Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging

May combine two claims.

The abnormal arteriolar wall appeared thickened as it passed through the infarct rather than proximal to it, with signal indicating thrombus in the lumen and blood products in and around the arteriole wall.

“The arteriolar wall appeared thickened as it passed through the ‘infarct’ not proximal to it (as one might expect with a typical cortical atherothromboembolic infarct), with signal indicating thrombus in the lumen and blood products in and around the arteriole wall.”

May combine two claims.

In earlier work, with subjects lying supine in the MR scanner for more than half an hour, an increasing gradient of gadolinium from frontal to occipital white matter was identified, suggesting gravity-dependence of BBB permeability.

“In earlier work, where the subject was lying supine in the MR scanner for more than half an hour, we identified an increasing gradient of gadolinium from the frontal to the occipital white matter suggesting some gravity-dependence of BBB permeability143”

• cites [143] Topakian, 2010, Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Increasing age and WMH scores were independently associated with lower MCA flow velocities (on average, a 0.2 cm/s fall in velocity per year increase in age, p=0.045; a 3.75 cm/s fall in flow velocity per point increase in WMH score, p=0.004).

“Increasing age and WMH scores were independently associated with lower MCA flow velocities (on average, a 0·2 cms−1 fall in velocity per year increase in age, p=0·045; a 3·75 cms−1 fall in flow velocity per point increase in WMH score, p=0·004).”

• cites [70] Wong, 2002, Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study, Ann Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Using clinical features and CT alone to separate lacunar from non-lacunar stroke is inaccurate and has likely distorted epidemiological and observational studies of risk factor associations.

“Reliance on clinical features and CT scanning to differentiate lacunar from non-lacunar stroke is imprecise and has probably confounded epidemiological and observational studies of risk factor associations.17”

• cites [17] Potter, 2010, Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Imaging shows that acute lacunar lesions are usually larger than old lesions, which has questioned the maximum permissible size of acute lacunar infarcts and emphasised the importance of lesion age.

“Imaging shows that acute lesions are usually larger than old lesions, has questioned the maximum permissible sizes of acute lacunar infarcts45 and emphasised the importance of noting the age of the lesion (Figure 3).”

• cites [45] Doubal, 2011, Characteristics of patients with minor ischaemic strokes and negative MRI: a cross sectional study, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Arteriolar occlusion may occur late and does not account for the early pathology of SVD.

“However, arteriolar occlusion may be a late stage phenomenon and does not explain the early pathology.”

May combine two claims.

Only about half of recent infarcts are visible on CT, whereas at least 70% are visible on MR diffusion-weighted imaging.

“Only about 50% of recent infarcts are visible on CT,43 whereas at least 70% are visible on MR DWI.44”

• cites [43] Franke, 1991, Residual lesions on computed tomography after intracerebral hemorrhage, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [44] Wardlaw, 2003, Visible infarction on computed tomography is an independent predictor of poor functional outcome after stroke, and not of haemorrhagic transformation, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Clinical subtyping alone misclassifies about 20% of acute lacunar syndromes as cortical stroke and vice versa, adding noise to studies that omit DWI.

“Stroke subtyping on clinical features alone is imperfect, misdiagnosing about 20% of acute lacunar clinical syndromes as cortical stroke and vice versa,17 and will lead to ‘noise’ in studies that do not include DWI.”

• cites [17] Potter, 2010, Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Fisher's pathological studies were mostly done long after the original stroke and concentrated on the lacune.

“Fisher’s pathological studies, mostly conducted long after the original stroke, focused on the lacune (fluid filled cavity) that was thought to represent the originally symptomatic lacunar infarct.”

• cites [31] Fisher, 1991, Lacunar infarcts: a review, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There are few studies of human lacunar stroke pathology and few correlations between pathology and imaging.

“there are few studies of human lacunar stroke pathology,19 and few pathology-imaging correlations.20”

• cites [19] Bailey, 2012, Pathology of lacunar ischaemic stroke in humans—a systematic review, Brain Pathol sourceNot checked yet

  Not checked in the free run.

• cites [20] Gouw, 2011, Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Many stroke trials have not explicitly separated ischaemic stroke subtypes, so they may have missed subtype-specific differences in treatment response.

“Many trials have not differentiated ischaemic stroke subtypes explicitly, potentially overlooking any differences in treatment response between subtypes.18”

• cites [18] Palacio, 2012, Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Endothelial damage leads to vessel wall thickening and stiffness and impaired autoregulation.

“vessel wall thickening and stiffness, impaired autoregulation”

May combine two claims.

Advanced MRI can detect sub-visible damage including altered white matter integrity, disrupted axonal connections, increased brain water content, altered myelination and secondary focal thinning of cortical grey matter.

“Additional “sub-visible” damage detectable on advanced MRI (e.g. diffusion tensor imaging, DTI, magnetization transfer ratio, MTR) includes altered white matter integrity and disrupted axonal connections,38,39 increased brain water content,40 altered myelination,39 and secondary focal thinning of the cortical grey matter.41”

• cites [38] O'Sullivan, 2010, Imaging small vessel disease: lesion topography, networks, and cognitive deficits investigated with MRI, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [39] Bastin, 2009, Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age, Neurobiol Aging sourceNot checked yet

  Not checked in the free run.

• cites [40] MacLullich, 2009, Higher systolic blood pressure is associated with increased water diffusivity in normal-appearing white matter, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Endothelial damage leads to vessel wall damage, inflammation, demyelination and glial scarring.

“damage to the vessel wall, inflammation, demyelination, glial scarring”

May combine two claims.

The lacune still dominates the field and is much more likely to be recognised as causing a clinical lacunar stroke than non-cavitated lesions.

“The lacune still dominates the field,9 being much more likely to be recognised as responsible for a clinical lacunar stroke than are non cavitated lesions.23”

• cites [9] Vermeer, 2007, Silent brain infarcts: a systematic review, Lancet Neurol sourceNot checked yet

  Not checked in the free run.

• cites [23] Potter, 2010, Wide variation in definition, detection, and description of lacunar lesions on imaging, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Not all acute DWI-confirmed lacunar infarcts cavitate; some large ones disappear completely and others appear long term like non-cavitated WMH.

