Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction.

Neurodegeneration in mitochondrial disorders is considered irreversible because of limited metabolic plasticity in neurons, yet the cell-autonomous implications of mitochondrial dysfunction for neuronal metabolism in vivo are poorly understood. Here, we profiled the cell-specific proteome of Purkinje neurons undergoing progressive OXPHOS deficiency caused by disrupted mitochondrial fusion dynamics. We found that mitochondrial dysfunction triggers a profound rewiring of the proteomic landscape, culminating in the sequential activation of precise metabolic programs preceding cell death. Unexpectedly, we identified a marked induction of pyruvate carboxylase (PCx) and other anaplerotic enzymes involved in replenishing tricarboxylic acid cycle intermediates. Suppression of PCx aggravated oxidative stress and neurodegeneration, showing that anaplerosis is protective in OXPHOS-deficient neurons. Restoration of mitochondrial fusion in end-stage degenerating neurons fully reversed these metabolic hallmarks, thereby preventing cell death. Our findings identify a previously unappreciated pathway conferring resilience to mitochondrial dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

A mixed methods epidemiological investigation of preventable deaths among U.S. Army soldiers assigned to a rehabilitative warrior transition unit.

BACKGROUND: The prevalence of medical risk factors for suicide (e.g., mental disorders, severe disability, social disruption) may be higher among WTs compared to traditional Army units. Likewise, the extent to which traditional factors that protect soldiers from developing serious mental disorders (e.g., social support, unit cohesion, leadership) are present among soldiers assigned to the WTU is unclear. OBJECTIVES: An epidemiological consultation (EPICON) was conducted in 2010 to assess potential causes for a perceived high rate of suicides and preventable deaths in U.S. Army Warrior Transition Units (WTUs) and to identify potential improvements to the system of care. METHODS OF STUDY: The EPICON focused on: (1) risk factors for suicide/preventable deaths; (2) chronic pain management; (3) utilization of and access to WTU medical and behavioral health (BH) services; and (4) the impact of the WTU environment on mission focus and warrior disposition. BH history was examined for soldiers who died by suicide or preventable death while assigned to the WTU (index cases) and a representative comparison group of non-index case soldiers. Surveys and focus groups were conducted at four WTUs with Warriors in Transition (WTs) and key support staff. RESULTS: The use of psychotropic and/or CNS depressant medications, prevalence of BH diagnoses and substance use disorders, polypharmacy, alcohol use, and a high cumulative number of stressors were identified as important risk factors for preventable deaths in the WTC. Areas of potential improvement to the system of care included addressing negative perceptions of the WTU environment, lack of social support, barriers to accessing BH services and issues related to coordination of care. CONCLUSIONS: There was no one single risk factor found to be associated with an increased likelihood of preventable deaths within the WTU. The unique design and operation of the WTUs as environments focused on treatment and rehabilitation provide both benefits and challenges to recovery and risk mitigation.

Mechanisms of neuronal damage in multiple sclerosis and its animal models: role of calcium pumps and exchangers.

Multiple sclerosis is an inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Increasing evidence indicates that neuronal pathology and axonal injury are early hallmarks of multiple sclerosis and are major contributors to progressive and permanent disability. Yet, the mechanisms underlying neuronal dysfunction and damage are not well defined. Elucidation of such mechanisms is of critical importance for the development of therapeutic strategies that will prevent neurodegeneration and confer neuroprotection. PMCA2 (plasma-membrane Ca(2+)-ATPase 2) and the NCX (Na(+)/Ca(2+) exchanger) have been implicated in impairment of axonal and neuronal function in multiple sclerosis and its animal models. As PMCA2 and NCX play critical roles in calcium extrusion in cells, alterations in their expression or activity may affect calcium homoeostasis and thereby induce intracellular injury mechanisms. Interventions that restore normal PMCA2 and NCX activity may prevent or slow disease progression by averting neurodegeneration.

Identification of differentially expressed proteins in experimental autoimmune encephalomyelitis (EAE) by proteomic analysis of the spinal cord.

The present study used isobaric tags for relative and absolute quantitation (iTRAQ) to identify novel targets in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The expression of 41 proteins was significantly altered in the inflamed spinal cord. Twenty of these are implicated in EAE for the first time and many have previously been shown to play a role in antigen processing, inflammation, neuroprotection, or neurodegeneration.

Prospective randomized comparison of the safety and effectiveness of placement of endocardial pacemaker and defibrillator leads using the extrathoracic subclavian vein guided by contrast venography versus the cephalic approach.

