A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes, however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25mg/kg) over non thrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with NIHSS <5 and visible arterial occlusion or perfusion deficit within 12 hours of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin Scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial and full recanalization on follow up CT Angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. TRIAL REGISTRY NAME: A Randomized Controlled Trial of tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion, Registration number: NCT02398656; URL: https://clinicaltrials.gov/study/NCT02398656.

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack.

Background: Stroke, even when minor, increases the risk of dementia. We aimed to determine whether patients with transient ischaemic attack (TIA) exhibit higher rates of cerebral and regional atrophy 1-year after first stroke symptoms and evaluate the relationship with small vessel disease and cognitive performance. Methods: TIA patients and controls without cognitive symptoms underwent high-resolution T1-weighted MRI and cognitive testing at baseline and 1-year. Percent brain volume change (PBVC) was measured, and the location of regional atrophy and small vessel disease (CSVD) burden was evaluated. Neuropsychological testing assessed memory, processing speed, and executive function. Results: A total of 76 TIA patients and 53 controls of mean age 67 (SD = 8) and 68 years (SD = 8) were recruited. TIA patients demonstrated greater improvement of visual memory and executive function at 1-year. TIA patients had greater median PBVC/year compared to controls (-0.79% [(-1.22)-(-0.38)] vs. -0.41% [(-0.62)-0.19]; p < 0.001), and higher rates of volume loss (ml/year) in subcortical gray (-0.53 [(-1.09)-(-0.06)] vs. -0.13 [(-0.61)-0.31]; p < 0.05) and white matter (-2.21 [-5.47, 0.40] vs. -0.93 [(-3.43)-2.10]; p < 0.05). Linear regression showed that TIA, age, and systolic blood pressure (SBP) were associated with greater cerebral volume loss over 1-year. There was no significant relationship between PBVC and 1-year cognition. Conclusion: A near two-fold increase in rate of cerebral atrophy 1-year after TIA is associated with higher SBP emphasizing the need for improved treatment of SBP. Cerebral and regional atrophy rates may be used to select patients for vascular risk reduction trials or novel therapeutics in future dementia prevention trials.

Visualization of atrophy of medial temporal lobes and the septal nuclei in patients with transient ischaemic attack and controls.

Introduction: Transient ischaemic attack (TIA) is associated with increased risk of cognitive decline and dementia as early as one-year post-event. Regional brain atrophy measurements may predict future cognitive decline. Aims: 1) To determine whether Medial Temporal Atrophy (MTA) scores and interseptal distance (ISD) measurements are greater in patients with TIA compared to controls; and 2) To determine whether MTA and ISD predicts cognitive change one year after TIA. Methods: Baseline demographic, vascular risk factors, structural imaging and cognitive tests scores were compared between 103 Patients with TIA and 103 age-and-sex-matched controls from the Predementia Neuroimaging of Transient Ischaemic Attack (PREVENT) Study. MTA was assessed using the Schelten's Scale, and ISD was calculated as the distance between the septal nucleus of each hemisphere. Multiple linear regression models were used to evaluate how MTA and ISD related to cognitive change after adjusting for covariates. Results: Patients with TIA had larger ISD measurements (1.4 mm [SD=1.2] vs. 0.9 mm [SD=1.0]); p < 0.001) and higher right/left MTA scores (both p < 0.05) compared to controls. At baseline, controls performed significantly better on the RAVLT (total recall), BVMT (total and delayed recall) and the Trail Making Task (A and B) compared to patients with TIA. However, at one-year follow-up there was no evidence of decline in the patients with TIA compared with controls. Higher MTA and ISD scores were not associated with cognitive decline. Conclusions: Patients with TIA had higher MTA scores and ISD measurements than controls, but neither were predictors of cognitive decline at one year. Future studies with longer follow-up periods will be required to determine whether higher MTA scores and ISD predict risk of cognitive decline in patients with TIA.

Vascular Brain Lesions, Cognitive Reserve, and Their Association with Cognitive Profile in Persons with Early-Stage Cognitive Decline.