“Whatever the true proportion, not all lesions cavitate: some quite large acute DWI-confirmed lacunar infarcts disappear completely (Figure 3) while others appear long term like a non-cavitated WMH.”

May combine two claims.

On axial MRI, perivascular spaces appear round when perpendicular to the imaging plane and linear when parallel, typically round in the basal ganglia and linear in subcortical white matter.

“On MR imaging, PVS appear round where perpendicular to and linear where parallel to the imaging plane, so typically on axial imaging are round in the basal ganglia and linear in the subcortical white matter of the lateral parts of the temporal, parietal and frontal lobes (Figures 1 and 4).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Visible perivascular spaces around perforating arterioles have long been observed histologically in older people, often with other SVD features, but were often dismissed as a tissue-processing artefact.

“Visible PVS around perforating arterioles, although observed for many years histologically in older people often in association with other SVD features, were often dismissed as an artefact of tissue processing (Figure 4).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Microbleeds are small punctuate hypointensities on T2* or susceptibility-weighted imaging measuring up to 10 mm, corresponding to small collections of haemosiderin-laden macrophages around small perforating vessels.

“Other features of SVD include microbleeds, which are small punctuate areas of hypointensity on T2* or susceptibility-weighted imaging measuring up to 10mm in diameter corresponding to small collections of haemosiderin-laden macrophages around small perforating vessels.20,57”

• cites [20] Gouw, 2011, Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

• cites [57] Rouhl, 2012, Vascular inflammation in cerebral small vessel disease, Neurobiol Aging sourceNot checked yet

  Not checked in the free run.

May combine two claims.

WMH are distributed in periventricular and deep white matter, basal ganglia, pons and occasionally other brainstem and cerebellar white matter; they are almost always symmetric and usually numerous in the hemispheres before appearing in the brainstem, eventually coalescing.

“They are distributed in the periventricular and deep white matter of the cerebral hemispheres, in the basal ganglia (i.e. deep grey matter), in the pons and occasionally in other parts of the brainstem and cerebellar white matter. They are almost always symmetrically distributed and are usually numerous in the cerebral hemispheres before appearing in the brainstem. Eventually, when very numerous,”

May combine two claims.

Probability mapping shows that acute DWI-proven symptomatic lacunar infarcts are mainly located in the primary motor and sensory pathways, which explains why such small lesions present as stroke while other SVD lesions accumulate silently.

“Probability mapping shows that the main location of acute DWI-proven symptomatic lacunar infarcts is in the primary motor and sensory pathways (note distribution in all images shown),47 explaining why such small lesions present as stroke whereas other SVD lesions accumulate ‘silently’ but otherwise have very similar long term appearances.”

• cites [47] Donnan, 1991, The stroke syndrome of striatocapsular infarction, BrainNot checked yet

  Not checked in the free run.

May combine two claims.

In the WASID trial, only 38 of 347 patients were randomised after a lacunar stroke, the rest being cortical territorial; all recurrent strokes in the 11 patients entering WASID with a lacunar index stroke were non-lacunar.

“In the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial to reduce recurrent stroke in patients with intracranial artery stenosis, only 38/347 (11%) were randomised in the trial following a lacunar stroke the rest being cortical territorial; all recurrent strokes in the 11 patients entering WASID with a lacunar index stroke were non-lacunar.67”

• cites [67] Bang, 2007, Clinical MRI cutoff points for predicting lacunar stroke may not exist: need for a grading rather than a dichotomizing system, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Infarct patterns associated with atheromatous MCA stenosis vary between studies, perhaps because of patient selection, and many are large enough to be striatocapsular rather than true lacunar.

“Infarct patterns associated with atheromatous MCA stenosis vary between studies, perhaps related to patient selection; many appearing large enough to be striatocapsular rather than true lacunar.66”

• cites [66] Del Bene, 2012, Do risk factors for lacunar ischaemic stroke vary with the location or appearance of the lacunar infarct?, Cerebrovasc DisNot checked yet

  Not checked in the free run.

May combine two claims.

Many lacunes were never symptomatic and appear silently in the brain.

“Many lacunes were never symptomatic but appear silently in the brain (Supplementary Figure 3 for pathology examples).9”

• cites [9] Vermeer, 2007, Silent brain infarcts: a systematic review, Lancet Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

An acute lacunar infarct can be caused by embolism, but no more than 10-15% of lacunar infarcts and few WMH can be traced to emboli across individual cohort studies and meta-analyses.

“An acute lacunar infarct can be caused by embolism, but no more than 10-15% of lacunar infarcts and few WMH can be traced to emboli across a range of individual cohort studies and meta-analyses.61-63”

• cites [61] Ferrand, 1902Not checked yet

  Not checked in the free run.

• cites [62] Jackson, 2010, Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [63] Mead, 2002, Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischaemic stroke: innocent bystanders?, J Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Lesions larger than 15 mm are sometimes called lacunes, but larger lesions are more likely to have been caused by mechanisms other than SCD.

“Lesions larger than 15mm in some literature are considered as lacunes, but in general the larger the lesion the more likely that the lesion was caused by mechanisms other than SCD (Supplementary Figure 2).”

May combine two claims.

WMH are more common and more extensive in patients with acute lacunar stroke than in other stroke subtypes, and are associated with lacunes, perivascular spaces, microbleeds and brain atrophy.

“WMH are more common and more extensive in patients with acute lacunar stroke (vs. other stroke subtypes),32 associated with lacunes,50 perivascular spaces,33 microbleeds34 and brain atrophy.35”

• cites [32] Rost, 2010, White matter hyperintensity volume is increased in small vessel stroke subtypes, Neurology sourceNot checked yet

  Not checked in the free run.

• cites [50] Moreau, 2012, Cavitation after acute symptomatic lacunar stroke depends on time, location, and MRI sequence, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [33] Doubal, 2010, Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Microbleeds are associated with lacunar stroke and WMH and are clearly part of the SVD spectrum.

“Microbleeds are associated with lacunar stroke and WMH,34,58 and are clearly part of the spectrum of SVD.”

• cites [34] Cordonnier, 2007, Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting, Brain sourceNot checked yet

  Not checked in the free run.

