Role of systemic inflammation in cerebral small vessel disease.
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Date
29/11/2016Author
Wiseman, Stewart John
Metadata
Abstract
Cerebral small vessel disease (SVD) is a distinct microvascular disorder that can lead to
lacunar stroke, an important stroke subtype that accounts for a quarter of all ischaemic
strokes. SVD is associated with imaging biomarkers such as white matter hyperintensities
(WMH). The cause of SVD is largely unknown, although inflammation and blood-brain
barrier failure via endothelial dysfunction have been implicated. Elevated plasma
biomarkers of inflammation are associated with coronary heart disease and large vessel
stroke but the role of inflammation in SVD is less well understood. Our hypothesis is that
inflammation plays a role in SVD and we sought to examine this by reviewing the
literature for evidence of this, and by conducting a brain imaging study of patients with a
known inflammatory disease and reviewing the images for evidence of inflammation and
SVD, and comparing findings with controls groups.
Section A: This thesis begins with a systematic review and meta-analysis of 13 plasma
biomarkers of four physiological processes (coagulation, fibrinolysis, endothelial
dysfunction and inflammation) in lacunar stroke versus non-lacunar stroke (to control for
having any stroke) and non-stroke (to compare to the general population). We sought to
know if there were differences in these biomarkers between lacunar stroke and other
stroke subtypes and non-stroke controls as a way of generating hypotheses for the disease
mechanisms that might lead to lacunar stroke. Findings revealed differences in several
biomarkers between lacunar stroke and healthy controls but only fibrinogen, D-dimer,
von Willebrand factor and interleukin-6 were different (all significantly lower in lacunar
stroke) between lacunar stroke and other stroke subtypes. There was heterogeneity
between studies, including variations in the definition of lacunar stroke and most studies
measured the biomarkers in the acute phase post stroke, which is potentially confounding.
To further examine plasma biomarkers of inflammation and endothelial dysfunction in
SVD, we used data from a prior study of mild stroke conducted at the Brain Research
Imaging Centre, University of Edinburgh, UK. Lacunar stroke patients were compared
to cortical stroke patients. The lacunar group had lower levels of tissue plasminogen
activator independent of age, sex and vascular risk factors but we found no difference in
the other plasma biomarkers.
Section B: Non-resolving systemic inflammation is a feature of inflammatory
autoimmune rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus
erythematosus (SLE). These patients are at increased risk of stroke but much knowledge
relates to stroke in general; less is known about associations with stroke subtypes
including SVD, or when in life stroke risk is greatest. Consequently, we sought to better
understand the influence of inflammatory rheumatic diseases on stroke and SVD. The
review and meta-analysis of cerebrovascular disease in rheumatic diseases showed an
excess risk of stroke in RA, SLE, ankylosing spondylitis, gout and psoriasis over the
general population. Meta-analyses of stroke subtypes (ischaemic and haemorrhagic) in
RA and SLE showed an excess risk of stroke over the general population. Stroke risk
across rheumatic diseases was highest in those aged <50 years and reduced with ageing.
We then requested data from NHS Lothian covering 15 years so that we could assess
stroke, including stroke subtypes, among patients diagnosed with various arthropathies.
We linked 6,613 rheumatology patients’ records with stroke admission records, grouped
the various rheumatic diseases into the two main types of arthritis, inflammatory and non-inflammatory,
and also compared the strokes in these rheumatology patients to general
population data. There was no difference in stroke prevalence between inflammatory and
degenerative (non-inflammatory) arthropathies, although the strokes occurred up to two
decades earlier than in the general population.
Section C: Lastly, we conducted MRI neuroimaging in patients with SLE and reviewed
and meta-analysed diffusion tensor imaging (DTI) (an imaging technique used to assess
sub-visible white matter microstructure damage) in SLE to place our findings into
context. The research question here was to ascertain if patients with a known
inflammatory disease had brain imaging evidence of SVD, and to compare findings to
controls. We compared imaging markers of SVD and DTI between SLE patients and age-matched
healthy controls and sought associations between the imaging biomarkers and
plasma biomarkers of inflammation and endothelial dysfunction, measures of fatigue and
cognition, and scores of rheumatic disease activity. Fifty-one patients were recruited.
There was higher mean diffusivity in all white matter tracts versus controls indicating a
diffuse increase in brain water mobility in SLE. Meta-analysis confirmed higher mean
diffusivity in SLE patients versus controls. Fatigue in SLE was significantly higher than
a normal reference range and was associated with depression, anxiety, higher body mass
index, lower mean diffusivity and some blood markers of inflammation and endothelial
dysfunction. The most fatigued were youngest which explained the association with
lower mean diffusivity. Damage to the brain’s white matter microstructure may be
accelerated in SLE as the age-related declines in the general population are normally seen
much later in life. The aging pattern is consistent with inflammation-related
microvascular-mediated brain damage where the inflammation is systemic in origin.
Summary: This thesis has demonstrated an increase in SVD burden in the inflammatory
rheumatic disease SLE and increased stroke risk at younger ages in other inflammatory
rheumatic diseases. Thus, systemic inflammation as seen in inflammatory rheumatic
diseases could have effects on the brain directly, including influencing stroke risk which
is clinically noteworthy and would benefit from further testing in appropriately designed
studies such as an inception cohort that follows inflammatory rheumatic patients from
diagnosis, with regular brain imaging to track brain changes and correlates with
inflammatory profiles and impact on cognition.
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