Functional, cognitive and physical outcomes 3 years after minor lacunar or cortical ischaemic stroke.

OBJECTIVE: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear. METHODS: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale). RESULTS: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5). Cognitive impairment at 3 years affected all ACE-R subdomains and was associated with ACE-R 1 year (ß=1.054, p<0.001) and NART (ß=1.023, p<0.05). Poor physical function was associated with stroke severity (TUG, ß=1.064, p<0.01) and recurrent stroke (9HPT, ß=1.130, p<0.05 right, ß=1.214, p<0.05 left). Higher ACE-R scores were associated with faster TUG (ß=-0.279, p<0.05) and 9HPT (right ß=-0.257, p<0.05; left ß=-0.302, p=0.05) and inversely with dependency (mRS=3-5, OR 0.88, 95% CI 0.80 to 0.97). We adjusted analyses for demographic, stroke and known risk factors. In-person and remote assessments were highly correlated. CONCLUSIONS: Cognitive, physical impairments and depression are common and interrelated 3 years after minor stroke. Cognitive and physical impairments require rehabilitation after minor stroke and argue for better integration of stroke and dementia services.

Small Vessel Disease and Dietary Salt Intake: Cross-Sectional Study and Systematic Review.

BACKGROUND: Higher dietary salt intake increases the risk of stroke and may increase white matter hyperintensity (WMH) volume. We hypothesized that a long-term higher salt intake may be associated with other features of small vessel disease (SVD). METHODS: We recruited consecutive patients with mild stroke presenting to the Lothian regional stroke service. We performed brain magnetic resonance imaging, obtained a basic dietary salt history, and measured the urinary sodium/creatinine ratio. We also carried out a systematic review to put the study in the context of other studies in the field. RESULTS: We recruited 250 patients, 112 with lacunar stroke and 138 with cortical stroke, with a median age of 67.5 years. After adjustment for risk factors, including age and hypertension, patients who had not reduced their salt intake in the long term were more likely to have lacunar stroke (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.10-3.29), lacune(s) (OR, 2.06; 95% CI, 1.09-3.99), microbleed(s) (OR, 3.4; 95% CI, 1.54, 8.21), severe WMHs (OR, 2.45; 95% CI 1.34-4.57), and worse SVD scores (OR, 2.17; 95% CI, 1.22-3.9). There was limited association between SVD and current salt intake or urinary sodium/creatinine ratio. Our systematic review found no previously published studies of dietary salt and SVD. CONCLUSION: The association between dietary salt and background SVD is a promising indication of a potential neglected contributory factor for SVD. These results should be replicated in larger, long-term studies using the recognized gold-standard measures of dietary sodium.

Endothelial Function, Inflammation, Thrombosis, and Basal Ganglia Perivascular Spaces in Patients with Stroke.

BACKGROUND AND OBJECTIVE: Recent studies suggest perivascular spaces are a marker of small vessel disease, blood-brain barrier permeability, and inflammation, but little is known about their risk factors and associations with peripheral blood markers. MATERIALS AND METHODS: In prospectively recruited patients with recent minor ischemic stroke, we investigated the influence of age, sex, hypertension, diabetes, and smoking on the severity of perivascular spaces in the basal ganglia seen on T2-weighted magnetic resonance imaging. We assessed plasma markers of endothelial function (von Willebrand factor, intracellular adhesion molecule-1), inflammation (interleukin-6, tumor necrosis factor-alpha, C-reactive protein), and thrombosis (fibrinogen, prothrombin fragments 1 + 2, thrombin-antithrombin complex, tissue plasminogen activator, D-dimer). We used a validated semi-automated method to measure basal ganglia perivascular spaces count and volume. We tested uni- and multivariable associations between blood markers and basal ganglia perivascular spaces count and volume. FINDINGS: In 100 patients (median age: 67 years, range: 37-92), on adjusted analysis, basal ganglia perivascular spaces count was associated with age (r = .117, P = .003) and hypertension (r = 2.225, P = .013). On multivariable linear regression, adjusted for age, sex, hypertension, smoking and diabetes, reduced von Willebrand factor was associated with increased basal ganglia perivascular spaces count (r = -.025, P = .032). CONCLUSION: The association of increased basal ganglia perivascular spaces count with reduced von Willebrand factor is novel. As von Willebrand factor may promote cerebral endothelial integrity, insufficient von Willebrand factor is consistent with dysfunctional cerebral endothelium and increased basal ganglia perivascular spaces in cerebral small vessel disease. Quantitative perivascular spaces measurement may increase sensitivity to detect cerebral endothelial dysfunction.