• cites [58] Shoamanesh, 2011, Cerebral microbleeds: histopathological correlation of neuroimaging, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Visible perivascular spaces surround small deep perforating arterioles as they pass through deep grey and white matter and are made visible on T2- or T1-weighted MRI by fluid with signal similar to CSF.

“Virchow-Robin, or visible perivascular spaces (PVS) surround the small deep perforating arterioles as they pass through the deep grey and white matter, made visible on T2- or T1-weighted MR by containing increased fluid of similar signal to CSF.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

WMH are rounded areas of decreased attenuation on CT, increased signal on T2-weighted and FLAIR imaging, often decreased on T1-weighted MRI, but not as attenuated or intense as CSF.

“White matter hyperintensities (WMH) are rounded areas of decreased attenuation on CT, increased signal on T2-weighted and FLAIR, often decreased on T1-weighted MR imaging with respect to normal brain, but not as attenuated or intense as CSF (Figure 1 and 3).”

May combine two claims.

A few visible perivascular spaces may be normal at any age, but many are not normal.

“While a few visible PVS may be normal at any age,51 many are not normal.33,52,53”

• cites [51] Vermeer, 2003, Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [33] Doubal, 2010, Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [52] Groeschel, 2006, Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature, Neuroradiology sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Lacunes are cerebrospinal fluid-containing cavities in deep grey or white matter, typically larger than 3 mm and smaller than 15 mm in diameter.

“Lacunes are small cerebrospinal fluid-containing cavities located in the deep grey or white matter, typically larger than 3mm and (most consider) smaller than 15mm in diameter (Figure 1 and 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Fisher suggested that atherosclerosis and embolism affected the largest perforating arterioles, 200-850 μm in diameter.

“Fisher suggested that atherosclerosis and embolism affected the largest perforating arterioles (200-850μm diameter).31”

• cites [31] Fisher, 1991, Lacunar infarcts: a review, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Perivascular spaces are present in larger numbers in association with WMH and with symptomatic lacunar ischaemic stroke.

“The relevance of PVS to SVD is illustrated by their presence in larger numbers in association with WMH33,53 and with symptomatic lacunar ischaemic stroke.33,54”

• cites [33] Doubal, 2010, Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [53] MacLullich, 2004, Enlarged perivascular spaces are associated with cognitive function in healthy elderly men, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

• cites [54] Zhu, 2010, Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The commonest pathological abnormality in SVD is a diffuse intrinsic disease of smaller arterioles 40-200 μm in diameter, called arteriolosclerosis, lipohyalinosis or fibrinoid necrosis depending on severity, which Fisher thought largely resulted from hypertension.

“The commonest abnormality described pathologically19,27,30,31 is a diffuse, intrinsic disease of the smaller (40-200μm diameter) arterioles, referred to by Fisher as arteriolosclerosis, lipohyalinosis or fibrinoid necrosis depending on its severity, which he thought largely to result from hypertension.”

• cites [19] Bailey, 2012, Pathology of lacunar ischaemic stroke in humans—a systematic review, Brain Pathol sourceNot checked yet

  Not checked in the free run.

• cites [27] Fisher, 1965, Lacunes: small, deep cerebral infarcts, Neurology sourceNot checked yet

  Not checked in the free run.

• cites [30] Fisher, 1982, Lacunar strokes and infarcts: a review, Neurology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The few acute lacunar infarcts caused by emboli are more likely to be in the basal ganglia, but otherwise appear similar to acute lacunar infarcts caused by intrinsic arteriolar disease.

“The few acute lacunar infarcts that are due to emboli are more likely to be in the basal ganglia, but in all other respects appear similar to acute lacunar infarcts due to intrinsic arteriolar disease.65”

• cites [65] Macdonald, 1995, Emboli enter penetrating arteries of monkey brain in relation to their size, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Perivascular spaces are not simply a consequence of global brain atrophy, because they are frequently seen in patients with little atrophy, although they might be an alternative manifestation of atrophy.

“They are not simply a consequence of global brain atrophy53 as they are frequently seen in patients who have little atrophy, although they might be an alternative manifestation of atrophy.”

• cites [53] MacLullich, 2004, Enlarged perivascular spaces are associated with cognitive function in healthy elderly men, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tight internal carotid and intracranial artery stenosis is equally frequent on the contralateral and ipsilateral sides of an acute lacunar stroke, suggesting that the stenosis is unlikely to have caused the infarct.

“Tight internal carotid and intracranial artery stenosis is equally frequent on the contralateral as on the ipsilateral side to an acute lacunar stroke suggesting that the stenosis is unlikely to have caused the infarct.62”

• cites [62] Jackson, 2010, Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy?, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Acute lesions larger than 20 mm in axial diameter are likely to be striatocapsular, caused by middle cerebral artery embolism or occlusion, or by atheroma occluding multiple perforating arterioles.

“Acute lesions larger than 20mm axial diameter are likely to be striatocapsular, i.e. due to middle cerebral artery (MCA) embolism/occlusion or atheroma occluding multiple perforating arterioles.46”

• cites [46] Bang, 2004, The course of patients with lacunar infarcts and a parent arterial lesion: similarities to large artery vs small artery disease, Arch Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hypertension is likely to add harm and is at least modifiable.

“Nonetheless, hypertension is likely to add harm and is at least modifiable.”

May combine two claims.

Intracranial stenosis is common in some ethnic groups but very uncommon in Caucasians, yet 25% of ischaemic strokes in Caucasians are lacunar.

“Intracranial stenosis, although apparently common in some ethnic groups, is very uncommon (<1-2%) in Caucasians70 and yet 25% of ischaemic strokes are lacunar in type in Caucasians.”

• cites [70] Wong, 2002, Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study, Ann Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

High field MR at 7T may identify microatheromatous perforating arteriolar plaques, but the reliability and relevance of this are not yet determined.

“High field MR (7T) may identify microatheromatous perforating arteriolar plaques45 but the reliability and relevance is yet to be determined.77”

• cites [45] Doubal, 2011, Characteristics of patients with minor ischaemic strokes and negative MRI: a cross sectional study, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

• cites [77] Benavente, 2012, The Secondary Prevention of Small Subcortical Strokes (SPS3) study: results of the antiplatelet trial, Cerebrovasc DisNot checked yet

  Not checked in the free run.

