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Tuesday, September 02, 2014
by Jamie Talan
Since the first risk gene for late-onset Alzheimer’s disease was identified 20 years ago, researchers have been trying to understand why people with a certain polymorphism for the apolipoprotein E gene, E4 (APOE4), have a higher risk of developing Alzheimer’s disease (AD) than those with E2 or E3 polymorphisms.
Now, scientists at the University of California, San Francisco (UCSF) contend there is evidence to suggest that reducing the amount of APOE4 in the brain may offer a new venue for treating AD. The report appears in the Aug. 11 online edition of the Journal of the American Medical Association-Neurology (JAMA Neurology).
Mary J. Malloy, MD, and John Kane, MD, PhD and their colleagues at UCSF have been studying a man who was born without any form of APOE and has since childhood had unusually extensive abnormal growths called xanthomas on his hands, feet, elbows, knees, and ears. As a consequence of the lack of APOE, he has severe dysbetalipoproteinemia, which causes elevated levels of cholesterol and triglycerides in the blood.
Tuberous xanthomas, dermatologic manifestations of a lipid disorder. From: Gold DH, MD, and Weingeist TA, MD, PhD. Color Atlas of the Eye in Systemic Disease. Baltimore: Lippincott Williams & Wilkins, 2001.
Given the interest in APOE4 and the risk for AD, the scientists set out to do an extensive neurocognitive and neurological assessment of this patient to ask the obvious question: Would he be at increased risk for AD or have some serious neurological defect? He was 40 years old at the time of these tests.
There has been a concern that a “knockdown” therapy directed at APOE could have serious harmful effects on the brain because APOE is a constituent protein of the brain. The authors of the JAMA Neurology study reported, however, that the man who lacked APOE had an essentially normal cognitive profile and showed no signs of AD pathology in the brain. The researchers concluded that people may be able to thrive cognitively without an APOE gene and thus treatments that attempted to reduce expression of E4 might help, and, at worst, would not be harmful.
The patient was referred to Dr. Malloy, a co-director of the Adult Lipid Clinic and director of the Pediatric Lipid Clinic at UCSF, for help in controlling his high cholesterol and triglyceride levels. DNA analysis identified a large deletion in the APOE gene that blocked all production of the protein. The mutation is on an E3 allele background. It was the first such case that Dr. Malloy had seen in her career. Although several cases have been reported in the medical literature that could involve complete deletion of the APOE protein, no previous report included extensive neurocognitive assessment.
Dr. Malloy referred the patient to Bruce Miller, MD, who directs the dementia center at UCSF. There, the patient underwent a complete neurocognitive assessment, including an MRI to look for pathological structural changes, and a spinal tap to assess possible amyloid build-up in the cerebrospinal fluid. Test results were all in the normal range.
Jacqui Duncan, MD, a professor of ophthalmology at UCSF, conducted an extensive ophthalmic evaluation to detect functional deficits because it is known that APOE is produced also in the retina. All of the tests on the brain and eyes were normal.
If APOE was so important for normal brain function, why didn’t this patient show any cognitive deficits? Dr. Malloy viewed this as an important clue in understanding the role of APOE in AD.
She pointed out that many scientists and pharmaceutical companies have not sought to develop strategies that target APOE because they didn’t know what damage might be done by altering a protein thought to be critical for normal brain function. But, said Dr. Malloy: “It appears that having no APOE is better than having the APOE4 protein. APOE is apparently not critical for normal brain function.”
The research team will continue to monitor this patient over time to see whether any cognitive problems emerge. His high cholesterol and triglycerides put him at greater risk for cardiovascular disease, and he will be treated aggressively with emerging lipid-lowering medications, Dr. Malloy said. The patient has also donated skin cells that the UCSF group is using to make neurons for testing.
UCSF’s Dr. Miller, who holds the A.W. and Mary Margaret Clausen distinguished professorship in neurology, said the findings “hint more at things than offering proof. One would think that a complete absence of a protein has a devastating effect on the brain. It doesn’t.”
Look for the full story and expert commentary in the September 18 issue of Neurology Today. For more coverage of the link between APOE and Alzheimer’s disease, browse our archives here: http://bit.ly/apoE-AD.
Friday, August 29, 2014
by Rebecca Hiscott
A high intake of dietary salt, or sodium chloride, is associated with worsening multiple sclerosis (MS) symptoms, according a study published in the August 28 online issue of the Journal of Neurology, Neurosurgery & Psychiatry.
