Anna Tietze

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 role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study

Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor–positive and estrogen receptor–negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2655–60)

The Relationship between Tumor Blood Flow, Angiogenesis, Tumor Hypoxia, and Aerobic Glycolysis

Antiangiogenic therapies are being pursued as a means of starving tumors of their energy supply. Although numerous studies show that such therapies render tumors hypoxic, just as many studies have, surprisingly, shown improved tumor oxygenation. These contradicting findings challenge both the original rationale for antiangiogenic therapy and our understanding of the physiology of tissue oxygenation. The flow-diffusion equation, which describes the relation between blood flow and the extraction of freely diffusible molecules in tissue, was recently extended to take the heterogeneity of capillary transit times (CTH) into account. CTH is likely to be high in the chaotic microvasculature of a tumor, increasing the effective shunting of blood through its capillary bed. We review the properties of the extended flow-diffusion equation in tumor tissue. Elevated CTH reduces the extraction of oxygen, glucose, and cytotoxic molecules. The extent to which their net extraction is improved by antiangiogenic therapy, in turn, depends on the extent to which CTH is normalized by the treatment. The extraction of oxygen and glucose are affected to different extents by elevated CTH, and the degree of aerobic glycolysis-known as the Warburg effect-is thus predicted to represent an adaptation to the CTH of the local microvasculature.

Capillary Transit Time Heterogeneity and Flow-Metabolism Coupling after Traumatic Brain Injury

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic’ ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

Changes in 3‐dimensional bone structure indices in hypoparathyroid patients treated with PTH(1‐84): A randomized controlled study

Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high bone mineral density (BMD) despite conventional treatment with calcium supplements and active vitamin D analogues. To assess effects of PTH substitution therapy on 3‐dimensional bone structure, we randomized 62 patients with hypoPT into 24 weeks of treatment with either PTH(1‐84) 100 µg/day subcutaneously or similar placebo as an add‐on therapy. Micro‐computed tomography was performed on 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24 weeks of treatment. Compared with placebo, PTH caused a 27% lower trabecular thickness (p < 0.01) and 4% lower trabecular bone tissue density (p < 0.01), whereas connectivity density was 34% higher (p < 0.05). Trabecular tunneling was evident in 11 (48%) of the biopsies from the PTH group. Patients with tunneling had significantly higher levels of biochemical markers of bone resorption and formation. At cortical bone, number of Haversian canals per area was 139% higher (p = 0.01) in the PTH group, causing a tendency toward an increased cortical porosity (p = 0.09). At different subregions of the hip, areal BMD (aBMD) and volumetric BMD (vBMD), as assessed by dual‐energy X‐ray absorptiometry (DXA) and quantitative computed tomography (QCT), decreased significantly by 1% to 4% in the PTH group. However, at the lumbar spine, aBMD decreased by 1.8% (p < 0.05), whereas vBMD increased by 12.8% (p = 0.02) in the PTH compared with the placebo group.

Mean Diffusional Kurtosis in Patients with Glioma: Initial Results with a Fast Imaging Method in a Clinical Setting

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an MR imaging technique that provides microstructural information in biologic systems. Its application in clinical studies, however, is hampered by long acquisition and postprocessing times. We evaluated a new and fast (2 minutes 46 seconds) diffusional kurtosis imaging method with regard to glioma grading, compared it with conventional diffusional kurtosis imaging, and compared the diagnostic accuracy of fast mean kurtosis (MK′) to that of the widely used mean diffusivity. MATERIALS AND METHODS: MK′ and mean diffusivity were measured in the contrast-enhancing tumor core, the perifocal hyperintensity (indicated on T2 FLAIR images), and the contralateral normal-appearing white and gray matter of 34 patients (22 with high-grade and 12 with low-grade gliomas). MK′ and mean diffusivity in the different tumor grades were compared by using a Wilcoxon rank sum test. Receiver operating characteristic curves and the areas under the curve were calculated to determine the diagnostic accuracy of MK′ and mean diffusivity. RESULTS: MK′ in the tumor core, but not mean diffusivity, differentiated high-grade from low-grade gliomas, and MK′ differentiated glioblastomas from the remaining gliomas with high accuracy (area under the curveMK′ = 0.842; PMK′ < .001). MK′ and mean diffusivity identified glioblastomas in the group of high-grade gliomas with similar significance and accuracy (area under the curveMK′ = 0.886; area under the curvemean diffusivity = 0.876; PMK′ = .003; Pmean diffusivity = .004). The mean MK′ in all tissue types was comparable to that obtained by conventional diffusional kurtosis imaging. CONCLUSIONS: The diffusional kurtosis imaging approach used here is considerably faster than conventional diffusional kurtosis imaging methods but yields comparable results. It can be accommodated in clinical protocols and enables exploration of the role of MK′ as a biomarker in determining glioma subtypes or response evaluation.

BOLD MRI in sheep fetuses: a non-invasive method for measuring changes in tissue oxygenation.

The purpose of this descriptive study was to correlate changes in the blood oxygen level‐dependent (BOLD) magnetic resonance imaging (MRI) signal with direct measurements of fetal tissue oxygenation.

Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting

OBJECTIVE Mutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme. METHODS By extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected. RESULTS In vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable. CONCLUSIONS The noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer’s disease

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimers disease. We hypothesized that neuroinflammation occurs early in Alzheimers disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.