May combine two claims.

Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage and death in patients with lacunar stroke, possibly because lacunar patients lacked large artery atheromatous disease to prevent, which is further evidence that SVD is largely non-atheromatous.

“Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage (mostly systemic) and death in patients with lacunar stroke,13,76 possibly because patients with lacunar as opposed to other ischaemic stroke subtypes lacked any large artery atheromatous disease to prevent (eg myocardial infarction, large artery stroke, etc),18 further evidence of the largely non-atheromatous nature of”

• cites [13] 2012, Effects of clopidogrel added to aspirin in patients with recent lacunar stroke, N Engl J Med sourceNot checked yet

  Not checked in the free run.

• cites [76] Bezerra, 2012, Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study, Neurology sourceNot checked yet

  Not checked in the free run.

• cites [18] Palacio, 2012, Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials, Stroke sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The perforating arteriolar lumen and atheroma in the perforating arteriole wall are difficult to identify on conventional imaging.

“The perforating arteriolar lumen and atheroma in the perforating arteriole wall are difficult to identify on conventional imaging.”

May combine two claims.

Although MCA stenosis may occasionally lead to lacunar stroke, most strokes in patients with intracranial stenosis are non-lacunar.

“Thus while MCA stenosis may occasionally lead to lacunar stroke,68,69 most strokes (>90%) in patients with intracranial stenosis are non-lacunar.67”

• cites [67] Bang, 2007, Clinical MRI cutoff points for predicting lacunar stroke may not exist: need for a grading rather than a dichotomizing system, Cerebrovasc Dis sourceNot checked yet

  Not checked in the free run.

• cites [68] Khan, 2012, Risk factors and outcome of patients with symptomatic intracranial stenosis presenting with lacunar stroke, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [69] Adachi, 2002, MRI findings of small subcortical “lacunar-like” infarction resulting from large vessel disease, J Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hypertension is a key risk factor for WMH, but its relationship with blood pressure is complex.

“Hypertension is a key risk factor for WMH79-83 but the relationship with blood pressure (BP) is complex.”

• cites [79] Lammie, 1997, Nonhypertensive cerebral small-vessel disease. An autopsy study, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [80] Dufouil, 2001, Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort, Neurology sourceNot checked yet

  Not checked in the free run.

• cites [81] de Leeuw, 2002, Hypertension and cerebral white matter lesions in a prospective cohort study, Brain sourceNot checked yet

  Not checked in the free run.

• cites [82] van Dijk, 2004, The association between blood pressure, hypertension, and cerebral white matter lesions: Cardiovascular Determinants of Dementia Study, Hypertension sourceNot checked yet

  Not checked in the free run.

• cites [83] Gottesman, 2010, Blood pressure and white-matter disease progression in a biethnic cohort. Atherosclerosis Risk in Communities (ARIC) Study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

If the apparent WMH-hypertension relationship is partly explained by genetic co-association, antihypertensive treatment may not be as effective in preventing SVD as hoped, even if it is very effective in preventing large artery atheromatous disease.

“If the apparent WMH-hypertension relationship is partly explained by genetic co-association, then antihypertensive treatment may not be as effective in preventing SVD as is hoped, even if it is very effective in preventing large artery atheromatous disease.”

May combine two claims.

Concurrent smoking appears to be a key risk factor for WMH and their progression, whereas statins did not prevent WMH progression.

“In terms of other common vascular risk factors, concurrent smoking also appears to be a key risk factor for WMH and their progression,97 whereas statins did not prevent WMH progression.12”

• cites [97] Schmidt, 2011, Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease, Brain sourceNot checked yet

  Not checked in the free run.

• cites [12] ten Dam, 2005, Effect of pravastatin on cerebral infarcts and white matter lesions, Neurology sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The limited effectiveness of antihypertensive treatment in trials may be related to the short intervention period or the relatively young age range of included patients.

“This may be related to the short intervention period or youngish age range of the included patients.”

May combine two claims.

Many patients with SVD are not hypertensive; among 70 consecutive autopsies in patients with pathologically verified SVD, vascular risk factors were mostly absent.

“Many patients with SVD are not hypertensive, e.g. amongst 70 consecutive autopsies in patients with pathologically-verified SVD, vascular risk factors were mostly absent.78”

• cites [78] Kang, 2010, Lenticulostriate arteries in chronic stroke patients visualised by 7 T magnetic resonance angiography, Int J Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Elevated blood pressure some years previously appears more strongly associated with WMH than concurrent blood pressure in some studies, although it is unclear whether diastolic or systolic blood pressure is more important.

“Elevated BP some years previously appears to be more strongly associated with WMH in some studies than concurrent BP, although it is unclear whether diastolic84,85 or systolic82 BP are more important.”

• cites [84] Godin, 2011, Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study, Circulation sourceNot checked yet

  Not checked in the free run.

• cites [85] Marcus, 2011, Baseline and longitudinal increases in diastolic blood pressure are associated with greater white matter hyperintensity volume: the northern Manhattan study, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [82] van Dijk, 2004, The association between blood pressure, hypertension, and cerebral white matter lesions: Cardiovascular Determinants of Dementia Study, Hypertension sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Homocysteine appears not to be related to large artery atherothrombotic disease such as myocardial infarction, but there may be an association with SVD.

“While homocysteine appears not to be related to large artery atherothrombotic disease (eg myocardial infarction), there may be an association with SVD.98”

• cites [98] van Dijk, 2008, Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both white matter tract integrity and WMH burden are highly heritable.

“Both white matter tract integrity88,89 and WMH burden90-93 are highly heritable.”

• cites [88] Dufouil, 2005, Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy, Circulation sourceNot checked yet

  Not checked in the free run.

• cites [89] Chiang, 2009, Genetics of brain fiber architecture and intellectual performance, J Neurosci sourceNot checked yet

  Not checked in the free run.

• cites [90] Kohannim, 2012, Predicting white matter integrity from multiple common genetic variants, Neuropsychopharmacology sourceNot checked yet

  Not checked in the free run.

• cites [91] Carmelli, 1998, Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [92] Turner, 2004, Heritability of leukoaraiosis in hypertensive sibships, Hypertension sourceNot checked yet

  Not checked in the free run.