The purpose of this prospective randomized study was to compare the safety and efficacy of the cephalic approach versus a contrast-guided extrathoracic approach for placement of endocardial leads. Despite an increased incidence of lead fracture, the intrathoracic subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by lead placement in the extrathoracic subclavian or axillary vein, these approaches have not gained acceptance. A total of 200 patients were randomized to undergo placement of pacemaker or implantable defibrillator leads via the contrast-guided extrathoracic subclavian vein approach or the cephalic approach. Lead placement was accomplished in 99 of the 100 patients randomized to the extrathoracic subclavian vein approach as compared to 64 of 100 patients using the cephalic approach. In addition to a higher initial success rate, the extrathoracic subclavian vein medial approach was determined to be preferable as evidenced by a shorter procedure time and less blood loss. There was no difference in the incidence of complications. In conclusion, these results demonstrate that lead placement in the extrathoracic subclavian vein guided by contrast venography is effective and safe. It was also associated with no increased risk of complications as compared with the cephalic approach. These findings suggest that the contrast-guided approach to the extrathoracic portion of the subclavian vein should be considered as an alternative to the cephalic approach.

Design and synthesis of 2-oxo-imidazolidine-4-carboxylic acid hydroxyamides as potent matrix metalloproteinase-13 inhibitors.

A novel series of imidazolidinone-based matrix metalloproteinase (MMP) inhibitors was discovered by structural modification of pyrrolidinone la. Potent inhibition of MMP-13 was exhibited by the analogues having 4-(4-fluorophenoxy)phenyl (4a, IC50 = 3 nM) and 4-(naphth-2-yloxy)phenyl (4h, IC50 = 4 nM) as P1' groups.

Contrast agent-enhanced magnetic resonance imaging of skeletal muscle damage in animal models of muscular dystrophy.

Membrane lesions play an early role in the pathogenesis of muscular dystrophy. Using a new albumin-targeted contrast agent (MS-325), sarcolemmal integrity of two animal models for muscular dystrophy was studied by MRI. Intravenously injected MS-325 does not enter skeletal muscle of normal mice. However, mdx and Sgca-null mutant mice, animal models for Duchenne and sarcoglycan-deficient limb-girdle muscular dystrophy, respectively, showed significant accumulation of MS-325 in skeletal muscle. The results suggest that contrast agent-enhanced MRI could serve as a common, noninvasive imaging procedure for evaluating the localization, extent, and mechanisms of skeletal muscle damage in muscular dystrophy. Furthermore, this method is expected to facilitate assessment of therapeutic approaches in these diseases.

Computed tomography vs. magnetic resonance imaging of acute bacterial sinusitis: a rabbit model.

PURPOSE: Computed topography (CT) and magnetic resonance imaging (MRI) are important, both clinically and in a research setting, in assessing bacterial sinusitis (BS). The use of CT scanning to evaluate sinus opacification in a reversible model of rabbit acute sinusitis has been reported. MRI offers the potential for better visualization of soft tissue and fluid changes within the paranasal sinuses. MRI has potential as a research tool in animal models of sinusitis. This article compares the use of CT and MRI in measuring maxillary sinus opacification in rabbits during experimental, reversible BS. MATERIALS AND METHODS: In 2 independent trials, New Zealand White rabbits were imaged for baseline anatomy, and BS was generated by sinus inoculation with Staphylococcus aureus. Serial imaging was performed as a measure of the progression and resolution of BS during the trials. Two experienced, independent reviewers then scored each CT and MRI for percent opacification of the maxillary sinus. These scores were analyzed to assess the degree of agreement between the reviewers. RESULTS: The correlation coefficients for CT and MRI were 0.6816 and 0.3584, respectively. The Z-statistic comparing these correlation coefficients was significant (P < .0001), indicating that CT is a more precise measure of reversible BS in this rabbit model. Differences in mean scan time and cost per scan were also significantly different (P < .0001), with CT being both quicker and less expensive. CONCLUSIONS: Greater interobserver consistency of scan interpretation, with less time and cost, make CT the preferred tool for measuring BS in this rabbit model. Attributes of MRI such as better resolution of fluid-tissue interfaces and custom surface coil design for visualization of specific anatomic structures are discussed as they may increase the effectiveness of MRI as an imaging modality in future sinusitis research.

Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice.

