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Wednesday, April 16, 2014


Scientists at Johns Hopkins University School of Medicine have identified the elusive mechanism that might be responsible for the jerky movements, unsteady gait, and cognitive and psychiatric problems of Huntington’s disease (HD), an autosomal genetic disorder that usually emerges in adulthood. 

     Working with mouse models of HD, the scientists found that mutant huntingtin protein interrupts the transcription of specificity protein 1 (Sp1), the transcriptional activator of cystathionine gamma lyase (CSE), an enzyme that contributes to the synthesis of the amino acid cysteine from cystathionine. The lack of CSE contributes to the oxidative stress and mitochondrial dysfunction found in the HD brain, they reported in the March 26 online edition of Nature.

     The researchers found decreased levels of CSE in the striatum, hippocampus, hypothalamus, and brainstem of the HD mice. In postmortem tissue from human HD patients, they found CSE levels were profoundly reduced in the striatum and moderately reduced in the cerebral cortex, but not in the cerebellum. The amount of depletion of CSE correlated with severity of Huntington’s disease.

      They also looked at CSE levels in postmortem tissue from patients with other neurodegenerative diseases, and found that the CSE was not reduced in brain tissue from patients with amyotrophic lateral sclerosis, multiple sclerosis, or spinocerebellar ataxia (SCA), even though SCA, like HD, results from a mutant gene that contains too many CAG repeats.  

     Adding cysteine to the diet of HD mice delayed onset of motor abnormalities, such as hind limb clasping, poor rotarod performance, and weak grip strength; increased survival; and partially reversed decreases in brain weight and striatal volume.

The research began when first author Bindu Diana Paul, PhD, a molecular neuroscientist in the laboratory of Solomon H. Snyder, MD, in the department of neuroscience at Johns Hopkins University School of Medicine, noticed that the CSE knockout mice she had been studying behaved like HD mice when she picked them up. Instead of struggling to get free like normal mice, they clasped their hind paws together, which suggested a neurological deficit. 

      Few people had studied CSE in the brain, so Dr. Snyder and Dr. Paul investigated and found that CSE was lower than normal in HD mice and humans with the disease. They found that mutant huntingtin protein was binding to the transcription factor that turned the CSE gene on or off, which resulted in depletion of CSE and, presumably, of cysteine. 

The findings could have clinical implications, Dr. Snyder told Neurology Today. “This work implies that the loss of CSE may be a major cause of neurologic disability, and that replacing the missing cysteine with N-acetylcysteine (a precursor of cysteine) might be therapeutic,” he said. “N-acetylcysteine is an antioxidant that people have been taking for many years.”

     See what Huntington’s disease specialists had to say about this research in the May 1 issue of Neurology Today. Read our previous stories on Huntington’s disease here.

Monday, April 07, 2014
by Jamie Talan

Researchers identified 10 lipids or fats that were powerful enough to predict phenoconversion to either mild cognitive impairment (MCI) or Alzheimer’s disease (AD) within a two- to three-year study period with 90 percent accuracy.

     While the findings emerged from a relatively small sample of patients, experts in the field told Neurology Today that the results, published online first on March 9 in Nature Medicine, are encouraging and should be replicated in larger data sets. Identifying preclinical AD disease with a blood test — much like screening for cholesterol for heart disease and/or stroke — could change the course of the disease for future generations of older people, they said.

Howard J. Federoff, MD, PhD, executive dean of Georgetown University School of Medicine, who led the research team, noted that others have identified potential blood markers but none have been replicated so far. The problem, he said, is that there are substantial circadian variations in metabolism and finding a true signature is difficult.

      Knowing that there are changes in metabolism and gene expression throughout the day and in response to eating and medication, the researchers added a critical design change to their study: they collected blood after a night of fasting and before a person had any of his or her daily medications on board. He believes that this pure blood sample helped in the identification of these newly identified markers.

“I think that our success in identifying these markers is because of the way we looked at the blood and our collection method,” said Dr. Federoff.

The researchers enrolled and monitored 525 healthy people for five years; all were at least 70 years old and were living independently in the community. Over the course of the study, 74 of them met criteria for MCI or mild AD. Forty-six had incidental MCI or AD when they entered the study and 28 had phenoconverted from a cognitively fit state to MCI or AD. The average time to phenoconversion was 2.5 years. The scientists had a control group of age-, gender-, and education-matched cognitively normal people.  
     Using tandem mass spectrometry to identify metabolites, the researchers analyzed 124 plasma samples from 106 study participants. They were able to identify and qualify lipids, amino acids, and biogenic amines. 

In the third year of the study, they selected 53 people diagnosed with MCI or AD whose blood would be screened for metabolomics and lipidomic biomarker discovery. Eighteen patients had converted during the observational period. They compared the findings with 53 people in the control group. 

Dr. Federoff said that the analysis showed significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, phosphatidylcholines (PC), taurine, and acylcarnitines (AC) in the converters. They identified 10 lipids that were depleted in the converters and not the controls.

