Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aß in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.

Automated estimation of salvageable tissue: Comparison with expert readers.

PURPOSE: To assess the performance of an automatic perfusion-diffusion mismatch outlining algorithm, in a cohort of acute ischemic stroke patients imaged as part of a multicenter study. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) from 167 patients with anterior circulation strokes scanned at either 3T or 1.5T systems were analyzed retrospectively through an automatic perfusion-diffusion mismatch detection algorithm. In addition, four expert raters manually outlined perfusion lesions on time-to-peak (TTP) maps and diffusion lesions on diffusion-weighted images (DWI), and reference perfusion-diffusion mismatch masks were obtained as the areas where at least three experts were in agreement that tissue was part of the perfusion-weighted imaging (PWI) lesion, but not the diffusion lesion. Per-subject analyses of mismatch volumes and mismatch overlap were subsequently performed. RESULTS: The use of the automatic perfusion-diffusion mismatch detection algorithm resulted in a 4.0 ml mean (standard deviation 28.7 ml) difference in mismatch volume compared to the reference expert consensus (Pearson correlation, r = 0.91, P < 0.0001). The median spatial agreement was 0.71, with an interquartile range of 0.28. CONCLUSION: We demonstrated excellent agreement between the perfusion-diffusion mismatch masks estimated by our proposed automatic algorithm and those achieved by expert consensus.

Automated decision-support system for prediction of treatment responders in acute ischemic stroke.

MRI is widely used in the assessment of acute ischemic stroke. In particular, it identifies the mismatch between hypoperfused and the permanently damaged tissue, the PWI-DWI mismatch volume. It is used to help triage patients into active or supportive treatment pathways. COMBAT Stroke is an automated software tool for estimating the mismatch volume and ratio based on MRI. Herein, we validate the decision made by the software with actual clinical decision rendered. Furthermore, we evaluate the association between treatment decisions (both automated and actual) and outcomes. COMBAT Stroke was used to determine PWI-DWI mismatch volume and ratio in 228 patients from two European multi-center stroke databases. We performed confusion matrix analysis to summarize the agreement between the automated selection and the clinical decision. Finally, we evaluated the clinical and imaging outcomes of the patients in the four entries of the confusion matrix (true positive, true negative, false negative, and false positive). About 186 of 228 patients with acute stroke underwent thrombolytic treatment, with the remaining 42 receiving supportive treatment only. Selection based on radiographic criteria using COMBAT Stroke classified 142 patients as potential candidates for thrombolytic treatment and 86 for supportive treatment; 60% sensitivity and 29% specificity. The patients deemed eligible for thrombolytic treatment by COMBAT Stroke demonstrated significantly higher rates of compromised tissue salvage, less neurological deficit, and were more likely to experience thrombus dissolving and reestablishment of normal blood flow at 24 h follow-up compared to those who were treated without substantial PWI-DWI mismatch. These results provide evidence that COMBAT Stroke, in addition to clinical assessment, may offer an optimal framework for a fast, efficient, and standardized clinical support tool to select patients for thrombolysis in acute ischemic stroke.

Acute stroke: automatic perfusion lesion outlining using level sets.

PURPOSE: To develop a user-independent algorithm for the delineation of hypoperfused tissue on perfusion-weighted images and evaluate its performance relative to a standard threshold method in simulated data, as well as in acute stroke patients. MATERIALS AND METHODS: The study was approved by the local ethics committee, and patients gave written informed consent prior to their inclusion in the study. The algorithm identifies hypoperfused tissue in mean transit time maps by simultaneously minimizing the mean square error between individual and mean perfusion values inside and outside a smooth boundary. In 14 acute stroke patients, volumetric agreement between automated outlines and manual outlines determined in consensus among four neuroradiologists was assessed with Bland-Altman analysis, while spatial agreement was quantified by using lesion overlap relative to mean lesion volume (Dice coefficient). Performance improvement relative to a standard threshold approach was tested with the Wilcoxon signed rank test. RESULTS: The mean difference in lesion volume between automated outlines and manual outlines was -9.0 mL ± 44.5 (standard deviation). The lowest mean volume difference for the threshold approach was -25.8 mL ± 88.2. A significantly higher Dice coefficient was observed with the algorithm (0.71; interquartile range [IQR], 0.42-0.75) compared with the threshold approach (0.50; IQR, 0.27- 0.57; P , .001). The corresponding agreement among experts was 0.79 (IQR, 0.69-0.83). CONCLUSION: The perfusion lesions outlined by the automated algorithm agreed well with those defined manually in consensus by four experts and were superior to those obtained by using the standard threshold approach. This user-independent algorithm may improve the assessment of perfusion images as part of acute stroke treatment. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121622/-/DC1.

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model.

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

The capillary dysfunction hypothesis of Alzheimer's disease.

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.

Incidence and mortality of pancreatic cancer in the Nordic countries 1971-2000.

Pancreatic cancer (PC) is the sixth most frequent cause of death from cancer in Europe in men as well as women. Apart from smoking, little is known about the aetiology of PC. This study examines trends in incidence and mortality of PC in Denmark, Finland, Iceland, Norway, and Sweden from 1971 to 2000, using the database NORDCAN, with data on incident cases of PC derived from the national cancer registries and data on deaths from PC from the national registries on causes of death. The analysis included 91 842 incident cases and 96 430 deaths from PC in a total population of about 23 million. The mean age at diagnosis was 69 years for males in the Nordic countries for the period 1996-2000 and 72 years for females. Using the age-specific rates from year 2000 to calculate the cumulative risk, 8.4 of 1 000 Nordic men and 6.7 of 1 000 Nordic women will develop PC before the age of 75 years. Over the past 30 years incidence and mortality rates have been decreasing in males and remained stable without any particular trend in females whether examined by calendar time or birth cohort. However, there are considerable difficulties in obtaining true estimates of the incidence and mortality from PC, since less than 60% of incident cases are verified histologically and autopsy rates have decreased over time.