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is the most common cause of LGMD with a sarcoglycan defect. We recently engineered a murine model for this progressive disease and we investigated the possibility of preventing the development of muscular dystrophy in these animals by adenovirus-mediated gene transfer of human alpha-sarcoglycan. Here we report that a single intramuscular injection of a first generation adenovirus into the skeletal muscle of neonate mice led to sustained expression of alpha-sarcoglycan at the sarcolemma of transduced myofibers for at least 7 months. The morphology of transduced muscles was consequently preserved. In addition, we have used contrast agent-enhanced magnetic resonance imaging (MRI) to investigate sarcolemmal integrity in adenovirus-injected animals and have thereby demonstrated maintenance of sarcolemmal function. In conclusion, we provide evidence that early virus-mediated gene transfer of a sarcoglycan protein constitutes a promising therapeutic strategy for LGMDs and that the benefits of this approach can easily and effectively be monitored by noninvasive methodologies such as MRI.

Discrimination between neoplastic and nonneoplastic brain lesions by use of proton MR spectroscopy: the limits of accuracy with a logistic regression model.

BACKGROUND AND PURPOSE: The most accurate method of clinical MR spectroscopy (MRS) interpretation remains an open question. We sought to construct a logistic regression (LR) pattern recognition model for the discrimination of neoplastic from nonneoplastic brain lesions with MR imaging-guided single-voxel proton MRS data. We compared the LR sensitivity, specificity, and receiver operator characteristic (ROC) curve area (Az) with the sensitivity and specificity of blinded and unblinded qualitative MRS interpretations and a choline (Cho)/N-acetylaspartate (NAA) amplitude ratio criterion. METHODS: Consecutive patients with suspected brain neoplasms or recurrent neoplasia referred for MRS were enrolled once final diagnoses were established by histopathologic examination or serial neurologic examinations, laboratory data, and imaging studies. Control spectra from healthy adult volunteers were included. An LR model was constructed with 10 input variables, including seven metabolite resonance amplitudes, unsuppressed brain water content, water line width, and the final diagnosis (neoplasm versus nonneoplasm). The LR model output was the probability of tumor, for which a cutoff value was chosen to obtain comparable sensitivity and specificity. The LR sensitivity and specificity were compared with those of qualitative blinded interpretations from two readers (designated A and B), qualitative unblinded interpretations (in aggregate) from a group of five staff neuroradiologists and a spectroscopist, and a quantitative Cho/NAA amplitude ratio > 1 threshold for tumor. Sensitivities and specificities for each method were compared with McNemar's chi square analysis for binary tests and matched data with a significance level of 5%. ROC analyses were performed where possible, and Az values were compared with Metz's method (CORROC2) with a 5% significance level. RESULTS: Of the 99 cases enrolled, 86 had neoplasms and 13 had nonneoplastic diagnoses. The discrimination of neoplastic from control spectra was trivial with the LR, reflecting high homogeneity among the control spectra. An LR cutoff probability for tumor of 0.8 yielded a specificity of 87%, a comparable sensitivity of 85%, and an area under the ROC curve of 0.96. Sensitivities, specificities, and ROC areas (where available) for the other methods were, on average, 82%, 74%, and 0.82, respectively, for readers A and B, 89% (sensitivity) and 92% (specificity) for the group of unblinded readers, and 79% (sensitivity), 77% (specificity), and 0.84 (Az) for the Cho/NAA > 1 criterion. McNemar's analysis yielded significant differences in sensitivity (n approximately 86 neoplasms) between the LR and reader A, and between the LR and the Cho/NAA > 1 criterion. The differences in specificity between the LR and all other methods were not significant (n approximately 13 nonneoplasms). Metz's analysis revealed a significant difference in Az between the LR and the Cho/NAA ratio criterion.

Joint Commission International accreditation: relationship to four models of evaluation.

OBJECTIVE: To describe the components of the new Joint Commission International (JCI) accreditation program for hospitals, and compare this program with the four quality evaluation models described under the ExPeRT project (visitatie, ISO, EFQM, organizational accreditation). RESULTS: All the models have in common with the JCI program the use of explicit criteria or standards, and the use of external reviewers. The JCI program is clearly an organizational accreditation approach with evaluation of all the 'systems' of a health care organization. The JCI model evaluates the ability of an organization to assess and monitor its professional staff through internal mechanisms, in contrast with the external peer assessment used by the visitatie model. The JCI program provides a comprehensive framework for quality management in an organization, expanding the boundaries of the quality leadership and management found in the EFQM model, and beyond the quality control of the ISO model. The JCI organizational accreditation program was designed to permit international comparisons, difficult under the other models due to country specific variation. CONCLUSION: We believe that the organizational accreditation model, such as the international accreditation program, provides a framework for the convergence and integration of the strengths of all the models into a common health care quality evaluation model.

Utility of simultaneously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients.

An interleaved gradient-echo (GE) / spin-echo (SE) EPI sequence was used to acquire images during the first pass of a susceptibility contrast agent, in patients with brain tumors. Maps of 1) GE (total) rCBV (relative cerebral blood volume), 2) SE (microvascular) rCBV, both corrected for T(1) leakage effects, and 3) (DeltaR(2)*/DeltaR(2)), a potential marker of averaged vessel diameter, were determined. Both GE rCBV and DeltaR(2)*/DeltaR(2) correlated strongly with tumor grade (P = 0.01, P = 0.01, n = 15), while SE rCBV did not (P = 0.24, n = 15). When the GE rCBV data were not corrected for leakage effects, the correlation with tumor grade was no longer significant (P = 0.09, n = 15). These findings suggest that MRI measurements of total blood volume fraction (corrected for agent extravasation) and DeltaR(2)*/DeltaR(2), as opposed to maps of microvascular volume, may prove to be the most appropriate markers for the evaluation of tumor angiogenesis (the induction of new blood vessels) and antiangiogenic therapies. Magn Reson Med 43:845-853, 2000.

Perceiving the lengths of rods wielded in different media.

In two experiments, we investigated the ability of participants to report the lengths of rods wielded in air or water. Homogeneous aluminum rods were employed in Experiment 1. The inertia of the rods was manipulated in Experiment 2 through the use of attached masses. Although the torques required in order to wield rods in water are substantially greater than those required to wield rods in air, the perceived lengths of rods wielded in the two media were very similar. Perceived length was found to be a function primarily of inertia in both media. The experiments also revealed a small influence of resistance due to the denser medium of water. The results demonstrate the ability of perceivers to extract a physical invariant from a complex array of forces. The discussion is focused on the role of invariants in dynamic touch.

Simultaneous gradient-echo/spin-echo EPI of graded ischemia in human skeletal muscle.

The goal of this study was to evaluate the usefulness of blood oxygenation level-dependent (BOLD) methodologies to provide temporal and spatial information about skeletal muscle perfusion. A simultaneous gradient echo (GE) and spin-echo (SE) imaging sequence (GE/SE) with alternating TE was used to acquire images of leg skeletal muscle throughout a stepped reactive hyperemia paradigm. The change in both the GE and SE relaxation rates (deltaR2*, deltaR2) measured during ischemia and reactive hyperemia scaled with the duration of cuff inflation (the ischemic period) plateaued for cuff inflations lasting longer than 120 seconds and were greater in soleus muscle than in gastrocnemius. The ratio deltaR2*/deltaR2 was found to be less during the reactive hyperemia period relative to ischemia. Considering that a greater proportion of capillary vessels are perfused during reactive hyperemia than during ischemia, this finding suggests that magnetic susceptibility methodologies, with their dependence on compartment size, may provide a measure of the relative distribution of small and large vessels in skeletal muscle.

Water diffusion and exchange as they influence contrast enhancement.

The contrast-enhanced magnetic resonance imaging (MRI) signal is rarely a direct measure of contrast concentration; rather it depends on the effect that the contrast agent has on the tissue water magnetization. To correctly interpret such studies, an understanding of the effects of water movement on the magnetic resonance (MR) signal is critical. In this review, we discuss how water diffusion within biological compartments and water exchange between these compartments affect MR signal enhancement and therefore our ability to extract physiologic information. The two primary ways by which contrast agents affect water magnetization are discussed: (1) direct relaxivity and (2) indirect susceptibility effects. For relaxivity agents, for which T1 effects usually dominate, the theory of relaxation enhancement is presented, along with a review of the relevant physiologic time constants for water movement affecting this relaxation enhancement. Experimental issues that impact accurate measurement of the relaxation enhancement are discussed. Finally, the impact of these effects on extracting physiologic information is presented. Susceptibility effects depend on the size and shape of the contrast agent, the size and shape of the compartment in which it resides, as well as the characteristics of the water movement through the resulting magnetic field inhomogeneity. Therefore, modeling of this effect is complex and is the subject of active study. However, since susceptibility effects can be much stronger than relaxivity effects in certain situations, they may be useful even without full quantitation.