Rachael L. Deardorff

Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression

BACKGROUND AND PURPOSE: Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. MATERIALS AND METHODS: This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. RESULTS: With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82–0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80–0.82|, P < .001). CONCLUSIONS: These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.

Non-Gaussian diffusion MRI assessment of brain microstructure in mild cognitive impairment and Alzheimer's disease☆

We report the first application of a novel diffusion-based MRI method, called diffusional kurtosis imaging (DKI), to investigate changes in brain tissue microstructure in patients with mild cognitive impairment (MCI) and AD and in cognitively intact controls. The subject groups were characterized and compared in terms of DKI-derived metrics for selected brain regions using analysis of covariance with a Tukey multiple comparison correction. Receiver operating characteristic (ROC) and binary logistic regression analyses were used to assess the utility of regional diffusion measures, alone and in combination, to discriminate each pair of subject groups. ROC analyses identified mean and radial kurtoses in the anterior corona radiata as the best individual discriminators of MCI from controls, with the measures having an area under the ROC curve (AUC) of 0.80 and 0.82, respectively. The next best discriminators of MCI from controls were diffusivity and kurtosis (both mean and radial) in the prefrontal white matter (WM), with each measure having an AUC between 0.77 and 0.79. Finally, the axial diffusivity in the hippocampus was the best overall discriminator of MCI from AD, having an AUC of 0.90. These preliminary results suggest that non-Gaussian diffusion MRI may be beneficial in the assessment of microstructural tissue damage at the early stage of MCI and may be useful in developing biomarkers for the clinical staging of AD.

Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery

OBJECTIVE Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. METHODS This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. RESULTS Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. CONCLUSIONS Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Effects of Aprotinin or Tranexamic Acid on Proteolytic/Cytokine Profiles in Infants After Cardiac Surgery

BACKGROUND After cardiopulmonary bypass (CPB), elaboration of cytokines, and subsequent induction of interstitial proteases, such as matrix metalloproteinases (MMPs), can result in a complex postoperative course. The serine protease inhibitor, aprotinin, which has been used in congenital heart surgery putatively for modulating fibrinolysis is now unavailable, necessitating the use of lysine analogues such as tranexamic acid (TXA). The present study tested the hypothesis that distinctly different plasma profiles of signaling molecules and proteases would be differentially affected after the administration of aprotinin or TXA in the context of congenital cardiac surgery and CPB. METHODS Thirty-seven patients (age, 4.8 +/- 0.3 months) undergoing corrective surgery for ventricular septal defect and tetralogy of Fallot received either aprotinin (n = 22) or TXA (n = 15). Using a high throughput multiplex suspension immunoassay, plasma was serially quantified for cytokines and MMPs: before aprotinin or TXA (baseline), after separation from CPB, and 4, 12, 24, and 48 hours post-CPB. RESULTS Tumor necrosis factor-alpha increased initially after CPB in both the aprotinin and TXA groups, but at 24 and 48 hours post-CPB was approximately 50% lower in the aprotinin group (p < 0.05). The IL-10 levels were threefold higher in the TXA group compared with the aprotinin group immediately post-CBP (p < 0.05). Plasma levels of MMP types associated with inflammation, MMP-8, and MMP-9, were twofold higher in the late post-CPB period in the TXA group when compared with the aprotinin group. CONCLUSIONS After ventricular septal defect or tetralogy of Fallot repair in children, cytokine induction occurs, which is temporally related to the emergence of a specific MMP profile. Moreover, these unique findings demonstrated differential effects between the serine protease inhibitor aprotinin and the lysine analogue TXA with respect to cytokine and MMP induction in the early postoperative period. The different cytokine-proteolytic profile between these antifibrinolytics may in turn influence biologic processes in the postoperative period.

Microvascular basis for growth of small infarcts following occlusion of single penetrating arterioles in mouse cortex

Small cerebral infarcts, i.e. microinfarcts, are common in the aging brain and linked to vascular cognitive impairment. However, little is known about the acute growth of these minute lesions and their effect on blood flow in surrounding tissues. We modeled microinfarcts in the mouse cortex by inducing photothrombotic clots in single penetrating arterioles. The resultant hemodynamic changes in tissues surrounding the occluded vessel were then studied using in vivo two-photon microscopy. We were able to generate a spectrum of infarct volumes by occluding arterioles that carried a range of blood fluxes. Those resulting from occlusion of high-flux penetrating arterioles (flux of 2 nL/s or higher) exhibited a radial outgrowth that encompassed unusually large tissue volumes. The gradual expansion of these infarcts was propagated by an evolving insufficiency in capillary flow that encroached on territories of neighboring penetrating arterioles, leading to the stagnation and recruitment of their perfusion domains into the final infarct volume. Our results suggest that local collapse of microvascular function contributes to tissue damage incurred by single penetrating arteriole occlusions in mice, and that a similar mechanism may add to pathophysiology induced by microinfarcts of the human brain.

Functional deficits induced by cortical microinfarcts

Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia.

Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics

OBJECTIVE A robust release of endothelin-1 with subsequent endothelin-A subtype receptor activation occurs in patients after cardiac surgery requiring cardiopulmonary bypass. Increased endothelin-A subtype receptor activation has been identified in patients with poor left ventricular function (reduced ejection fraction). Accordingly, this study tested the hypothesis that a selective endothelin-A subtype receptor antagonist administered perioperatively would favorably affect post-cardiopulmonary bypass hemodynamic profiles in patients with a preexisting poor left ventricular ejection fraction. METHODS Patients (n = 29; 66 +/- 2 years) with a reduced left ventricular ejection fraction (37% +/- 2%) were prospectively randomized in a blinded fashion, at the time of elective coronary revascularization or valve replacement requiring cardiopulmonary bypass, to infusion of the highly selective and potent endothelin-A subtype receptor antagonist sitaxsentan at 1 or 2 mg/kg (intravenous bolus; n = 9, 10 respectively) or vehicle (saline; n = 10). Infusion of the endothelin-A subtype receptor antagonist/vehicle was performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass. Endothelin and hemodynamic measurements were performed at baseline, at separation from cardiopulmonary bypass (time 0), and at 0.5, 6, 12, and 24 hours after cardiopulmonary bypass. RESULTS Baseline plasma endothelin (4.0 +/- 0.3 fmol/mL) was identical across all 3 groups, but when compared with preoperative values, baseline values obtained from age-matched subjects with a normal left ventricular ejection fraction (n = 37; left ventricular ejection fraction > 50%) were significantly increased (2.9 +/- 0.2 fmol/mL, P < .05). Baseline systemic (1358 +/- 83 dynes/sec/cm(-5)) and pulmonary (180 +/- 23 dynes/sec/cm(-5)) vascular resistance were equivalent in all 3 groups. As a function of time 0, systemic vascular resistance changed in an equivalent fashion in the post-cardiopulmonary bypass period, but a significant endothelin-A subtype receptor antagonist effect was observed for pulmonary vascular resistance (analysis of variance; P < .05). For example, at 24 hours post-cardiopulmonary bypass, pulmonary vascular resistance increased by 40 dynes/sec/cm(-5) in the vehicle group but directionally decreased by more than 40 dynes/sec/cm(-5) in the 2 mg/kg endothelin-A subtype receptor antagonist group (P < .05). Total adverse events were equivalently distributed across the endothelin-A subtype receptor antagonist/placebo groups. CONCLUSION These unique findings demonstrated that infusion of an endothelin-A subtype receptor antagonist in high-risk patients undergoing cardiac surgery was not associated with significant hemodynamic compromise. Moreover, the endothelin-A subtype receptor antagonist favorably affected pulmonary vascular resistance in the early postoperative period. Thus, the endothelin-A subtype receptor serves as a potential pharmacologic target for improving outcomes after cardiac surgery in patients with compromised left ventricular function.

Circulating matrix metalloproteinase levels after ventricular septal defect repair in infants

BACKGROUND Surgery for congenital heart disease initiates a complex inflammatory response that can influence the postoperative course. However, broad integration of the cytokine and proteolytic cascades (matrix metalloproteinases: MMPs), which may contribute to postoperative outcomes, has not been performed. METHODS AND RESULTS Using a low-volume (50-60 μL), high-sensitivity, multiplex approach, we serially measured a panel of cytokines (interleukins 2, 4, 6, 8, and 10, tumor necrosis factor alpha, interleukin 1β, and granulocyte-macrophage colony stimulating factor) and matrix metalloproteinases (matrix metalloproteinases 2, 3, 7, 8, 9, 12, and 13) in patients (n = 9) preoperatively and after repair of ventricular septal defect. Results were correlated with outcomes such as inotropic requirement, oxygenation, and fluid balance. Serial changes in perioperative plasma levels of the cytokines and matrix metalloproteinases exhibited distinct temporal profiles. Plasma levels of interleukins 2, 8, and 10 and matrix metalloproteinase 9 peaked within 4 hours, whereas levels of matrix metalloproteinase 3 and 8 remained elevated at 24 and 48 hours after crossclamp removal. Area-under-the-curve analysis of early cytokine levels were associated with major clinical variables, including inverse correlations between early interleukin 10 levels and cumulative inotrope requirement at 48 hours (r: -0.85; P < .005) and late matrix metalloproteinase 7 levels and cumulative fluid balance (r: -0.90; P < .001). CONCLUSIONS The unique findings of this study were that serial profiling a large array of cytokines and proteolytic enzymes after surgery for congenital heart disease can provide insight into relationships between changes in bioactive molecules to early postoperative outcomes. Specific patterns of cytokine and matrix metalloproteinase release may hold significance as biomarkers for predicting and managing the postoperative course after surgery for congenital heart disease.

Comparison of Diffusion Metrics Obtained at 1.5T and 3T in Human Brain With Diffusional Kurtosis Imaging.

To quantitatively compare diffusion metrics for human brain estimated with diffusional kurtosis imaging (DKI) at applied field strengths of 1.5 and 3T.

COMPARING HIPPOCAMPAL EFFECT SIZE BETWEEN ALZHEIMER’S DISEASE AND HEALTHY CONTROLS USING OLDER AND NEWER VERSIONS OF SPM AND FREESURFER

Background: Cerebral microinfarcts (CMI) have been commonly observed in Alzheimer’s Disease (AD) and associated with cognitive impairment (vanVeluw et al., 2017). Previous animal studies demonstrated that CMI may impair white matter pathways and affect brain function that extends beyond lesion boundaries (Summers et al., 2017). Nevertheless, how CMI influences brain structural connectivity in living humans remains largely unknown. Hence, we for the first time aimed to investigate topological features of brain structural networks in relation to CMI presence. We hypothesized that patients with CMI would show disrupted structural network topology in higher-order cognitive networks (the default mode (DMN) and executive networks (ECN)) (Chong et al., 2017). Methods:We examined the structural connectivity based on diffusionMRI data of 92 AD (26 with CMI), 83 cognitive-impairment-no-dementia (CIND, 28 with CMI) and 28 healthy controls without CMI (Table 1). CMIs were