• cites [93] Atwood, 2004, Genetic variation in white matter hyperintensity volume in the Framingham Study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Many sporadic cases and the monogenetic variants of SVD occur in normotensive patients.

“Many sporadic cases and the monogenetic variants of SVD occur in normotensive patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The association between SVD and blood pressure may be at the genetic locus level rather than directly causal.

“It is possible that the association between SVD and BP is at the genetic locus level rather than being directly causal.94,95”

• cites [94] Kochunov, 2009, Analysis of genetic variability and whole genome linkage of whole-brain, subcortical, and ependymal hyperintense white matter volume, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [95] Kochunov, 2010, Whole brain and regional hyperintense white matter volume and blood pressure: overlap of genetic loci produced by bivariate, whole-genome linkage analyses, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Up to age 60, the increase in BBB permeability per decade is probably less marked, suggesting that loss of endothelial integrity may start at different ages and progress at different rates, with some evidence of an exponential rather than linear decline with advancing age.

“Up to age 60, the increase in BBB permeability per decade is probably less marked, suggesting that, as with many ageing-related features, loss of endothelial integrity may start in different people at different ages and progress at different rates, with some evidence of an exponential rather than linear decline in function with advancing age.121”

• cites [121] Pollock, 1997, Perivascular spaces in the basal gangli of the human brain: their relationship to lacunes, J Anat sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Autoregulation occurs mainly at the arteriolar level, while local rapid blood flow responses to neuronal activity also involve capillary responses mediated by pericytes.

“Autoregulation largely occurs at arteriolar level, but local rapid blood flow responses to neuronal activity also involve capillary responses mediated through pericytes.114,116”

• cites [114] Abbott, 2004, Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology, Neurochem Int sourceNot checked yet

  Not checked in the free run.

• cites [116] Abbott, 2006, Astrocyte-endothelial interactions at the blood-brain barrier, Nat Rev Neurosci sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Arteriolar wall changes are patchy and diffuse and result in both vessel lumen dilation and narrowing, as well as stiffened vessels with loss of normal autoregulation.

“The arteriolar wall changes would be patchy and diffuse and result both in vessel lumen dilation and narrowing, as described by Fisher, and stiffened vessels with loss of normal autoregulation, as long suspected in SVD.102,103”

• cites [102] Lammie, 1998, Incomplete lacunar infarction (type 1b lacunes), Acta Neuropathol sourceNot checked yet

  Not checked in the free run.

• cites [103] Stevenson, 2010, A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls, Stroke sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The brain contains more glia, endothelial cells and pericytes than neurons.

“there are more glia, endothelial cells and pericytes in the brain than there are neurons”

• cites [114] Abbott, 2004, Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology, Neurochem Int sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

Because endothelial tight junctions are tighter in capillaries than in arterioles, endothelial failure would be seen earlier in larger proximal perforating arterioles than in capillaries, leading to proximal arteriolar disease and lacunar infarcts in the basal ganglia before diffuse WMH in the centrum semiovale.

“The hypothetical consequence is that the effects of endothelial failure would be seen earlier in the larger proximal perforating arterioles than in capillaries, leading for example as seen in some patients, to differential development of proximal arteriolar disease and lacunar infarcts in the basal ganglia in advance of more diffuse WMH in the centrum semiovale where tissue is served by smaller ar”

May combine two claims.

Regional differences in PVS anatomy could explain the complex association, with SVD pathology leading to visible PVS and perforating arteriolar damage/lacunar infarcts mainly in the basal ganglia, whereas multiple WMH tend to form mainly in the centrum semiovale.

“The regional differences in PVS anatomy could explain this complex association, with SVD pathology leading to visible PVS as well as perforating arteriolar damage and lacunar infarcts mainly in the basal ganglia, whereas multiple WMH tend to form mainly in the centrum semiovale.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The surface area of the cerebrovascular endothelium approximates that of a tennis court.

“the surface area of the cerebrovascular endothelium approximates that of a tennis court”

• cites [114] Abbott, 2004, Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology, Neurochem Int sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

About 20% of resting cardiac output is required to service the brain's metabolic demands.

“around 20% of the cardiac output at rest is required to service the metabolic demands of the brain.114”

• cites [114] Abbott, 2004, Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology, Neurochem Int sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inflammation is a prominent, long-observed but poorly understood component of SVD; inflammatory cell infiltrates were noted pathologically over 110 years ago in penetrating arterioles and perivascular tissue in SVD and consistently since, and plasma inflammatory markers are elevated in lacunar stroke and genetically associated with WMH progression and lacunar infarcts.

“inflammatory cell infiltrates were noted pathologically over 110 years ago in the penetrating arterioles and perivascular tissue in SVD,60 and consistently ever since (Figure 5, Supplementary Figure 3);19 plasma inflammatory markers are elevated in lacunar stroke56,127 and also associated genetically with WMH progression and lacunar infarcts.128”

• cites [60] Greenberg, 2009, Cerebral microbleeds: a guide to detection and interpretation, Lancet Neurol sourceNot checked yet

  Not checked in the free run.

• cites [19] Bailey, 2012, Pathology of lacunar ischaemic stroke in humans—a systematic review, Brain Pathol sourceNot checked yet

  Not checked in the free run.

• cites [56] Wuerfel, 2008, Perivascular spaces—MRI marker of inflammatory activity in the brain?, Brain sourceNot checked yet

  Not checked in the free run.

• cites [127] Bell, 2012, Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, Nature sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The cerebrovascular endothelium forms a key part of the blood-brain barrier.

“At the capillary level, the endothelium forms a key part of the blood-brain barrier (BBB),109”

• cites [109] Simpson, 2010, Alterations of the blood-brain barrier in cerebral white matter lesions in the ageing brain, Neurosci Lett sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Loss of normal endothelial function results in leakage of plasma fluid components and migration of cells into the vessel wall, disrupting normal architecture including arteriolar smooth muscle and causing fibrin deposition.

“The concept emerging from these new observations was that the loss of normal endothelial function would result in leakage of plasma fluid components and migration of cells into the vessel wall with disruption of the normal architecture including damaged arteriolar smooth muscle and fibrin deposition (recognised as lipohyalinosis and fibrinoid necrosis, Figure 5).101”

• cites [101] Wardlaw, 2003, Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

High dietary salt intake raises blood pressure and increases stroke risk, although the salt-stroke association is non-linear and not wholly accounted for by hypertension.

