Download Inflammation and autoimmunity in cerebral small vessel disease

Imaging features and inflammatory markers in
cerebral small vessel disease
10 WEEK REVIEW AND THESIS OUTLINE
Stewart Wiseman
Brain Research Imaging Centre, School of Clinical Sciences
with Rheumatic Diseases Unit, Centre for Molecular Medicine
January 2013
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Pages
Thesis outline
3-4
Appendices
A: Chapter breakdown
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B: Small imaging experiment on a local cohort of lupus patients
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C: What I have done so far
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D: Plans for the remainder of first year
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E: Mind map
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F: Reading list (example of papers read)
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Thesis outline
This thesis will investigate inflammation in cerebral small vessel disease. Is there evidence of
more peripheral inflammation in cerebral small vessel disease? Specifically, do patients with
specific inflammatory arthropathies have more evidence of cerebral small vessel disease?
Imaging of cerebral small vessel disease
Cerebral small vessel disease expresses itself clinically in various ways. It may present as a
clinically distinct lacunar stroke. In ageing, it expresses as cognitive impairment, vascular
dementia and gait disturbances. These clinical manifestations mostly have typical imaging
features including acute lacunar infarcts, lacunes (holes in the brain left behind from old infarcts
or bleeds), cerebral microbleeds, white matter hyperintensities and enlarged perivascular
spaces.
Lacunar stroke is a specific stroke subtype. Its aetiology, like that of cerebral small vessel
disease, is unknown. Hypotheses include atheroma, endothelial dysfunction, blood brain barrier
dysfunction, or other as yet unknown process. Inflammation is thought to play a role.
The imaging features of cerebral small vessel disease combined with symptoms such as
dizziness or cognitive decline point to a diffuse process. Imaging, however, should be used
cautiously because for example a proportion of clinically evident lacunar strokes do not have an
acute infarct on imaging. Conversely, small infarcts on imaging may appear without overt
neurological signs. Those that cause symptoms may do so because of their location in the
primary motor and sensory pathways.
The inflammatory hypothesis
The role of the human immune system is to keep us healthy. It can react innately in seconds
resulting in acute inflammation, where increased blood flow brings the necessary cells and
molecules to a specific site to repair damage or fight invading pathogens. The immune system
also reacts adaptively, lasting days to weeks. An inflammatory response is thus a desirable
physiological process which terminates when homeostasis is achieved.
A chronic inflammatory response points to a permanent imbalance in the body. Prolonged or
inappropriate inflammatory activity can, paradoxically, cause damage. In autoimmune disease
for example, instead of attacking pathogens the immune system targets the body’s own
molecules and tissues. Might a dysfunctional inflammatory process be present in cerebral small
vessel disease?
There are known associations between several inflammatory joint diseases and mostly large
vessel atheramatous stroke and cardioembolism (eg, rheumatoid arthritis, Takayasu disease
and systemic lupus erythematosus). Might there also be specific evidence that chronic
inflammation, as measured by blood markers, joint pain or specific rheumatic diagnoses, is
associated with features of cerebral small vessel disease? Is it possible the structure or
function of the cerebral small vessel endothelium is disrupted by inflammation in this disease as
a model for other sources of inflammation, thus predisposing a person to any manifestations of
cerebral small vessel disease?
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Why is this important?
Lacunar stroke accounts for 25% of ischaemic strokes (20% of all strokes) and is therefore an
important public health issue. Cerebral small vessel disease accounts directly for or contributes
substantially to 45% of all dementias. The problem is likely to get bigger as the population of
Scotland ages. It is important to gain further knowledge on the processes involved in cerebral
small vessel disease and lacunar stroke as it has implications for prevention, diagnosis and
management as well as the design of studies and drug trials that need to differentiate stroke
subtypes. Anti-inflammatory treatment in rheumatic disease is common and often effective at
alleviating the symptoms of painful or immobile joints. If inflammation is associated with
features of cerebral small vessel disease, such as increased blood brain barrier permeability or
volume of white matter lesions, then it could have implications for future treatment choices.
What will we do to investigate these issues?
Firstly, we will review the evidence for peripheral blood markers of inflammation in lacunar
stroke.
Secondly, we will review the evidence for inflammatory joint disease in stroke in general and
cerebral small vessel disease in particular.
Thirdly, once the literature has been assessed, we will re-visit data held locally from four studies
of relevant populations of patients. The Edinburgh Stroke Study, Mild Stroke Study I, Mild
Stroke Study II and Lothian Birth Cohort 1936 each have imaging (together with measures
thereon such as lesion scoring and volume measurements), some have blood markers and the
LBC 1936 has some data on rheumatic disease. Where possible, with ethical approval when
required, we will fill in any data gaps by performing new measurements or gathering additional
information. We will investigate these datasets for associations between imaging features and
inflammatory features.