Diffusion-weighted imaging and diagnosis of transient ischemic attack.

OBJECTIVE: Magnetic resonance (MR) diffusion-weighted imaging (DWI) is sensitive to small acute ischemic lesions and might help diagnose transient ischemic attack (TIA). Reclassification of patients with TIA and a DWI lesion as "stroke" is under consideration. We assessed DWI positivity in TIA and implications for reclassification as stroke. METHODS: We searched multiple sources, without language restriction, from January 1995 to July 2012. We used PRISMA guidelines, and included studies that provided data on patients presenting with suspected TIA who underwent MR DWI and reported the proportion with an acute DWI lesion. We performed univariate random effects meta-analysis to determine DWI positive rates and influencing factors. RESULTS: We included 47 papers and 9,078 patients (range = 18-1,693). Diagnosis was by a stroke specialist in 26 of 47 studies (55%); all studies excluded TIA mimics. The pooled proportion of TIA patients with an acute DWI lesion was 34.3% (95% confidence interval [CI] = 30.5-38.4, range = 9-67%; I(2) = 89.3%). Larger studies (n > 200) had lower DWI-positive rates (29%; 95% CI = 23.2-34.6) than smaller (n < 50) studies (40.1%; 95% CI = 33.5-46.6%; p = 0.035), but no other testable factors, including clinician speciality and time to scanning, reduced or explained the 7-fold DWI-positive variation. INTERPRETATION: The commonest DWI finding in patients with definite TIA is a negative scan. Available data do not explain why ⅔ of patients with definite specialist-confirmed TIA have negative DWI findings. Until these factors are better understood, reclassifying DWI-positive TIAs as strokes is likely to increase variance in estimates of global stroke and TIA burden of disease.

Blood-brain barrier permeability and long-term clinical and imaging outcomes in cerebral small vessel disease.

BACKGROUND AND PURPOSE: Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease. It is not known if BBB changes predate progression of small vessel disease. METHODS: We followed-up patients with nondisabling lacunar or cortical stroke and BBB permeability magnetic resonance imaging after their original stroke. Approximately 3 years later, we assessed functional outcome (Oxford Handicap Score, poor outcome defined as 3-6), recurrent neurological events, and white matter hyperintensity (WMH) progression on magnetic resonance imaging. RESULTS: Among 70 patients with mean age of 68 (SD ± 11) years, median time to clinical follow-up was 39 months (interquartile range, 30-45) and median Oxford Handicap Score was 2 (interquartile range, 1-3); poor functional outcome was associated with higher baseline WMH score (P<0.001) and increased basal ganglia BBB permeability (P=0.046). Among 48 patients with follow-up magnetic resonance imaging, WMH progression at follow-up was associated with baseline WMH (ANCOVA P<0.0001) and age (ANCOVA P=0.032). CONCLUSIONS: Further long-term studies to evaluate the role of BBB dysfunction in progression of small vessel disease are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.

Clinical relevance and practical implications of trials of perfusion and angiographic imaging in patients with acute ischaemic stroke: a multicentre cohort imaging study.

BACKGROUND: In randomised trials testing treatments for acute ischaemic stroke, imaging markers of tissue reperfusion and arterial recanalisation may provide early response indicators. OBJECTIVE: To determine the predictive value of structural, perfusion and angiographic imaging for early and late clinical outcomes and assess practicalities in three comprehensive stroke centres. METHODS: We recruited patients with potentially disabling stroke in three stroke centres, performed magnetic resonance (MR) or CT, including perfusion and angiography imaging, within 6 h, at 72 h and 1 month after stroke. We assessed the National Institutes of Health Stroke Scale (NIHSS) score serially and functional outcome at 3 months, tested associations between clinical variables and structural imaging, several perfusion parameters and angiography. RESULTS: Among 83 patients, median age 71 (maximum 89), median NIHSS 7 (range 1-30), 38 (46%) received alteplase, 41 (49%) had died or were dependent at 3 months. Most baseline imaging was CT (76%); follow-up was MR (79%) despite both being available acutely. At presentation, perfusion lesion size varied considerably between parameters (p<0.0001); 40 (48%) had arterial occlusion. Arterial occlusion and baseline perfusion lesion extent were both associated with baseline NIHSS (p<0.0001). Recanalisation by 72 h was associated with 1 month NIHSS (p=0.0007) and 3 month functional outcome (p=0.048), whereas tissue reperfusion, using even the best perfusion parameter, was not (p=0.11, p=0.08, respectively). CONCLUSION: Early recanalisation on angiography appeared to predict clinical outcome more directly than did tissue reperfusion. Acute assessment with CT and follow-up with MR was practical and feasible, did not preclude image analysis, and would enhance trial recruitment and generalisability of results.