Researchers from the Raúl Carrera Institute for Neurological Research in Buenos Aires, Argentina, and the Brigham and Women’s Hospital Center for Neurologic Diseases in Boston, MA, conducted an observational study using a cohort of 70 patients with relapsing-remitting MS to examine the link between sodium intake and worsening of MS symptoms. Patients had brain and spinal cord MRIs at baseline, at three months and at six months, and researchers measured clinical, radiological and sodium intake data over a follow-up period of two years.
Patients were required to provide urine samples at three, six, and nine months to assess changes in salt consumption, and blood and urine samples were collected at 12 months. The researchers measured levels of sodium and creatinine – a marker of inflammatory activity – in the urine, as well as levels of serum sodium and vitamin D in the blood. They assessed patients’ disability status at baseline and at the end of the study, and looked for any development of new MS symptoms or worsening of pre-existing symptoms, confirmed via neurological examination. The primary outcome was defined as the number of relapses occurring over the two-year study period.
Intracranial and spinal cord lesions in multiple sclerosis. From: Yochum And Rowe's Essentials of Skeletal Radiology, Third Edition. Philadelphia: Lippincott Williams & Wilkins, 2004.
“We found a positive correlation between exacerbation rate and sodium intake in a multivariate model adjusted for age, gender, disease duration, treatment, vitamin D levels, BMI and smoking status,” the authors wrote.
They found that patients with a high sodium intake, defined according to World Health Organization (WHO) guidelines as more than 4.8 grams per day (g/day), had an exacerbation rate that was 3.95-fold higher than patients with the WHO recommended intake of 2 g/day or less. Patients with an average sodium intake (2 to 4.8 g/day) had a 2.75-fold higher exacerbation rate. Males were found to have higher sodium levels than females.
Those with a high sodium intake were also found to have a 3.4-fold increased chance of developing a new brain lesion on MRI scans, and had eight more T2 lesions on average than patients with the recommended dietary salt intake.
The researchers were able to confirm their findings in a replication study involving 52 patients with relapsing-remitting MS.
However, the authors stressed that their findings show an association between high sodium intake and worsening MS symptoms, but not causation. “We cannot exclude the possibility of reverse causation: individuals with more relapses received more steroids and thus their salt intake and excretion is increased because they have higher disease activity and not the other way around,” they wrote.
They suggested that future clinical trials could determine whether reducing salt intake is helpful for patients with MS.
For more coverage of salt intake and MS, browse our archives here: http://bit.ly/salt-MS.
Thursday, August 28, 2014
by Rebecca Hiscott
Adults with cognitive impairment are at a significantly higher risk of stroke than those with normal cognition, according to a study published in the August 25 issue of the Canadian Medical Association Journal (CMAJ).
Researchers from the United States, Taiwan, and South Korea conducted a systemic review and meta-analysis of 18 studies involving a total of 121,879 participants and 7,799 cases of stroke, in order to establish a link between impaired cognition and stroke. Past research investigating the link between cognitive impairment and stroke risk has been inconclusive, they noted.
Computed tomographic appearance of acute ischemic stroke and subarachnoid hemorrhage.
Participants who were cognitively impaired at baseline had a 39 percent higher risk of stroke than those with normal cognitive function, the researchers found. Cognitive impairment was associated with a high risk of ischemic and fatal stroke in particular.
Stroke risk increased to 64 percent when the authors broadened the definition of cognitive impairment.
“Cognitive impairment should be more broadly recognized as a possible early clinical manifestation of cerebral infarction, so that timely management of vascular risk factors can be instituted to potentially prevent future stroke events and to avoid further deterioration of cognitive health,” they wrote.
They also noted that conversely, risk factors for stroke such as hypertension, hyperlipidemia, diabetes, obesity, and physical inactivity have been linked to cognitive impairment in past studies. Stroke itself also increases the risk of future cognitive impairment.
While some neurologists already recommend screening for cognitive impairment after a patient experiences a stroke, “our findings suggest that identifying people with cognitive impairment may provide an even bigger opportunity to reduce the future burden of stroke through the timely implementation of evidence-based prevention strategies,” the authors concluded.
For more coverage of cognitive impairment and stroke, browse our archives here: http://bit.ly/cognition-stroke.
Wednesday, August 27, 2014
by Rebecca Hiscott
Children and teenagers with autism have extra synapses in the brain due to a defect in the synapse pruning process that occurs during normal brain development, according to a study published in the August 21 online issue of Neuron.
In normal brain development, a burst of synapse formation occurs in infancy. Later, a pruning process occurs, eliminating nearly half of the extra synapses by the time a child reaches adolescence. But in autistic adolescents, that pruning process appears to be inhibited, researchers from the Columbia University Medical Center (CUMC), the University of Rochester, and Mount Sinai’s Ichan School of Medicine found.