Background: Cognitive reserve may protect against the effects of brain pathology, but few studies have looked at whether cognitive reserve modifies the adverse effects of vascular brain pathology. Objective: We determined if cognitive reserve attenuates the associations of vascular brain lesions with worse cognition in persons with subjective concerns or mild impairment. Methods: We analyzed 200 participants aged 50-90 years from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. Cognition was measured using the Montreal Cognitive Assessment and a neuropsychological test battery. High vascular lesion burden was defined as two or more supratentorial infarcts or beginning confluent or confluent white matter hyperintensity. Cognitive reserve proxies included education, occupational attainment, marital status, social activities, physical activity, household income, and multilingualism. Results: Mean age was 72.8 years and 48% were female; 73.5% had mild cognitive impairment and 26.5% had subjective concerns. Professional/managerial occupations, annual household income≥$60,000 per year, not being married/common law, and high physical activity were independently associated with higher cognition. Higher vascular lesion burden was associated with lower executive function, but the association was not modified by cognitive reserve. Conclusion: Markers of cognitive reserve are associated with higher cognition. Vascular lesion burden is associated with lower executive function. However, cognitive reserve does not mitigate the effects of vascular lesion burden on executive function. Public health efforts should focus on preventing vascular brain injury as well as promoting lifestyle factors related to cognitive reserve, as cognitive reserve alone may not mitigate the effects of vascular brain injury.

The Cognitive Sequelae of Transient Ischemic Attacks-Recent Insights and Future Directions.

There is now considerable evidence that Transient Ischemic Attack (TIA) carries important sequelae beyond the risk of recurrent stroke, particularly with respect to peri-event and post-event cognitive dysfunction and subsequent cognitive decline. The occurrence of a TIA could provide an important window in understanding the relationship of early mixed vascular-neurodegenerative cognitive decline, and by virtue of their clinical relevance as a "warning" event, TIAs could also furnish the opportunity to act preventatively not only for stroke prevention but also for dementia prevention. In this review, we discuss the current state of the literature regarding the cognitive sequelae associated with TIA, reviewing important challenges in the field. In particular, we discuss definitional and methodological challenges in the study of TIA-related cognitive impairment, confounding factors in the cognitive evaluation of these patients, and provide an overview of the evidence on both transient and long-term cognitive impairment after TIA. We compile recent insights from clinical studies regarding the predictors and mediators of cognitive decline in these patients and highlight important future directions for work in this area.

Diagnosing Alzheimer's Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe.

BACKGROUND: Toxic amyloid-ß (Aß) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. OBJECTIVE: To develop a novel method for early Alzheimer's disease (AD) detection, we used blood leukocytes, that could act as "sentinels" after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. METHODS: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. RESULTS: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aß42 and t-Tau metrics further improved the AUC to 0.93. CONCLUSION: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Quantitative detection of grey and white matter amyloid pathology using a combination of K114 and CRANAD-3 fluorescence.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that exacts a huge toll on the patient, the healthcare system and society in general. Abundance and morphology of protein aggregates such as amyloid ß plaques and tau tangles, along with cortical atrophy and gliosis are used as measures to assess the changes in the brain induced by the disease. Not all of these parameters have a direct correlation with cognitive decline. Studies have shown that only particular protein conformers can be the main drivers of disease progression, and conventional approaches are unable to distinguish different conformations of disease-relevant proteins. METHODS AND RESULTS: Using the fluorescent amyloid probes K114 and CRANAD-3 and spectral confocal microscopy, we examined formalin-fixed paraffin-embedded brain samples from different control and AD cases. Based on the emission spectra of the probes used in this study, we found that certain spectral signatures can be correlated with different aggregates formed by different proteins. The combination of spectral imaging and advanced image analysis tools allowed us to detect variability of protein deposits across the samples. CONCLUSION: Our proposed method offers a quicker and easier neuropathological assessment of tissue samples, as well as introducing an additional parameter by which protein aggregates can be discriminated.