Systematic review of perfusion imaging with computed tomography and magnetic resonance in acute ischemic stroke: heterogeneity of acquisition and postprocessing parameters: a translational medicine research collaboration multicentre acute stroke imaging study.

BACKGROUND AND PURPOSE: Heterogeneity of acquisition and postprocessing parameters for magnetic resonance- and computed tomography-based perfusion imaging in acute stroke may limit comparisons between studies, but the current degree of heterogeneity in the literature has not been precisely defined. METHODS: We examined articles published before August 30, 2009 that reported perfusion thresholds, average lesion perfusion values, or correlations of perfusion deficit volumes from acute stroke patients <24 hours postictus. We compared acquisition parameters from published studies with guidance from the Acute Stroke Imaging Research Roadmap(1). In addition, we assessed the consistency of postprocessing parameters. RESULTS: Twenty computed tomography perfusion and 49 perfusion-weighted imaging studies were included from 7152 articles. Although certain parameters were reported frequently, consistently, and in line with the Roadmap proposals, we found substantial heterogeneity in other parameters, and there was considerable variation and underreporting of postprocessing methodology. CONCLUSIONS: There is substantial scope to increase homogeneity in future studies, eg, through reporting standards.

Computed tomography and magnetic resonance perfusion imaging in ischemic stroke: definitions and thresholds.

OBJECTIVE: Cerebral perfusion imaging with computed tomography (CT) or magnetic resonance (MR) is widely available. The optimum perfusion values to identify tissue at risk of infarction in acute stroke are unclear. We systematically reviewed CT and MR perfusion imaging in acute ischemic stroke. METHODS: We searched for papers on MR or CT perfusion performed <24 hours after stroke that assessed perfusion thresholds, mean perfusion lesion values, or lesion volumes. We extracted definitions and perfusion values. We compared definitions and evaluated perfusion thresholds for "nonviable"/"at risk" and "at risk"/"not at risk tissue" thresholds. RESULTS: Among 7,152 papers, 69 met inclusion criteria for analysis of definitions (49 MR and 20 CT), 21 MR (n = 551), and 10 CT (n = 266) papers, median sample size 22, provided thresholds. We found multiple definitions for tissue states, eg, tissue at risk, 18; nonviable tissue, 12; 16, no definition. Perfusion parameters varied widely; eg, 9 different MR, 6 different CT parameters for the "at risk"/"not at risk threshold." Median threshold values varied up to 4-fold, eg, for the "at risk"/"not at risk threshold," median cerebral blood flow ranged from 18 to 37ml/100g/min; mean transit time from 1.8 to 8.3 seconds relative to the contralateral side. The influence of reperfusion and duration of ischemia could not be assessed. INTERPRETATION: CT and MR perfusion imaging viability thresholds in stroke are derived from small numbers of patients, variable perfusion analysis methods and definitions of tissue states. Greater consistency of methods would help determine reliable perfusion viability values for wider clinical use of perfusion imaging.

A systematic review of the utility of 1.5 versus 3 Tesla magnetic resonance brain imaging in clinical practice and research.

OBJECTIVE: MRI at 3 T is said to be more accurate than 1.5 T MR, but costs and other practical differences mean that it is unclear which to use. METHODS: We systematically reviewed studies comparing diagnostic accuracy at 3 T with 1.5 T. We searched MEDLINE, EMBASE and other sources from 1 January 2000 to 22 October 2010 for studies comparing diagnostic accuracy at 1.5 and 3 T in human neuroimaging. We extracted data on methodology, quality criteria, technical factors, subjects, signal-to-noise, diagnostic accuracy and errors according to QUADAS and STARD criteria. RESULTS: Amongst 150 studies (4,500 subjects), most were tiny, compared old 1.5 T with new 3 T technology, and only 22 (15 %) described diagnostic accuracy. The 3 T images were often described as "crisper", but we found little evidence of improved diagnosis. Improvements were limited to research applications [functional MRI (fMRI), spectroscopy, automated lesion detection]. Theoretical doubling of the signal-to-noise ratio was not confirmed, mostly being 25 %. Artefacts were worse and acquisitions took slightly longer at 3 T. CONCLUSION: Objective evidence to guide MRI purchasing decisions and routine diagnostic use is lacking. Rigorous evaluation accuracy and practicalities of diagnostic imaging technologies should be the routine, as for pharmacological interventions, to improve effectiveness of healthcare. KEY POINTS : • Higher field strength MRI may improve image quality and diagnostic accuracy. • There are few direct comparisons of 1.5 and 3 T MRI. • Theoretical doubling of the signal-to-noise ratio in practice was only 25 %. • Objective evidence of improved routine clinical diagnosis is lacking. • Other aspects of technology improved images more than field strength.

