplatelet (clop/asp) therapy harmful and stopped early Lower than expected stroke incidence

29 Case 3 Co-incidental SVD 80 yr with atrial fibrillation - CHADSVASC2 3 MRI shows microbleeds 70 yr with acute MCA infarct 2 hours ago MRI/CT show white matter disease

30 Suggestions for Clinical Care in Patients with Microbleeds Anticoagulation and other therapies in patients with silent microbleeds It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication (eg, AF). When anticoagulation is needed, a novel oral anticoagulant is preferred over warfarin. Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation. It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication. MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies. Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH. Implement preventive care recommended by AHA/ASA guidelines for primary prevention of ischemic stroke. It is reasonable to provide preventive care recommended by AHA/ASA guidelines for prevention of ICH.

thrombolysis or antithrombotics. b) Aspirin. c) IV tpa 0.9 mg/kg then thrombectomy.

31 Microbleed Scenario: Acute Ischemic Stroke 77 year woman NIHSS 16 Acute ischemic stroke due to RMCA occlusion Multiple microbleeds on SWI Plan of management: a) No thrombolysis or antithrombotics. b) Aspirin. c) IV tpa 0.9 mg/kg then thrombectomy. d) IV tpa 0.6 mg/kg then EVT. e) Straight to EVT, without tpa. Slide adapted from E Smith

32 Risk for sich after TPA Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tpa sich Pooled OR 2.87 for ICH post TPA in the presence of microbleeds Unclear whether 5.6% risk increase for sich outweighs 12% risk reduction for ischemic stroke disability expected from tpa. Charidimou A, et al. Neurology 2015;85:

33 Clinical Suggestions for Acute Ischemic Stroke Therapy in Patients with Microbleeds Safety of acute ischemic stroke therapy in patients with silent microbleeds It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and evidence of microbleeds if it is otherwise indicated. It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and evidence of microbleeds. In acute ischemic stroke patients with microbleeds, bypassing intravenous alteplase therapy to proceed directly to endovascular thrombectomy is an unproven strategy.

34 Other SVD treatment targets? Weak blood vessel lining: strengthen cell junctions Poor blood vessel function: increase nitric oxide Inflammation : anti-inflammatory? Statins, nitrates, pentoxyfiline, cilostazol, dipyridamole, etc. Trials are ongoing, e.g. LACI-1, LACI-2, PRESERVE?Salt, exercise, green vegetables, nutrient bars

35 RCTs of cilostazol and nitrates in SVD n=44/60 12 weeks Edinburgh Nottingham 1. Cilostazol 2. Nitrate 3. Both early 4. Both late Tolerability CVR measures Pulse wave analysis n=400 1 yr July 2017 >30 UK centres 1. Cilostazol 2. Nitrate 3. Both 4. Neither Clinical outcomes MRI at one year

36 SVD trials Difficult heterogenous patient groups Low stroke recurrence rate (3% p.a.) Cognitive testing time consuming Do they measure the correct outcomes?

37 For now? Apply guideline treatments: Lower blood pressure Lower lipids Use antiplatelet drugs, but not ASA+Clop long term Lifestyle advise smoking, salt reduction, exercise Trials of existing agents and novel agents More animal data to lead to human trials

38 Conclusions SVD important, defined by imaging Silent may not be silent Stroke and dementia linked Treatment options at present limited

The Epidemiology of Stroke and Vascular Risk Factors in Cognitive Aging

The Epidemiology of Stroke and Vascular Risk Factors in Cognitive Aging REBECCA F. GOTTESMAN, MD PHD ASSOCIATE PROFESSOR OF NEUROLOGY AND EPIDEMIOLOGY JOHNS HOPKINS UNIVERSITY OCTOBER 20, 2014 Outline