Fourthly, we will conduct a small targeted case-control imaging study on a local cohort of
patients with a chronic inflammatory autoimmune disease to assess for the presence of cerebral
small vessel disease (see Appendix). We will quantify findings by measuring brain volumes,
white matter lesion volumes, counting lacunes and scoring scans for enlarged perivascular
spaces. Associations with the underlying rheumatic disease (blood marker levels, pain scoring)
will be investigated. Comparisons to an appropriate control group will be assessed.
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Appendix A
Chapter breakdown
Chapter 1: SETTING THE SCENE
Cerebral small vessel disease and lacunar stroke
The Immune system
Chronic inflammatory diseases
Lupus
Define stroke. Prevalence and cost to society. Explain the differences between stroke
subtypes. Define lacunar stroke. Outline the lacunar hypothesis. Magnetic resonance imaging
sequences for lacunar stroke. Who gets a lacunar stroke? Define cerebral small vessel disease
(CSVD). Imaging feature of CSVD. Risk factors.
Overview of the immune system. Chemokines. Cytokines. Innate immunity in the brain.
Adaptive immunity in the brain. The blood brain barrier / small vessel endothelium.
Overview of rheumatology. What is inflammation and how is it measured? Overview of chronic
inflammatory diseases.
Define lupus, a systemic multi-organ disease. Prevalence in Scotland. What is antiphopholipid
syndrome (‘sticky blood’)?
Chapter 2: LITERATURE REVIEWS
Systematic Review: Plasma and serum markers in stroke subtypes
Systematic Review: TNF-α in stroke subtypes
Literature Review: Lacunar stroke and inflammatory diseases
Chapter 3: Inflammation in the Edinburgh Stroke Study and Mild Stroke Study I
Analysis of blood markers of inflammation in these cohorts: is there a difference between
lacunar and non-lacunar patients? Correlation of inflammatory markers with white matter lesion
volumes.
Chapter 4: IMAGING EXPERIMENT: Investigating CSVD in a cohort of lupus patients
Rationale for investigating this cohort. Aims. Methods. Results. Discussion.
Chapter 5: Conclusions and suggestions for future research
Summary of findings. Synthesis of what this thesis adds. What’s next?
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Appendix B
Small imaging experiment on a local cohort of lupus patients
Systemic lupus erythematousus (lupus) is an autoimmune disease affecting multiple organ
systems, including the brain. Its association with stroke subtypes including lacunar stroke is
less clear. Antiphospholipid syndrome (also known as Hughes syndrome or ‘sticky blood’) is a
clotting disorder common in lupus patients and because it is a clotting disorders one might
assume ischaemic stroke is more prevent in this cohort. What is the evidence? More
specifically, what evidence exists for lacunar stroke or cerebral small vessel disease in this
cohort?
A patient group with lupus is well characterised within the Rheumatic Diseases Unit. We would
seek ethical approval and grant funding to undertake a small targeted case-control imaging
study, aiming to recruit from this group. We would assess cerebral small vessel disease in this
group by scoring the resultant scans for enlarged perivascular spaces, counting lacunes and
taking volume measurements of white matter lesions.
We will apply statistical techniques to assess the resultant imaging markers in the lupus group
with controls.
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Appendix C
What I have done so far
Learning how to do systematic reviews
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Read JMW's paper on how to do them
Read Susan Shenkin's (CCACE) PowerPoint “Intro to systematic reviews and how to do them”
Read Steff Lewis’s PowerPoint “Meta-analysis: summarising data for two arm trials”
Read Francesca Chappell’s PowerPoint “How to review a diagnostic study”
Read Will Whiteley's PowerPoint “Systematic reviews: an overview and posing the question”
Read Brenda Thomas’s PowerPoint “Effective literature searching”
Ran OVID search of Medline and EMBASE
1 hour meeting with Marshall Dozier, CMVM Librarian at Central Library
CCACE workshop on Systematic Reviews and Meta Analysis
Started to learn Review Manager 5.0 (eg, for forest plots)
Read several systematic review papers
Courses attended in 2012
December
CCACE workshop on systematic reviews and meta analysis @ Central Library run by the Centre for
Cognitive Ageing and Cognitive Epidemiology and the CMVM librarians
October
Good Clinical Practice - for non drug trials @ Wellcome Trust Clinical Research Facility, WGH
August
Brain Anatomy Dissection @ University of Edinburgh - Department of Anatomy (G. Findlater)
June
Pathology of Small Vessel Disease, Prof H Vinters, UCLA @ DCN, WGH
May
2nd Essential Stroke Imaging Course @ Liverpool Medical Institution
PhD “admin”
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Matriculated. Official PhD start date = 1 Oct 2012
Read CMVM “PG Students’ Handbook”
Read CMVM “A code of practice for supervisors and research students”
Watched a podcast for new PG students from Phillipa Saunders (PG Dean, Research)
Other
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Ad hoc attendance of the weekly MDT meeting on Ward 55 (stroke / imaging)
Watched a couple of YouTube videos from UCSF on the endothelium
Watched a couple of YouTube videos from UCSF on immunity
Attended a SINAPSE offsite induction event – 2 days with other new imaging PhD
students from across Scotland. The primary focus was development of communication
skills (eg, the ability to pitch for money) and networking opportunities.
References stored in reference management software
Desk and network access setup – work is stored on DCN servers for security / backup
Started to learn basic MRI image processing techniques (see Fig 1 overleaf)
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Fig 1. Fused red-green colour blend of Gradient Echo (left column) and FLAIR (right column) magnetic
resonance images to help segment periventricular and subcortical white matter lesions.
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Appendix D
Plans for the remainder of first year
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Complete quality assessment of selected papers then write-up “A systematic review of
plasma and serum markers of endothelial dysfunction, inflammation, coagulation and
fibrinolysis between lacunar stroke, other ischaemic stroke subtypes and non-stroke
controls.”
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Attend the “Edinburgh Clinical Academic Research Methodology” course.
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Attend an appropriate statistics course.
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Finish segmenting white matter lesions on the Edinburgh Stroke Study.
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Quantitative analysis of inflammatory blood marker data from the Edinburgh Stroke
Study and Mild Stroke Study I with white matter lesion volumes.
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Review the literature for lacunar stroke and cerebral small vessel disease in the context
of inflammatory diseases / arthrides.
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Do a systematic review of TNF- α in ischaemic stroke subtypes.
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Get a handle on the inflammatory data (bloods, specific rheumatic diagnoses, joint pain
questions) held on four studies for which we have imaging (Edinburgh Stroke Study, Mild
Stroke Study, Mild Stroke Study II, LBC 1936)
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Get a handle on the inflammatory data held on the RDU cohort of lupus patients.
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Appendix E
Mind map
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Appendix F
Reading list (example of papers read)
Adams, H.P., Bendixen, B.H., Kappelle, L.J., Biller, J., Love, B.B., Gordon, D.L. and Marsh, E.E.
1993. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter
clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 24(1), pp.35–41.
Ahmad, O., Wardlaw, J. and Whiteley, W.N. 2012. Correlation of levels of neuronal and glial
markers with radiological measures of infarct volume in ischaemic stroke: a systematic review.
Cerebrovascular Diseases, 33(1), pp.47–54.
Bailey, E.L., McCulloch, J., Sudlow, C. and Wardlaw, J.M. 2009. Potential animal models of
lacunar stroke. A systematic review. Stroke, 40(6), e451-8.
Bailey, E.L., Smith, C., Sudlow, C.L.M. and Wardlaw, J.M. 2011. Is the spontaneously
hypertensive stroke prone rat a pertinent model of sub cortical ischemic stroke? A systematic
review. International Journal of Stroke, 6, pp.434-444.
Bailey, E.L., Smith, C., Sudlow, C.L.M. and Wardlaw, J.M. 2012. Pathology of lacunar ischemic
stroke in humans – a systematic review. Brain Pathology, pp.1-9.
Bamford, J., Sandercock, P., Dennis, M., Burn, J. and Warlow, C. 1991. Classification and
natural history of clinically identifiable subtypes of cerebral infarction. Lancet, 337, pp.15211526.
Danton, G.H. and Dietrich, W.D. 2003. Inflammatory mechanisms after ischemia and stroke.
Journal of Neuropathology and Experimental Neurology, 62(2), pp.127–136.
Dantzer, R., O’Connor, J.C., Freund, G.G., Johnson, R.W. and Kelley, K.W. 2008. From
inflammation to sickness and depression: when the immune system subjugates the brain.
Nature reviews. Neuroscience, 9(1), pp.46–56.
Di Napoli, M., Schwaninger, M., Cappelli, R., Ceccarelli, E., Di Gianfilippo, G., Donati, C.,
Emsley, H.C.A., Forconi, S., Hopkins, S.J., Masotti, L., Muir, K.W., Paciucci, A., Papa, F.,
Roncacci, S., Sander, D., Sander, K., Smith, C.J., Stefanini, A. and Weber, D. 2005.
Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic
stroke: a statement for health care professionals from the CRP Pooling Project members.
Stroke, 36(6), pp.1316-1329.