Acute symptomatic hypoglycaemia mimicking ischaemic stroke on imaging: a systemic review.

BACKGROUND: Acute symptomatic hypoglycaemia is a differential diagnosis in patients presenting with stroke-like neurological impairment, but few textbooks describe the full brain imaging appearances. We systematically reviewed the literature to identify how often hypoglycaemia may mimic ischaemic stroke on imaging, common patterns and relationships with hypoglycaemia severity, duration, clinical outcome and add two new cases. METHODS: We searched EMBASE and Medline databases for papers reporting imaging in adults with symptomatic hypoglycaemia. We analysed the clinical presentation, outcome, brain imaging findings, duration and severity of hypoglycaemia, time course of lesion appearance, including two new cases. RESULTS: We found 42 papers describing computed tomography or magnetic resonance imaging in 65 patients, plus our two cases with symptomatic hypoglycaemia. Imaging abnormalities on computed tomography and magnetic resonance were uni or bilateral, cortical or sub-cortical. Thirteen (20%) mimicked cortical or lacunar stroke. Acute lesions had restricted diffusion on magnetic resonance or low attenuation on computed tomography, plus swelling; older lesions showed focal atrophy or disappeared, as with ischaemic stroke. The association between the depth or duration of hypoglycaemia, the severity or extent of neurological deficit, and the imaging abnormalities, was weak. CONCLUSION: Imaging abnormalities in patients with hypoglycaemia are uncommon but very variable, weakly associated with neurological deficit, and about a fifth mimic acute ischaemic stroke. Blood glucose testing should be routine in all patients with acute neurological impairment and hypoglycaemia should be included in the differential diagnosis of imaging appearances in patients presenting with acute stroke.

Little association between intracranial arterial stenosis and lacunar stroke.

Atheromatous middle cerebral artery (MCA) stenosis could cause lacunar stroke by occluding lenticulostriate artery origins, but atheroma is common, and previous studies lacked suitable controls. We aimed to determine if intracranial atheroma was more common in lacunar than in cortical ischaemic stroke. We recruited patients with lacunar stroke and controls with mild cortical stroke, confirmed the stroke subtype with magnetic resonance imaging and used transcranial Doppler ultrasound imaging to record flow velocity and focal stenoses in the basal intracranial arteries 1 month after stroke. We compared ipsi- and contralateral MCA mean flow velocities between stroke subtypes and tested for associations using linear mixed models. Amongst 67 lacunar and 67 mild cortical strokes, mean age 64 and 67 years, respectively, we found no difference in MCA mean flow velocity between cortical and lacunar patients. Increasing age and white matter lesion scores were independently associated with lower MCA flow velocities (0.2 cms(-1) fall in velocity per year increase in age, p = 0.045; 3.75 cms(-1) fall in flow velocity per point increase in white matter lesion score, p = 0.004). We found no intracranial arterial stenoses. MCA atheromatous stenosis is unlikely to be a common cause of lacunar stroke in white populations. Falling velocities with increasing white matter lesion scores may reflect progressive brain tissue loss leaving less tissue to supply.

Imaging neurovascular, endothelial and structural integrity in preparation to treat small vessel diseases. The INVESTIGATE-SVDs study protocol. Part of the SVDs@Target project.

Background: Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres. Methods: We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device. Discussion: INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials.

A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls.

BACKGROUND AND PURPOSE: The etiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke as a marker of small vessel disease. METHODS: We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (ie, large artery atheromatous) ischemic stroke or nonstroke control subjects. We calculated standardized mean difference (SMD) in vascular reactivity+/-95% CIs between small vessel disease and control groups. RESULTS: Sixteen publications (974 patients) were included. In lacunar stroke, cerebrovascular reactivity (n=534) was reduced compared with age-matched normal (SMD -0.94, 95% CI -1.17 to -0.70), but not age+risk factor-matched control subjects (SMD 0.08, 95% CI -0.36 to 0.53) or cortical strokes (SMD -0.29, 95% CI -0.69 to 0.11); forearm flow-mediated dilatation (n=401) was reduced compared with age-matched normal control subjects (SMD -1.04, 95% CI -1.33 to -0.75) and age+risk factor-matched control subjects (SMD -0.94, 95% CI -1.26 to -0.61), but not cortical strokes (SMD -0.23, 95% CI -0.55 to 0.08). CONCLUSIONS: Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, because a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include control subjects with nonlacunar stroke.