“High dietary salt intake raises blood pressure and increases stroke risk,130 although the salt-stroke association is non-linear and not wholly accounted for by hypertension.131”

• cites [130] Fornage, 2008, Biomarkers of inflammation and MRI-defined small vessel disease of the brain: the Cardiovascular Health Study, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [131] Huber, 2001, Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression, Am J Physiol Heart Circ Physiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The anatomy of perivascular spaces differs by location: basal ganglia perforating arterioles have two leptomeningeal layers, whereas arterioles entering deep white matter from superficial cortex have one.

“the basal ganglia perforating arterioles having two leptomeningeal layers whereas arterioles entering the deep white matter from the superficial cortex having one leptomeningeal layer.118,119”

• cites [118] Lecrux, 2011, The neurovascular unit in brain function and disease, Acta Physiol (Oxf) sourceNot checked yet

  Not checked in the free run.

• cites [119] Hawkins, 2005, The blood-brain barrier/neurovascular unit in health and disease, Pharmacol Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The cerebrovascular endothelium becomes increasingly permeable with normal ageing; normal subjects aged 70-80 have a near two-fold more permeable BBB compared with younger subjects.

“the cerebrovascular endothelium becomes increasingly permeable with normal ageing:121 normal subjects aged 70-80 have a near two-fold more permeable BBB compared with younger subjects.”

• cites [121] Pollock, 1997, Perivascular spaces in the basal gangli of the human brain: their relationship to lacunes, J Anat sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Basal ganglia PVS are associated with lacunar stroke, while total brain PVS are associated with WMH.

“basal ganglia PVS are associated with lacunar stroke, while total brain PVS (ie basal ganglia and centrum semiovale combined) are associated with WMH.33,54”

• cites [33] Doubal, 2010, Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [54] Zhu, 2010, Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Endothelial tight junctions are tightest in capillaries, where barrier function is most important, and relatively looser in arteriolar and venular endothelium.

“First, the endothelial tight junctions are tightest in capillaries where the barrier function is most important, and relatively looser in arteriolar and venular endothelium.109”

• cites [109] Simpson, 2010, Alterations of the blood-brain barrier in cerebral white matter lesions in the ageing brain, Neurosci Lett sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Loss of autoregulation in thickened, stiffened vessels would contribute to tissue damage by reducing vasodilatation, producing ischaemic changes superimposed on endothelial failure.

“Loss of the normal autoregulatory ability in the thickened, stiffened vessels would contribute further to tissue damage through reduced ability to vasodilate when required, leading to “ischaemic” changes107 superimposed on the endothelial failure.108”

• cites [107] Fazekas, 2005, MTI of white matter hyperintensities, Brain sourceNot checked yet

  Not checked in the free run.

• cites [108] Fernando, 2006, White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

WMH appear around PVS on imaging, suggesting focal failure of interstitial fluid drainage with increased focal brain water, or some effect of focal inflammatory cell activity as in multiple sclerosis.

“Interestingly,WMH appear around PVS on imaging (Figure 4), suggesting focal failure of interstitial fluid drainage136 with increased focal brain water,39 or some effect of focal inflammatory cell activity as in multiple sclerosis.55”

• cites [136] Bailey, 2011, Cerebral small vessel endothelial structural changes predate hypertension in stroke prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5-to 21-week old rats, Neuropathol Appl Neurobiol sourceNot checked yet

  Not checked in the free run.

• cites [39] Bastin, 2009, Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age, Neurobiol Aging sourceNot checked yet

  Not checked in the free run.

• cites [55] Potter G, Doubal F, Jackson CA, et al. Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke (in press).Not checked yet

  Not checked in the free run.

May combine two claims.

Increased endothelial expression of endothelial thrombomodulin is seen in arterioles in SVD, possibly indicating a protective mechanism against local thrombosis due to changes in blood flow secondary to altered arteriolar structure.

“Increased endothelial expression of endothelial thrombomodulin is seen in arterioles in SVD, possibly indicating a protective mechanism against local thrombosis due to changes in blood flow secondary to altered arteriolar structure.157”

• cites [157] Young, 2008, Neuropathologic correlates of white matter hyperintensities, Neurology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The presence of hypoxia-inducible factors in WMH at autopsy in elderly patients may be secondary to impaired autoregulation due to SVD, as vessel walls were thickened without luminal reduction; capillary endothelial and microglial activation were also observed.

“The presence of hypoxia-inducible factors in WMH at autopsy in elderly patients may be secondary to impaired autoregulation due to SVD, as vessel walls were thickened without luminal reduction; but capillary endothelial and microglial activation were also observed.107”

• cites [107] Fazekas, 2005, MTI of white matter hyperintensities, Brain sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Salt affects human vascular function by reducing nitric oxide and impairing vasodilatation.

“Salt affects human vascular function by reducing nitric oxide and impairing vasodilatation.133”

• cites [133] Strazzullo, 2009, Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies, BMJ sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Perivascular spaces drain interstitial fluid from the brain parenchyma and dilate visibly on MRI in overt inflammatory neurological disorders such as MS, in SVD, and associate with increased endothelial permeability in SVD.

“Perivascular spaces drain interstitial fluid from the brain parenchyma120 and dilate visibly on MR in overt inflammatory neurological disorders like MS,55,136 in SVD (Figure 1),56 and associate with increased endothelial permeability in SVD.122”

• cites [120] Zhang, 1990, Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum, J AnatNot checked yet

  Not checked in the free run.

• cites [55] Potter G, Doubal F, Jackson CA, et al. Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke (in press).Not checked yet

  Not checked in the free run.

• cites [136] Bailey, 2011, Cerebral small vessel endothelial structural changes predate hypertension in stroke prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5-to 21-week old rats, Neuropathol Appl Neurobiol sourceNot checked yet

  Not checked in the free run.

• cites [56] Wuerfel, 2008, Perivascular spaces—MRI marker of inflammatory activity in the brain?, Brain sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Ischaemia, which might occur secondary to endothelial dysfunction and impaired autoregulation, induces matrix metalloproteinase activity that damages endothelial tight junction proteins claudins and occludins, and could accelerate endothelial damage.