The findings represent “the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” study author David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at CUMC, said in a news release.
The researchers examined brains from 26 autistic children and adolescents between the ages of two and 20 years who had died from other causes. Brains from 22 children without autism were also examined. The researchers measured synapse density in Brodmann Area 21, a region of the temporal lobe implicated in social behavior and communication, in each brain by counting the number of spines branching from the cortical neurons.
Histologic appearance of neurons in cortical layer III of the temporal lobe in a patient with cortical dysplasia.
While brains from both groups had a similar number of synapses in early childhood spine density had decreased by around 41 percent in non-autistic adolescent brains, while spine density in autistic brains had only decreased by 16 percent (p=0.007).
“While our study examined a single brain region, spine pruning during early postnatal development occurs in cerebral cortex, cerebellum, olfactory bulb, and hippocampus,” the authors wrote. “As ASD[Autism Spectrum Disorder]-related neuropathology involves disruptions in connectivity across the brain, it is likely that additional ASD brain regions may feature spine pruning defects during different periods of synaptic development.”
The brains of autistic children also showed biomarkers indicating a malfunction in autophagy, the process by which a cell eliminates unnecessary or dysfunctional components. Using mouse models of autism, the researchers then demonstrated that the lack of autophagy was caused by hyperactivity of the mechanistic target of rapamycin (mTOR) protein, which hinders the brain’s ability to eliminate extra synapses.
The researchers also found that the immunosuppressant rapamycin was able to restore normal synaptic pruning in mice, even after these behaviors had already begun to appear.
Rapamycin is linked to a number of potential complications that may limit its use in treating autistic children, but “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said Dr. Sulzer.
“What’s remarkable about the findings is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning,” he added. “Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”
For more coverage of autism in childhood, browse our archives here: http://bit.ly/autism-child.
Tuesday, August 26, 2014
by Rebecca Hiscott
Colds and other minor infections may temporarily increase a child’s risk of stroke, according to a new study published in the August 20 online issue of Neurology. Previous research had established a link between minor infections and stroke risk in adults, but the latest study demonstrates a similar association in children.
Magnetic resonance angiography from children with first and recurrent arterial ischemic stroke.
Researchers from the University of California, San Francisco, and the Kaiser Permanente Northern California Division of Research looked at a database of 2.5 million children under 19 years of age from the Kaiser Pediatric Stroke Study, which examined predictors of perinatal hemorrhagic stroke in infants. They identified 102 children who had experienced an arterial ischemic stroke without evidence of a major infection such as meningitis, sepsis, or endocarditis, as well as 306 healthy age-matched controls, and reviewed medical records for up to two years before a child’s stroke.
The authors found that stroke risk increased for three days following a doctor’s visit for a minor infection (p=0.002), which the researchers attributed to a period of acute inflammation that decreases as an infection resolves. Children who experienced strokes were 12 times more likely to have had an infection in the days prior to the stroke.
“The risk rapidly diminishes after this period, with no increased risk of stroke beyond 1 week,” they wrote. “This suggests that infection has an acute and powerful effect on stroke risk that is transient, wanes quickly over days, and may be more robust in children than adults.”
Ten of the 102 children in the stroke group (9.8 percent) had visited a doctor for an infection within three days before the stroke, while only two of the 306 controls (0.7 percent) had done the same. Respiratory infections represented 80 percent of cases.
“These findings suggest that infection has a powerful but short-lived effect on stroke risk,” study author Heather Fullerton, MD, pediatric vascular neurologist and medical director of the Pediatric Brain Center at UCSF Benioff Children’s Hospital San Francisco, said in a news release.
The study authors emphasized that the children who had suffered a stroke as a result of infection were likely already predisposed to stroke. “Infection prevention is key for kids who are at risk of stroke, and we should make sure those kids are getting vaccinated against whatever infections – such as flu – that they can," Dr. Fullerton said.
In addition, the authors found no evidence that a greater number of infections over a two-year time period increased a child’s risk of stroke.
“While the study does show an increased risk, the overall risk of stroke among children is still extremely low,” Lars Marquardt, MD, DPhil, a professor of surgery in the department of neurology at the University of Erlangen-Nuremberg in Germany, wrote in an editorial published in the same issue of Neurology. “Parents should not be alarmed whatsoever if a child catches a cold.”
For more coverage of the link between infection and stroke, browse our archives here: http://bit.ly/stroke-infection.