“We posit that this ten-phospholipid biomarker panel…reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to amnesic MCI or AD, and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” the scientists wrote in the Nature Medicine paper.
“Our data has led to a new set of biological insights,” Dr. Federoff added. “This is an area of biology we have to probe more deeply.”
    Stay tuned for the full discussion of the findings and their implications for Alzheimer's researchers and patients in the April 17 issue of Neurology Today. For now, read our collection of articles on the search for Alzheimer's disease biomarkers: http://bit.ly/1oHxDp1.

Thursday, April 03, 2014

There has been a great deal of attention in the lay press recently to the legalization of medical marijuana — but what do the clinicians and prescribers think about these efforts? A new survey compiled by WebMD set out to answer this important question. Most doctors (including neurologists), they found, were optimistic about marijuana’s role in improving patient care.

The Medscape Medical Marijuana Physician Survey was completed by 1,544 physicians from more than 12 specialties between Feb. 25 and March 3, 2014. The invitations to the online survey were sent over e-mail to participants chosen at random by specialty. Neurologists, who were among the survey respondents, reported the highest number of patients asking if medical marijuana might help them (70 percent). 

When asked if they believed that marijuana “could deliver real benefit” to patients with certain conditions, 69 percent of clinicians answered “yes.” Furthermore, 68 percent of doctors said “marijuana should be a medical option for patients.” More than half of responders said medical marijuana should be legalized nationwide. (The margin of error of was ± 2.5% at a 95% confidence level.) 

How about neurologists? In an upcoming story in the April 17 issue of Neurology Today, we will look at what neurologists have to say about the potential benefits and knowledge gaps in offering medical marijuana to patients. For now, see our previous coverage on medical marijuana for neurological disorders:  http://bit.ly/1fnIhro.

Wednesday, April 02, 2014

For the 17th time in a decade, Congress has voted to delay the 24-percent cut in payment rates for physicians who accept Medicare patients. The Senate voted earlier this week to pass HR. 4302, which provides yet another temporary, 12-month patch to the Sustainable Growth Rate (SGR).

The SGR, which dictates how physicians are reimbursed for Medicare patients, was originally created by the Balanced Budget Act of 1997. Over the past decade, the cost of treating these patients has far exceeded the rate of GDP (gross domestic product) growth, so the SGR formula demands that these payments be cut. 

This latest SGR “patch” comes as a disappointment to the nearly 90 medical organizations and societies who have petitioned to repeal the SGR and enact a longer-term solution (see the letter here). 

“Unfortunately, passage of this short-term patch effectively ends the months and months of work done to develop bipartisan, bicameral legislation to permanently repeal the SGR. This is a major blow to everyone involved,” wrote Mike Amery, Esq. Legislative Counsel at the AAN.

The bill will also delay the implementation of ICD-10 diagnosis coding until Oct. 1, 2015. See Neurology Today’s advice on preparing for these changes here 

According to the AAN’s Capitol Hill Report, the additional effects of this bill include:

  • A 12-month extension of the geographic adjustment (GPCI) "floor" of 1.0 for physician work in the Medicare fee schedule
  • The Secretary of Health and Human Services would have discretion to continue suspending Recovery Audit Contractor post-payment audits under the "Two-midnight" policy through March 2015
  • Revises the laboratory fee schedule based on market-based private sector rates
  • Adjusts payments for CT equipment that does not meet certain dosage standards and implements appropriate use criteria for advanced imaging services
  • In 2024, adjustments to sequestration's physician cut would increase to 4 percent for the first six months, followed by zero percent for the second six months; this is done to amplify the impact of the cut and generate more savings

The AAN will continue to analyze and interpret the provisions of this newest patch, as well as the possible long-term solutions. Read Neurology Today’s collection of “Policy Watch” articles for more information on policy changes and how they affect your neurology practice: http://bit.ly/1iZMjdu.

Tuesday, April 01, 2014

For the first time, the US Food and Drug Administration (FDA) has approved the drug topiramate (Topamax) for migraine prevention in adolescents, ages 12 to 17. Topiramate is indicated for daily use in order to reduce the frequency of migraine headaches. The drug was first approved by the FDA in 1996 to prevent seizures. In 2004, topiramate was approved for migraine prevention in adults.

The approval is based on safety and efficacy data from a clinical trial of 103 adolescents (ages 12 to 17). The trial showed a significant decrease (p=0.016) in monthly migraine frequency in those individuals taking 100 mg of topiramate (72 percent) compared with those taking placebo (44 percent). The study was published in a 2009 edition of Pediatrics by Donald Lewis, MD, of Eastern Virginia Medical School, and colleagues.

Common adverse effects included paresthesia, upper respiratory infection, loss of appetite, and abdominal pain. The FDA warned that the drug should be dispensed with a Medication Guide that provides safety information about the drug. Some potentially serious side effects may include suicidal thoughts and behavior, depression, unusual changes in mood or behavior, and birth defects in infants born to women who take the drug during pregnancy. 

opiramate is manufactured by Janssen Pharmaceuticals, Inc. of Titusville, N.J.

Read our previous stories on migraine in adolescents: http://bit.ly/QCnpHC. Also, see Neurology Today’s previous coverage of topiramate: http://bit.ly/1fKrMG6.