“Ischaemia, which might occur secondary to endothelial dysfunction and impaired autoregulation,102 e.g. in stiffened vessels unable to respond to vasodilatory stimuli during exertion, induces matrix metalloproteinase activity which damages the endothelial tight junction proteins claudins and occludins, and could accelerate endothelial damage.137,138”

• cites [137] Bailey, 2011, Is the spontaneously hypertensive stroke prone rat a pertinent model of subcortical ischaemic stroke? A systematic review, Int J Stroke sourceNot checked yet

  Not checked in the free run.

• cites [138] Weller, 2009, Lymphatic drainage of the brain and the pathophysiology of neurological disease, Acta Neuropathol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Studies in CADASIL transgenic mice found no evidence for BBB dysfunction, but these mice also develop very little brain parenchymal pathology.

“Studies in CADASIL transgenic mice found no evidence for BBB dysfunction,149 but these mice also develop very little brain parenchymal pathology.”

• cites [149] Yao, 2012, Extensive white matter hyperintensities may increase brain volume in CADASIL, Stroke sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SVD is the commonest cause of vascular dementia and commonly occurs with Alzheimer's disease.

“SVD is the commonest cause of vascular dementia140 and SVD commonly occurs with Alzheimer’s disease.”

• cites [140] Zlokovic, 2008, The blood-brain barrier in health and chronic neurodegenerative disorders, Neuron sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Some larger lacunar lesions with cystic degeneration may be a consequence of end-stage occlusive SVD, as suggested by Fisher, but the pathophysiology of PVS and localised white matter changes is less well understood.

“While some, particularly larger lacunar lesions with cystic degeneration may be a consequence of end-stage occlusive SVD, as suggested by Fisher, the pathophysiology of PVS and localised white matter changes is less well understood.”

• cites FisherNot checked yet

  Not checked in the free run.

May combine two claims.

While tissue pathology changes seen at post mortem are frequently interpreted as ischaemic, there are changes that also support the endothelial dysfunction concept.

“In general, while tissue pathology changes seen at post mortem are frequently interpreted as “ischaemic”, there are changes that also support the endothelial dysfunction concept.”

May combine two claims.

Although gadolinium signal detected in brain with these MR techniques is very low, it was still possible to demonstrate increasing BBB permeability with increasing age and with increasing numbers of PVS.

“although the gadolinium signal detected in the brain with these MR techniques is very low, nonetheless it was still possible to demonstrate increasing BBB permeability with increasing age and with increasing numbers of PVS122”

• cites [122] Carare, 2008, Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology, Neuropathol Appl Neurobiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Damaged endothelium, passage of plasma proteins into the vessel wall and vessel wall damage, leakage of fluid, albumin, other plasma proteins, and inflammatory cells into perivascular tissue have long been observed.

“Damaged endothelium, passage of plasma proteins into the vessel wall and vessel wall damage,154 leakage of fluid,78,101 albumin,108 other plasma proteins, inflammatory cells120,155,156 into the perivascular tissue have long been observed (Figure 5).”

• cites [154] Smallwood, 2012, Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort, Neuropathol Appl Neurobiol sourceNot checked yet

  Not checked in the free run.

• cites [78] Kang, 2010, Lenticulostriate arteries in chronic stroke patients visualised by 7 T magnetic resonance angiography, Int J Stroke sourceNot checked yet

  Not checked in the free run.

• cites [101] Wardlaw, 2003, Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [108] Fernando, 2006, White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

High dietary salt exacerbates oxidative stress in salt-sensitive people; reduced salt intake reduces blood pressure, oxidative stress and vascular stiffness.

“High dietary salt exacerbates oxidative stress in salt-sensitive people;132 reduced salt intake not only reduced BP but also reduced oxidative stress and vascular stiffness.132”

• cites [132] Gardener, 2012, Dietary sodium and risk of stroke in the Northern Manhattan Study, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Interstitial fluid drainage along perivascular spaces may depend on milking of fluid by pulsation of adjacent arterioles, and this milking could become less effective as arterioles stiffen, for example with SVD.

“Interstitial fluid drainage along the perivascular spaces may be dependent on ’milking‘ of fluid by pulsation of the adjacent arterioles.139 The ‘milking’ could become less effective as arterioles stiffen e.g. with SVD.139”

• cites [139] Rosenberg, 2009, Inflammation and white matter damage in vascular cognitive impairment, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Evidence for endothelial dysfunction in SVD comes from CADASIL, a hereditary SVD caused by Notch3 mutations, where extensive WMH are associated with increased brain volume on MRI suggesting increased brain water content, and CSF/plasma albumin ratios are increased, consistent with BBB failure.

“Evidence for endothelial dysfunction in SVD also comes from CADASIL, a hereditary SVD caused by Notch3 mutations,146 where extensive WMH were associated with increased brain volume on MRI suggesting an increase of brain water content147 and CSF/plasma albumin ratios were increased,148 in keeping with BBB failure.”

• cites [146] Johnson, 2007, Imaging of amyloid burden and distribution in cerebral amyloid angiopathy, Ann Neurol sourceNot checked yet

  Not checked in the free run.

• cites [147] Wardlaw, 2013, Blood-brain barrier permeability and long term clinical and imaging outcomes in cerebral small vessel disease, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [148] Chabriat, 2009, Cadasil, Lancet Neurol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Using gadolinium contrast-enhanced MRI, background BBB in white matter remote from any acute infarct is more permeable in patients with lacunar than with large artery cortical stroke, in WMH than in normal appearing white matter, and in WMH in patients with vascular dementia.

“using gadolinium contrast-enhanced MR imaging, that the background BBB in white matter remote from any acute infarct is more permeable in patients with lacunar than with large artery cortical stroke (Figure 7),122 in WMH than in normal appearing white matter,141 and in WMH in patients with vascular dementia.142”

• cites [122] Carare, 2008, Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology, Neuropathol Appl Neurobiol sourceNot checked yet

  Not checked in the free run.