The neuroimaging of neurodegenerative and vascular disease in the secondary prevention of cognitive decline.

Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease (amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.

White matter tract microstructure and cognitive performance after transient ischemic attack.

BACKGROUND AND PURPOSE: Patients with transient ischemic attack (TIA) show evidence of cognitive impairment but the reason is not clear. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. We report WM changes using DTI and the relationship with neuropsychological performance in a cohort of transient ischemic attack (TIA) and non-TIA subjects. METHODS: Ninety-five TIA subjects and 51 non-TIA subjects were assessed using DTI and neuropsychological batteries. Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated and measurements were collected from WM tracts. Adjusted mixed effects regression modelled the relationship between groups and DTI metrics. RESULTS: Transient ischemic attack subjects had a mean age of 67.9 ± 9.4 years, and non-TIA subjects had a mean age 64.9 ± 9.9 years. The TIA group exhibited higher MD values in the fornix (0.36 units, P < 0.001) and lower FA in the superior longitudinal fasciculus (SLF) (-0.29 units, P = 0.001), genu (-0.22 units, P = 0.016), and uncinate fasciculus (UF) (-0.26 units, P = 0.004). Compared to non-TIA subjects, subjects with TIA scored lower on the Addenbrooke's Cognitive Assessment-Revised (median score 95 vs 91, P = 0.01) but showed no differences in scores on the Montreal Cognitive Assessment (median 27 vs 26) or the Mini-Mental State Examination (median 30). TIA subjects had lower scores in memory (median 44 vs 52, P < 0.01) and processing speed (median 45 vs 62, P < 0.01) but not executive function, when compared to non-TIA subjects. Lower FA and higher MD in the fornix, SLF, and UF were associated with poorer performance on tests of visual memory and executive function but not verbal memory. Lower FA in the UF and fornix were related to higher timed scores on the TMT-B (P < 0.01), and higher SLF MD was related to higher scores on TMT-B (P < 0.01), confirming worse executive performance in the TIA group. CONCLUSIONS: DTI scans may be useful for detecting microstructural disease in TIA subjects before cognitive symptoms develop. DTI parameters, white matter hyperintensities, and vascular risk factors underly some of the altered neuropsychological measures in TIA subjects.

Defining reperfusion post endovascular therapy in ischemic stroke using MR-dynamic contrast enhanced perfusion.

OBJECTIVES: Cerebral blood flow (CBF) measurements after endovascular therapy (EVT) for acute ischemic stroke are important to distinguish early secondary injury related to persisting ischemia from that related to reperfusion when considering clinical response and infarct growth. METHODS: We compare reperfusion quantified by the modified Thrombolysis in Cerebral Infarction Score (mTICI) with perfusion measured by MRI dynamic contrast-enhanced perfusion within 5 h of EVT anterior circulation stroke. MR perfusion (rCBF, rCBV, rTmax, rT0) and mTICI scores were included in a predictive model for change in NIHSS at 24 h and diffusion-weighted imaging (DWI) lesion growth (acute to 24 h MRI) using a machine learning RRELIEFF feature selection coupled with a support vector regression. RESULTS: For all perfusion parameters, mean values within the acute infarct for the TICI-2b group (considered clinically good reperfusion) were not significantly different from those in the mTICI <2b (clinically poor reperfusion). However, there was a statistically significant difference in perfusion values within the acute infarct region of interest between the mTICI-3 group versus both mTICI-2b and <2b (p = 0.02). The features that made up the best predictive model for change in NIHSS and absolute DWI lesion volume change was rT0 within acute infarct ROI and admission CTA collaterals respectively. No other variables, including mTICI scores, were selected for these best models. The correlation coefficients (Root mean squared error) for the cross-validation were 0.47 (13.7) and 0.51 (5.7) for change in NIHSS and absolute DWI lesion volume change. CONCLUSION: MR perfusion following EVT provides accurate physiological approach to understanding the relationship of CBF, clinical outcome, and DWI growth. ADVANCES IN KNOWLEDGE: MR perfusion CBF acquired is a robust, objective reperfusion measurement providing following recanalization of the target occlusion which is critical to distinguish potential therapeutic harm from the failed technical success of EVT as well as improve the responsiveness of clinical trial outcomes to disease modification.

Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: systematic review and meta-analysis.

BACKGROUND: The prevalence of ex vivo 'high on-treatment platelet reactivity (HTPR)' and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale ≥ 3) during follow-up. RESULTS: Antiplatelet-HTPR prevalence was 3-65% with aspirin, 8-56% with clopidogrel and 1.8-35% with aspirin-clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90-4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51-3.91) in patients with vs. those without 'antiplatelet-HTPR' on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without 'aspirin-HTPR' and 'dual antiplatelet-HTPR', respectively. Clopidogrel-HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet-HTPR (OR 2.65, 95% CI 1.00-7.01). DISCUSSION: Antiplatelet-HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted.

Recanalization following Endovascular treatment and imaging of PErfusion, Regional inFarction and atrophy to Understand Stroke Evolution-NA1 (REPERFUSE-NA1).

RATIONALE: Following endovascular treatment, poor clinical outcomes are more frequent if the initial infarct core or volume of irreversible brain damage is large. Clinical outcomes may be improved using neuroprotective agents that reduce stroke volume and improve recovery. AIM: The aim of the REPERFUSE NA1 was to replicate the preclinical neuroprotection study that significantly reduced infarct volume in a primate model of ischemia reperfusion. Specifically, REPERFUSE NA1 will determine if administration of the neuroprotectant NA1 prior to endovascular therapy can significantly reduce early (Day 2 subtract Day 1 diffusion-weighted imaging volume) and delayed secondary infarct (90-day whole brain atrophy plus FLAIR volume-Day 1 diffusion-weighted imaging volume) growth, as measured by magnetic resonance imaging. METHODS AND DESIGN: REPERFUSE-NA1 is a magnetic resonance imaging observational substudy of ESCAPE-NA1 (ClinicalTrialGov NCT02930018). A total of 150 acute stroke patients will be recruited (including 20% attrition) that have been randomized to either NA1 or placebo in the ESCAPE-NA1 trial. STUDY OUTCOMES: Primary-Early infarct growth measured using diffusion-weighted imaging will be at least 30% smaller in patients receiving NA1 compared to placebo. Secondary-Delayed secondary stroke injury at 90 days will be significantly reduced in patients receiving NA1 compared to placebo, as well as delayed secondary growth at 90 days. CONCLUSION: REPERFUSE-NA1 will demonstrate the effect of NA1 neuroprotection on reducing the early and delayed stroke injury after reperfusion treatment.

Temporal evolution and spatial distribution of quantitative T2 MRI following acute ischemia reperfusion injury.

BACKGROUND: Determining mechanisms of secondary stroke injury related to cerebral blood flow and the severity of microvascular injury contributing to edema and blood-brain barrier breakdown will be critical for the development of adjuvant therapies for revascularization treatment. AIM: To characterize the heterogeneity of the ischemic lesion using quantitative T2 imaging along with diffusion-weighted magnetic resonance imaging (DWI) within five hours of treatment. METHODS: Quantitative T2 magnetic resonance imaging was acquired within 5 h (baseline) and at 24 h (follow-up) of stroke treatment in 29 patients. Dynamic contrast enhanced permeability imaging was performed at baseline in a subgroup of patients. Absolute volume change and lesion percent change was determined for the quantitative T2, DWI, and absolute volume change sequences. A Gaussian process with RRELIEFF feature selection algorithm was used for prediction of relative quantitative T2 and DWI lesion growth, baseline and follow-up quantitative T2/DWI lesion ratios, and also NIHSS at 24 h and change in NIHSS from admission to 24 h. RESULTS: In n = 27 patients, median (interquartile range) lesion percent change was 114.8% (48.9%, 259.1%) for quantitative T2, 48.2% (-12.6%, 179.6%) for absolute volume change, and 62.7% (26.3%, 230.9%) for DWI, respectively. Our model, consisting of baseline NIHSS, CT ASPECTS, and systolic blood pressure, showed a strong correlation with quantitative T2 percent change (cross correlation R2 = 0.80). There was a strong predictive ability for quantitative T2/DWI lesion ratio at 24 h using baseline NIHSS and last seen normal to 24 h magnetic resonance imaging time (cross correlation R2 = 0.93). Baseline dynamic contrast enhanced permeability was moderately correlated to the baseline quantitative T2 values (rho = 0.38). CONCLUSION: Quantitative T2 imaging provides critical information for development of therapeutic approaches that could ameliorate microvascular damage during ischemia reperfusion.

