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September 17, 2010
ARDMS Updates and Headlines in the News:
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3D TEE Bests 2D TEE in Mitral Regurgitation Grading
Advanced Imaging Redefining Neurologic Disease
New Pathway Identified in Parkinson's Through Brain Imaging
3D TEE Bests 2D TEE in Mitral Regurgitation Grading
3D transesophageal echocardiography (TEE) is superior to 2D TEE for quantifying the severity of mitral regurgitation, according to researchers from Leiden University Medical Center in Leiden, the Netherlands.
In a paper published online in Circulation: Cardiovascular Imaging, a study team led by Miriam Shanks, MD, concluded that 3D TEE was both feasible and accurate compared to MRI quantitative assessment. The group also found that 3D TEE was less prone than 2D TEE to underestimate regurgitant volume.
The American Society of Echocardiography (ASE) emphasizes that quantitative techniques be used to assess mitral regurgitation to provide risk stratification and clinical management of patients with this condition. However, the standard approach of 2D color-flow and Doppler echocardiography with the proximal isovelocity surface area (PISA) method has been problematic for grading regurgitant volume (marker of volume overload) and effective regurgitant orifice area (descriptor of lesion severity), according to the researchers.
Hoping to make use of recent 3D TEE technology advances, the study team sought to compare the performance of 2D and 3D TEE using MRI as a reference method (Circulation: Cardiovascular Imaging, September 1, 2010).
The researchers studied 30 patients (20 men, 10 women; mean age, 63.3 years) who were clinically referred for TEE and cardiac MRI for assessment of mitral regurgitation. Exclusion criteria included patients with irregular heart rhythm, a history of mitral valve replacement, significant aortic or tricuspid valve regurgitation, or absolute contraindications to TEE and MRI.
All patients received 2D and 3D TEE as well as a cardiac MRI on the same day.
Both 2D and 3D TEE were performed using an iE33 ultrasound scanner (Philips Healthcare, Andover, MA) with an X7-2t fully sampled matrix-array TEE transducer.
After complete 2D, color, pulsed-, and continuous-wave Doppler images were obtained for assessing cardiac structures and function, the researchers quantitatively determined mitral regurgitation severity from the four-chamber views obtained at midesophageal level with zero-degree tilt.
In both TEE methods, mitral effective regurgitant orifice area and regurgitant volume were estimated. Mitral effective regurgitant orifice area was calculated from 3D TEE using planimetry of the color Doppler flow from "en face" views, while regurgitant volume was determined by multiplying the mitral effective regurgitant orifice area by the velocity time integral of the regurgitant jet on the continuous-wave Doppler, according to the authors.
2D measurements of effective regurgitant orifice area and regurgitant volume were generated using the standard proximal isovelocity surface area method.
MR images were captured on a Gyroscan ACS-NT/Intera 1.5-tesla scanner (Philips), with a five-element cardiac synergy coil. Mitral regurgitant volume was determined by subtracting the aortic flow volume from left ventricular stroke volume, according to the researchers.
The group discovered that 2D TEE underestimated the mitral effective regurgitant orifice area by a mean of 0.13 cm2 compared to 3D TEE. 2D TEE was also found to underestimate the regurgitant volume by 21.6% compared to 3D TEE and by 21.3% compared to MRI.
"In contrast, 3D TEE underestimated the [regurgitant volume] by only 1.2% when compared to MRI," the authors noted.
In other findings, the researchers noted that one-third of the patients in grade 1 (moderate regurgitation) and 50% or more of patients in grades 2 and 3 (moderate to severe regurgitation) would have been upgraded to a more severe grade based on the 3D TEE and MRI measurements, compared with what they would have received under 2D TEE.
The study team also detected good intraobserver variability (mean difference of 0.011 ± 0.16 cm2; intraclass correlation coefficient = 0.98) and interobserver variability (mean difference of 0.013 ± 0.14 cm2; intraclass correlation coefficient = 0.98) in a comparison of 3D mitral effective regurgitant orifice area measurements.
"The present study demonstrated that 3D TEE is feasible, and is more accurate in the quantitative assessment of both functional and organic mitral regurgitation when compared to 2D TEE," the authors concluded. "Given the potential strengths of 3D echocardiography, prospective studies to determine the importance of the 3D data for the clinical outcome may be needed.
View the article online
Article written by staff at auntminnie.com and adapted for the purposes of this newsletter.