• cites [141] Schley, 2006, Mechanisms to explain the reverse perivascular transport of solutes out of the brain, J Theor Biol sourceNot checked yet

  Not checked in the free run.

• cites [142] Dichgans, 2012, Prevention of Vascular Cognitive Impairment, Stroke sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In an animal model of spontaneous SVD, even modest short-term salt exposure exacerbated inflammation, oxidative stress and small vessel pathology, and to a lesser but measurable extent in control rats without raising blood pressure.

“In an animal model of spontaneous SVD, even modest short term salt exposure exacerbated inflammation, oxidative stress and small vessel pathology and to a lesser but nonetheless measureable extent in control rats without raising BP.134,135”

• cites [134] Al-Solaiman, 2009, Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans, J Hum Hypertens sourceNot checked yet

  Not checked in the free run.

• cites [135] Bragulat, 2001, Endothelial dysfunction in salt-sensitive essential hypertension, Hypertension sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Other models of human SVD using different mechanisms, such as induction of mild carotid stenosis with external carotid coils, also show evidence of BBB failure early after induction, predating brain damage, consistent with the notion that various stimuli might induce SVD through effects on the cerebrovascular endothelium.

“Other models of human SVD using quite different mechanisms such as induction of mild carotid stenosis with external carotid coils151 also show evidence of BBB failure early after induction predating brain damage and consistent with the notion that various stimuli might induce SVD through effects on the cerebrovascular endothelium.”

• cites [151] Joutel, 2010, Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease, J Clin Invest sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These observations support the concept that, while pathological changes seen at post mortem are frequently interpreted as ischaemic based on histological similarities to thromboembolic infarcts, there are changes that also support the altered BBB permeability concept.

“These observations support the concept that, while pathological changes seen at post mortem are frequently interpreted as “ischaemic”, based on their histological similarities to thromboembolic infarcts, there are changes that also support the altered BBB permeability concept.”

May combine two claims.

BBB was impaired in WMH, and there was increased astrocyte staining with IgG, suggesting BBB failure in deep white matter.

“Additionally BBB was impaired in WMH, and there was increased astrocyte staining with IgG, suggesting BBB failure in deep white matter.155”

• cites [155] Hughes, 1965, Origin of lacunes, Lancet sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a small longitudinal study, greater BBB permeability soon after non-disabling stroke was associated with dependency at three-year follow-up, older age, and having more WMH at initial stroke presentation, suggesting that BBB changes may predate progression of SVD.

“In a small longitudinal study, greater BBB permeability soon after non-disabling stroke was associated with dependency at three year follow-up, older age, and having more WMH at initial stroke presentation, suggesting that BBB may predate progression of SVD, but larger studies are required.145”

• cites [145] Starr, 2003, Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging, J Neurol Neurosurg Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The SHRSP shows inflammation and increased BBB permeability early in life, predating any rise in blood pressure or development of overt vessel wall or tissue damage.

“The SHRSP shows inflammation (again non-specific) and increased BBB permeability early in life,21 predating any rise in BP or development of overt vessel wall or tissue damage.150”

• cites [21] Bailey, 2009, Potential animal models of lacunar stroke: a systematic review, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [150] Dichgans, 1999, Cerebrospinal fluid findings in CADASIL, Neurology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The spontaneously hypertensive stroke-prone rat (SHRSP), the most relevant experimental model of sporadic SVD, has multiple modest endothelial and perivascular tissue defects in early life, including impaired endothelial tight junctions, poor myelination, overactive microglia, and a tendency to glial scarring detectable in protein expression.

“the most relevant experimental model of sporadic SVD, the spontaneously-hypertensive stroke prone rat (SHRSP),21,22,135 has multiple modest endothelial and perivascular tissue defects in early life,21 including impaired endothelial tight junctions, poor myelination, overactive microglia, and tendency to glial scarring detectable in protein expression.134”

• cites [21] Bailey, 2009, Potential animal models of lacunar stroke: a systematic review, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [22] Hainsworth, 2008, Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review, J Cereb Blood Flow Metab sourceNot checked yet

  Not checked in the free run.

• cites [135] Bragulat, 2001, Endothelial dysfunction in salt-sensitive essential hypertension, Hypertension sourceNot checked yet

  Not checked in the free run.

• cites [134] Al-Solaiman, 2009, Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans, J Hum Hypertens sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Other factors that might be associated both with jugular venous reflux and WMH, such as lung disease, were not evaluated.

“However other factors that might be associated both with jugular venous reflux and WMH, such as lung disease, were not evaluated.”

May combine two claims.

CBF and blood flow velocities fall with normal ageing.

“CBF and blood flow velocities fall with normal ageing.”

May combine two claims.

Jugular venous reflux increases with advancing age as do WMH; elderly subjects with more WMH had more jugular venous reflux detected on Doppler ultrasound not accounted for by hypertension, diabetes, hyperlipidaemia or smoking.

“Jugular venous reflux increases with advancing age as do WMH. Elderly subjects with more WMH had more jugular venous reflux detected on Doppler ultrasound not accounted for by hypertension, diabetes, hyperlipidaemia or smoking.”

• cites [161] ten Dam, 2007, Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities, Radiology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A reduction in CBF was observed using MR imaging in patients with more WMH in some but not other studies; both found associations between CBF and atrophy, suggesting that declining CBF might occur secondary to tissue loss rather than tissue loss and WMH occurring secondary to falling CBF.

“A reduction in CBF was observed using MR imaging methods in patients with more WMH in some,158 but not other159 studies; both found associations between CBF and atrophy suggesting that declining CBF might occur secondary to tissue loss, rather than that tissue loss and WMH occur secondary to falling CBF.”

• cites [158] Black, 2009, Understanding white matter disease. Imaging-pathological correlations in vascular cognitive impairment, Stroke sourceNot checked yet

  Not checked in the free run.

• cites [159] Giwa, 2012, Neuropathologic evidence of endothelial changes in cerebral small vessel disease, Neurology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Earlier work described a general lack of association between acute lacunar infarcts or WMH and carotid stenosis, suggesting that carotid stenosis is not a common mechanical cause in humans.

“Earlier, we described the general lack of association between acute lacunar infarcts or WMH and carotid stenosis, suggesting that carotid stenosis is not a common mechanical cause in humans.”