Longitudinal Brain Atrophy Rates in Transient Ischemic Attack and Minor Ischemic Stroke Patients and Cognitive Profiles.

Introduction: Patients with transient ischemic attack (TIA) and minor stroke demonstrate cognitive impairment, and a four-fold risk of late-life dementia. Aim: To study the extent to which the rates of brain volume loss in TIA patients differ from healthy controls and how they are correlated with cognitive impairment. Methods: TIA or minor stroke patients were tested with a neuropsychological battery and underwent T1 weighted volumetric magnetic resonance imaging scans at fixed intervals over a 3 years period. Linear mixed effects regression models were used to compare brain atrophy rates between groups, and to determine the relationship between atrophy rates and cognitive function in TIA and minor stroke patients. Results: Whole brain atrophy rates were calculated for the TIA and minor stroke patients; n = 38 between 24 h and 18 months, and n = 68 participants between 18 and 36 months, and were compared to healthy controls. TIA and minor stroke patients demonstrated a significantly higher whole brain atrophy rate than healthy controls over a 3 years interval (p = 0.043). Diabetes (p = 0.012) independently predicted higher atrophy rate across groups. There was a relationship between higher rates of brain atrophy and processing speed (composite P = 0.047 and digit symbol coding P = 0.02), but there was no relationship with brain atrophy rates and memory or executive composite scores or individual cognitive tests for language (Boston naming, memory recall, verbal fluency or Trails A or B score). Conclusion: TIA and minor stroke patients experience a significantly higher rate of whole brain atrophy. In this cohort of TIA and minor stroke patients changes in brain volume over time precede cognitive decline.

Diffusion-Weighted MRI Stroke Volume Following Recanalization Treatment is Threshold-Dependent.

PURPOSE: Infarct lesion segmentation has been problematic as there are a wide range of relative and absolute diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) thresholds that have been used for this purpose. We examined differences of stroke lesion volume and evolution evaluated by magnetic resonance imaging (MRI) during the immediate post-treatment phase (<5 h) and at 24 h. METHODS: In this study 33 acute ischemic stroke patients were imaged with MRI <5 h and 24 h post-reperfusion treatment. Lesion volumes were segmented on ADC maps and average DWI using literature cited absolute ADC and relative DWI thresholds. The segmented lesion volumes within both time points were compared and the absolute change in lesion volume (infarct growth) between the two time points was calculated and compared using Bland-Altman analysis. RESULTS: Lesion volumes differed significantly when different relative DWI or absolute ADC thresholds were used (p < 0.05), which held true for baseline as well as follow-up lesions. The median absolute changes in lesion volume from baseline to follow-up for ADC thresholds of 550 × 10-6 mm2/s, 600 × 10-6 mm2/s, 630 × 10-6 mm2/s and 650 × 10-6 mm2/s were 3.5 ml, 4.2 ml, 4.5 ml, and 6.5 ml, respectively (p < 0.05). Likewise, the median absolute changes in lesion volume from baseline to follow-up for DWI thresholds, k = 0.85, 1.28, 1.64, 1.96, and 2.7 were 10.1 ml, 7.3 ml, 5.7 ml, 5.4 ml and 4.2 ml, respectively (p < 0.05). CONCLUSION: Absolute lesion volumes and changes in lesion volumes (infarct growth) measured after recanalization treatment were dependent on absolute ADC and relative DWI thresholds, which may have clinical significance. Standardization of techniques for measuring DWI lesion volumes requires immediate attention.

Diffusion-weighted imaging lesion growth occurs despite recanalization in acute ischemic stroke: Implications for future treatment trials.

BACKGROUND: A proportion of patients presenting with acute small ischemic strokes have poor functional outcomes, even following rapid recanalization treatment. AIMS: Infarct growth may occur even after successful recanalization and could represent an appropriate endpoint for future stroke therapy trials. METHODS: Magnetic resonance diffusion-weighted imaging lesion volumes were obtained at 5 h (initial posttreatment) and 24 h (follow-up) after acute stroke treatment for n = 33 in ischemic stroke patients. Sample sizes per arm (90% power, 30% effect size) for diffusion-weighted imaging lesion growth between initial and 24 h, early change in the National Institutes of Health Stroke Scale between pre- and 24 h, National Institutes of Health Stroke Scale at 24 h, and diffusion-weighted imaging lesion volume at 24 h were estimated to power a placebo-controlled stroke therapy trial. RESULTS: For patients with poor recanalization (modified thrombolysis in cerebral infarction <2 a; modified arterial occlusion lesion = 0-2) (n = 11), the median diffusion-weighted imaging lesion growth was 8.1 (interquartile range: 4.5, 22.4) ml and with good recanalization (modified thrombolysis in cerebral infarction =2 b or 3; modified arterial occlusion lesion = 3) (n = 22), the median diffusion-weighted imaging lesion growth was 10.0 (interquartile range: 6.0, 28.2) ml ( P = 0.749). When considering a 30% effect size, the sample size required per arm to achieve significance in an acute stroke study would be: (1) N = 49 for the diffusion-weighted imaging lesion growth between initial posttreatment and follow-up time points, (2) N = 65 for the change in the National Institutes of Health Stroke Scale between admission and 24 h, (3) N = 259 for the National Institutes of Health Stroke Scale at 24 h, and (4) N = 256 for diffusion-weighted imaging volume at 24 h. CONCLUSION: Despite best efforts to recanalize the ischemic brain, early diffusion-weighted imaging lesion growth still occurs. Treatment trials in stroke should consider early diffusion-weighted imaging lesion growth as a surrogate outcome measure to significantly reduce sample sizes.

Validation of a proteomic biomarker panel to diagnose minor-stroke and transient ischaemic attack: phase 2 of SpecTRA, a large scale translational study.

OBJECTIVE: To validate our previously developed 16 plasma-protein biomarker panel to differentiate between transient ischaemic attack (TIA) and non-cerebrovascular emergency department (ED) patients. METHOD: Two consecutive cohorts of ED patients prospectively enrolled at two urban medical centers into the second phase of SpecTRA study (training, cohort 2A, n = 575; test, cohort 2B, n = 528). Plasma samples were analyzed using liquid chromatography/multiple reaction monitoring-mass spectrometry. Logistic regression models which fit cohort 2A were validated on cohort 2B. RESULTS: Three of the panel proteins failed quality control and were removed from the panel. During validation, panel models did not outperform a simple motor/speech (M/S) deficit variable. Post-hoc analyses suggested the measured behaviour of L-selectin and coagulation factor V contributed to poor model performance. Removal of these proteins increased the external performance of a model containing the panel and the M/S variable. CONCLUSIONS: Univariate analyses suggest insulin-like growth factor-binding protein 3 and serum paraoxonase/lactonase 3 are reliable and reproducible biomarkers for TIA status. Logistic regression models indicated L-selectin, apolipoprotein B-100, coagulation factor IX, and thrombospondin-1 to be significant multivariate predictors of TIA. We discuss multivariate feature subset analyses as an exploratory technique to better understand a panel's full predictive potential.

A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study.

BACKGROUND: Late-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer's vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline. METHODS: A total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer's pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid ß1-42) and by MR measurements of iron accumulation, a marker for Alzheimer's-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer's disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively. DISCUSSION: The PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.