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Advanced Imaging Redefining Neurologic Disease
Specialists are gaining new insights about the brain that are revolutionizing the field and beginning to have an effect on practice. Presenting here at the American Neurological Association 135th Annual Meeting, experts described how new diagnostic technologies such as functional magnetic resonance, diffusion tensor imaging, tractography, magnetoencephalography, and optical imaging are already redefining neurologic disease.
"We're starting to see there is an entire brain response to disease, and that much more is affected than just the site of injury," session chair Frances Jensen, MD, from Harvard University in Boston, Massachusetts, said. "We're learning there is actually a structural reorganization that takes place in the brain."
Those changes to network and regional brain connectivity are reportedly present in stroke, dementia, epilepsy, and even neuropsychiatric illnesses.
"We can think of anatomical connectivity like a highway," Maurizio Corbetta, MD, from Washington University in St. Louis, Missouri, said at the meeting. "Functional connectivity is also like a highway, but is weighted by traffic," he explained, noting that heavy traffic leads to high connectivity, and light traffic to low connectivity.
"A network that fires together, wires together, and might even expire together," he suggested.
Dr. Corbetta says that stroke and brain injury produce changes in functional connectivity even in regions of the brain that are not structurally damaged. Still, these physiological changes result in behavioral deficits.
Dr. Corbetta won the Foster Elting Bennett Memorial Lectureship Award for outstanding researchers and educators at the meeting.
Blurring Line Between Neurology and Psychiatry
This increasing understanding has called into question some of the arbitrary division between specialties. "The line between neurology and psychiatry is fading," Dr. Jensen said during an interview.
"In recent years, there is a growing appreciation of large-scale brain networks that support active human mentation," said presenter John Gabrieli, PhD, from the Massachusetts Institute of Technology in Cambridge.
Neuroimaging studies have historically concentrated on localizing mental functions in the brain. However, a growing appreciation of network and regional brain connectivity is shifting that focus. Imaging tools can now be used to examine developmental disorders such as dyslexia, autism, and attention-deficit hyperactivity disorder.
At the meeting here, Dr. Gabrieli described resting-state connectivity of the default-mode network, brain regions associated with introspection. He showed how this network is chronically hyperactivated and hyperconnected in patients with schizophrenia.
When healthy people are at rest, Dr. Gabrieli explained, the medial dorsolateral and prefrontal cortices are not correlated, but in patients with schizophrenia and bipolar disorder, they are linked. This may also explain cognitive dysfunction in both disorders.
Michael Greicius, MD, from Stanford University in Palo Alto, California, also addressed the default-mode network of the brain during his talk on Alzheimer's disease. The posterior regions of the default-mode network tend to overlap considerably with brain regions that show reduced glucose metabolism in the earliest stages of Alzheimer's disease, he pointed out, and even in young, healthy individuals at increased risk.
The default-mode network can be detected, characterized, and quantified using resting-state functional magnetic resonance imaging, Dr. Greicius noted. This measures interregional temporal correlations in signal fluctuations.
"Using these functional connectivity approaches, our group and others have demonstrated reduced functional connectivity in the default-mode network in Alzheimer's disease, mild cognitive impairment, healthy older controls with prominent amyloid plaque burden, and healthy older carriers of the ApoE4 allele," he said.
In addition to functional changes, this brain network also appears to undergo structural changes and overlap to some degree with maps of amyloid plaque distribution, Dr. Greicius explained.
Connectivity may also be altered in epilepsy, Ellen Grant, MD, from Harvard University, pointed out at the meeting. Dr. Grant showed how multiple modalities can be combined with conventional neurophysiology to understand seizure spread.
"This work is in practical use right now in epilepsy," Dr. Jensen added. "Epilepsy is a major connectivity disorder, and these imaging techniques are already being applied to patients."
The optimal management of a patient with epilepsy includes determining the focus of ictal onset and evaluating the extent of network involvement, Dr. Grant said at the meeting.
"Currently, 3T imaging with 32 channel coils and motion-corrected sequences provide the highest-quality images for detection of subtle structural lesions," she said. "But confirming ictal onset from identified structural lesions currently requires electroencephalography, magnetoencephalography, and intracranial grids and depth electrodes for validation."
Evaluating functional network involvement is performed with functional magnetic resonance imaging, neurological exam, and neuropsychological testing, as well as Wada tests in some centers, she notes.
"I hope clinicians will understand that the patient in front of them who is dealing with a deficit has this issue not only from a structural lesion, but also network involvement," Alex Carter, MD, who works with Dr. Corbetta at Washington University, said.
"We now have tools to assess these secondary abnormalities that we were previously unable to even look for," he noted.
View the article online
Article written by staff at medscape.com and adapted for the purposes of this newsletter.
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New Pathway Identified in Parkinson's Through Brain Imaging
A new study led by researchers at Columbia University Medical Center has identified a novel molecular pathway underlying Parkinson’s and points to existing drugs which may be able to slow progression of the disease.
The pathway involved proteins known as polyamines that were found to be responsible for the increase in build-up of other toxic proteins in neurons, which causes the neurons to malfunction and, eventually, die. Though high levels of polyamines have been found previously in patients with Parkinson's, the new study which appeared in an early online edition of Proceedings of the National Academy of Sciences is the first to identify a mechanism for why polyamines are elevated in the first place and how polyamines mediate the disease.
The researchers also demonstrated in a mouse model of Parkinson's disease that polyamine-lowering drugs had a protective effect.
"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," said Scott A. Small, MD, the senior author of the study and Herbert Irving Associate Professor of Neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's."
Currently, treatments for Parkinson's can help alleviate some of the disease's symptoms, but they cannot prevent the build-up of toxic proteins and the death of neurons caused by the disease. When polyamines were scrutinized decades ago as a potential therapy against cancer, polyamine-lowering drugs were tested and have completed the Phase 1 and 2 safety stages of clinical trials. However, whether the drugs can pass through the blood-brain barrier remains to be determined and further testing will be needed. If the drugs can reduce the level of polyamines in the brain, they may pave the way for a Parkinson's treatment that can slow the disease's progression.
"This research has the potential to progress quickly," said James Beck, PhD, director of research programs at the Parkinson's Disease Foundation, which helped support the research. "Equally exciting are the new avenues of research this study opens, hopefully leading to better treatments for Parkinson's Disease down the road."
Though many cellular defects have been found to cause rare, inherited forms of Parkinson's disease, most cases of Parkinson's are caused by unknown changes inside the brain's neurons.
The researchers used a wide variety of scientific techniques to search for still unidentified defects in the brain. The suite of techniques which started with high resolution brain imaging has been used to reveal previously unknown molecules in the brain that worsen Alzheimer's disease.
Imaging Reveals Brainstem Defect in Parkinson's Patients
Using high resolution functional magnetic resonance imaging (fMRI), Nicole Lewandowski, PhD, who is currently a post-doctoral research scientist in Dr. Small's lab, identified such regions in the brainstem of patients with Parkinson's. The scans showed that one region of the brainstem was consistently less active in these patients than in healthy control subjects. Also revealed in the scans was a neighboring region that was unaffected by the disease.
Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences.
"One such protein we found, called SAT1, stood out," said Dr. Small. "Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease."
Three Experiments Confirm Polyamines Are Pathogenic
To validate the finding, three separate studies in yeast, mice, and people were performed.
The yeast studies revealed that polyamines promote the accumulation of a toxic Parkinson's-causing protein in living cells, and not just in test tubes, as was known from previous research. Conducted by Gregory Petsko, PhD, the Gyula and Katica Tauber Professor of Biochemistry and Chemistry and Chair of Biochemistry at Brandeis University and Dagmar Ringe, PhD, the Harold and Bernice Davis Professor of Aging and Neurodegenerative Disease Research at Brandeis, the new studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. Furthermore, in a screen conducted for mediators of Parkinson's toxins in the lab of Susan Linquist, PhD, professor of biology in the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute at MIT, other genes related to polyamine transport were identified.
In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the UC San Diego School of Medicine, found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in nearly 100 patients with Parkinson's and additional genotyping in a further ~800 subjects (389 PD patients and 408 controls), enrolled in the Genetic Epidemiology of Parkinson's disease study at CUMC, Columbia geneticist Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, MPH, who is the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.
"Even though the variant was rare in patients with Parkinson's, finding it was surprising and further strengthens the possibility that defects in the polyamine pathway help to trigger the disease," said Dr. Small.
Dr. Small is now testing current polyamine-lowering drugs to see if the compounds can pass through the blood-brain barrier, or if they can be altered to do so. Drugs that pass through the blood-brain barrier can be administered more easily (e.g., they can be taken by mouth) instead of directly infusing them into the brain.
View the article online
Article written by staff at medicalnewstoday.com and adapted for the purposes of this newsletter.
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NewsWire. Copyright 2010. American Registry for Diagnostic Medical Sonography. The ideas and opinions expressed herein do not necessarily reflect those of ARDMS.
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