Stability of Estimated Premorbid Cognitive Ability over Time after Minor Stroke and Its Relationship with Post-Stroke Cognitive Ability.

Considering premorbid or "peak" adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke. Minor stroke patients (NIHSS < 8) were assessed at one to three months, one and three years' post-stroke. The National Adult Reading Test (NART) and Addenbrooke's Cognitive Examination-Revised (ACE-R) were used to estimate premorbid IQ (NART IQ) and current cognitive ability respectively at each time-point. Baseline demographics, vascular and stroke characteristics were included. Of the 264 patients recruited (mean age 66), 158 (60%), 151 (57%), and 153 (58%) completed cognitive testing at each time-point respectively. NART IQ initially increased (mean difference (MD) = 1.32, 95% CI = 0.54 to 2.13, p < 0.001) before decreasing (MD = -4.269, 95% CI = -5.12 to -3.41, p < 0.001). ACE-R scores initially remained stable (MD = 0.29, 95% CI = -0.49 to 1.07, p > 0.05) before decreasing (MD = -1.05, 95% CI = -2.08 to -0.01, p < 0.05). Adjusting for baseline variables did not change the relationship between NART IQ and ACE-R with time. Increases in NART IQ were associated with more education. For ACE-R, older age was associated with declines, and higher NART IQ and more education was associated with increases. Across 3 years, we observed fluctuations in estimated premorbid IQ and minor changes in current cognitive ability. Future research should aim to identify variables associated with these changes. However, studies of post-stroke cognition should account for premorbid IQ.

Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial.

BACKGROUND: Lacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression. METHODS: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546. FINDINGS: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol. INTERPRETATION: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified. FUNDING: Alzheimer's Society (AS-PG-14-033).

The impact of early-life intelligence quotient on post stroke cognitive impairment.

BACKGROUND: Cognitive impairment can complicate minor stroke, but there is limited information on risk factors including peak cognitive ability earlier in life. METHODS: We recruited patients with clinically-evident lacunar or minor non-lacunar ischaemic stroke, recorded clinical features, vascular risk factors, magnetic resonance imaging-detected stroke sub-type and small vessel disease burden. At 1-3 and 12 months after stroke, we assessed educational attainment (years of education), current cognition (Addenbrooke's Cognitive Examination-Revised), pre-morbid intelligence (National Adult Reading Test) and dependency (modified Rankin Scale). RESULTS: We recruited 157 patients (87 lacunar, 64 non-lacunar ischaemic strokes), median age 66 (inter-quartile range 56-74) years, 36/157 (23%) patients had a Addenbrooke's Cognitive Examination-Revised score < 82 at one to three months, 29/151 (19%) had a Addenbrooke's Cognitive Examination-Revised < 82 at one year. Lower National Adult Reading Test score (cognitive impairment per point on National Adult Reading Test odds ratio 0.91, 95% confidence interval 0.87, 0.95) and older age (per year of age odds ratio 1.04 (95% confidence interval 1.01, 1.08) predicted one-year cognitive impairment more than stroke severity (per point on National Institute of Health Stroke Scale odds ratio 0.96 (95% confidence interval 0.0.68, 1.31)) or vascular risk factors e.g. hypertension (odds ratio for diagnosis of hypertension 0.52 (95% confidence interval 0.24, 1.15). Cognitive impairment was associated with having more white matter hyper-intensities (odds ratio per point increase in Fazekas score 1.42, 95% confidence interval 1.11, 1.83). DISCUSSION: This observational study provides evidence that pre-morbid intelligence quotient and education predict cognition after stroke, and confirms the association between cognitive impairment and small vessel disease. CONCLUSION: Pre-morbid intelligence should be considered in future studies of post-stroke cognition.

Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination.

Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).

Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: results of a prospective cohort study.

BACKGROUND: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome. METHODS: We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up. RESULTS: Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65-0.80, p < 0.0001) increase per 1-ml baseline volume increment, and a 2.93-ml increase (95% CI 1.76-4.10, p < 0.0001) per point on the Fazekas scale. Using a mean difference of 1 ml in WMH volume between treatment groups, 80% power and 5% alpha, adjusting for all predictors and 2-year follow-up produced the smallest sample size (n = 642). Other study designs produced samples sizes from 2054 to 21,270. Sample size calculations using Fazekas score as an outcome with the same power and alpha, as well as an OR corresponding to a 1-ml difference, were sensitive to assumptions and ranged from 2504 to 18,886. CONCLUSIONS: Baseline WMH volume and Fazekas score predicted follow-up WMH volume. Study size was smallest using volumes and longer-term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to dropout and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies.

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease.

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage.