Accelerating regional atrophy rates in the progression from normal aging to Alzheimer’s disease

We investigated progression of atrophy in vivo, in Alzheimer’s disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1–6.2) for occipital atrophy and 15.8 (95% CI = 3.5–71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

Extracranial carotid disease and effect of intra-arterial treatment in patients with proximal anterior circulation stroke in MR CLEAN

Background: The presence of extracranial carotid disease (ECD) is associated with less favorable clinical outcomes in patients with acute ischemic stroke caused by intracranial proximal occlusion. Acute intra-arterial treatment (IAT) in the setting of extracranial and intracranial lesions is considered challenging, and whether it yields improved outcomes remains uncertain. Objective: To examine whether the presence of ECD modified the effect of IAT for intracranial proximal anterior circulation occlusion. Design: Prespecified subgroup analysis of a randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands. (Trial registrations: NTR1804 [Netherlands Trial Register] and ISRCTN10888758) Setting: 16 hospitals in the Netherlands. Patients: Acute ischemic stroke caused by proximal intracranial arterial occlusion of the anterior circulation. Extracranial carotid disease was defined as cervical internal carotid artery stenosis (>50%) or occlusion. Intervention: IAT treatment versus no IAT. Measurements: The primary outcome was functional outcome, as measured by the modified Rankin Scale at 90 days and reported as adjusted common odds ratio (acOR) for a shift in direction of a better outcome. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by ECD. Results: The overall acOR was 1.67 (95% CI, 1.21 to 2.30) in favor of the intervention. The acOR was 3.1 (CI, 1.7 to 5.8) in the prespecified subgroup of patients with ECD versus 1.3 (CI, 0.9 to 1.9) in patients presenting without ECD. Both acORs are in favor of the intervention (P for interaction = 0.07). Limitation: The study was not powered for subgroup analysis. Conclusion: Intra-arterial treatment may be at least as effective in patients with ECD as in those without ECD, and it should not be withheld in these complex patients with acute ischemic stroke

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial.

IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804