Doubal, F.N., Hokke, P.E. and Wardlaw, J.M. 2009. Retinal microvascular abnormalities and
stroke: a systematic review. Journal of Neurology, Neurosurgery and Psychiatry, 80(2),
pp.158–65.
Doubal, F.N., Rumley, A., Lowe, G.D.O., Dennis, M.S. and Wardlaw, J.M. Undated. Plasma
markers of endothelial function, coagulation, fibrinolysis and inflammation in lacunar stroke.
Unpublished.
Farrall, A.J. and Wardlaw, J.M. 2009. Blood-brain barrier: ageing and microvascular disease –
systematic review and meta-analysis. Neurobiology of Aging, 30(3), pp.337-52.
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Fisher, C.M. 1982. Lacunar strokes and infarcts: a review. Neurology, 32, pp.871-876.
Fromont, A., De Seze, J., Fleury, M.C., Maillefert, J.F. and Moreau, T. 2009. Inflammatory
demyelinating events following treatment with anti-tumor necrosis factor. Cytokine, 45, pp.5557.
Hasan, N., McColgan, P., Bentley, P., Edwards, R.J. and Sharma, P. 2012. Towards the
identification of blood biomarkers for acute stroke in humans: a comprehensive systematic
review. British Journal of Clinical Pharmacology, 74(2), pp.230-240.
Knottnerus, I.L.H., Cate, H.T., Lodder, J., Kessels, F. and van Oostenbrugge, R.J. 2009.
Endothelial dysfunction in lacunar stroke: a systematic review. Cerebrovascular Diseases, 27,
pp.519-526.
Knottnerus, I.L.H., Govers-Riemslag, J.W.P., Hamulyak, K., Rouhl, R.P.W., Staals, J., Spronk,
H.M.H., van Oerle, R., van Raak, E.P.M., Lodder, J., ten Cate, H. and van Oostenbrugge, R.J.
2010. Endothelial activation in lacunar stroke subtypes. Stroke, 41(8), pp.1617–1622.
Knottnerus, I.L.H., Winckers, K., ten Cate., Hackeng, T.M., Lodder, J., Rouhl, R.P.W., Staals, J.,
Govers-Riemslag, J.W.P., Bekers, O. and van Oostenbrugge, R.J. 2012. Levels of heparinreleasable TFPI are increased in first-ever lacunar stroke patients. Neurology, 78, pp.493-498.
Kane, I., Sandercock, P. and Wardlaw, J. 2007. Magnetic resonance perfusion diffusion
mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to
date. Journal of Neurology, Neurosurgery and Psychiatry, 78, pp.485-490.
Lammie, G.A., Brannan, F. and Wardlaw, J.M. 1998. Incomplete lacunar infarction (Type Ib
lacunes). Acta Neuropathology, 96, pp.163-171.
Lammie, G.A. 2000. Pathology of small vessel stroke. British Medical Bulletin, 56(2), pp.296306.
Morris, Z., Whiteley, W.N., Longstreth, W.T., Weber, F., Lee, Y., Tsushima, Y., Alphs, H., Ladd,
S.C., Warlow, C., Wardlaw, J.M. and Al-Shahi Salman, R. 2009. Incidental findings on brain
magnetic resonance imaging: systematic review and meta analysis. British Medical
Journal, 339, b3016.
Muir, K.W. 2002. Inflammation, blood pressure, and stroke: an opportunity to target primary
prevention? Stroke, 33(12), pp.2732-2733.
Muir, K.W., Tyrrell, P., Sattar, N. and Warburton, E. 2007. Inflammation and ischaemic stroke.
Current Opinion in Neurology, 20, pp.334-342.
Rouhl, R.P.W., Damoiseaux, J.G.M.C., Lodder, J., Theunissen, R.O.M.F.I.H., Knottnerus, I.L.H.,
Staals, J., Henskens, L.H.G., Kroon, A.A., de Leeuw, P.W., Tervaert, J.W.C. and van
Oostenbrugge, R.J. 2012. Vascular inflammation in cerebral small vessel disease.
Neurobiology of Aging, 33(8), pp.1800–1806.
Stevenson, S.F., Doubal, F.N., Shuler,K. and Wardlaw, J.M. 2010. A systematic review of
dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke,
41(6), e434–42.
Tuttolomondo, A., Di Raimondo, D., Di Sciacca, R., Pinto, A. and Licata, G. 2008. Inflammatory
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Wardlaw, J.M., Armitage, P., Dennis, M.S., Lewis, S., Marshall, I. and Sellar, R. 2000. The use
of diffusion-weighted magnetic resonance imaging to identify infarctions in patients with minor
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Farrall, A., Suddlow, C., Dennis, M and Dhillon, B. 2009. Lacunar stroke is associated with
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