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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.


Monday, August 25, 2014

by Rebecca Hiscott

 

Regular blood transfusions can reduce the risk of recurrent strokes and silent cerebral infarcts – or “silent strokes” – in children with sickle cell anemia who have previously had a silent stroke, according to an international, multi-center study published in the August 21 issue of the New England Journal of Medicine.

 

            Silent strokes are the most common neurologic injury associated with sickle cell disease, affecting an estimated one-third of children with the condition. Although they cause no immediately detectable symptoms, they have been shown to cause subclinical brain damage leading to decline in a child’s cognitive abilities, IQ, and academic performance, and to increase the risk of experiencing a repeat silent or overt stroke.

 

MRI scans from children with first and recurrent ischemic (arterial and venous) stroke and its mimics.

 

            Twenty-nine institutions in the United States, Canada, France, and the United Kingdom participated in the study, which evaluated 196 children between the ages of 5 to 15 years who had previously suffered a silent stroke. About half of the children were randomly assigned to receive blood transfusions, which were administered every 38 days or less over a median time period of three years. The other half of the children were assigned to observation. At baseline and at exit, the children underwent brain MRI scans, as well as neurologic and cognitive examinations.

 

Six percent of children (6 out of 99) in the transfusion group experienced another silent or overt stroke, compared with 14 percent (14 of 97) in the observation group. Children who received regular transfusions were found to have a 58 percent lower relative risk of suffering a second silent or overt stroke.

 

“The results of our study show that blood transfusions can play a critical role in preventing this insidious and potentially devastating condition,” study author James F. Casella, MD, director and Rainey Professor of Pediatric Hematology at the Johns Hopkins Children’s Center, said in a news release. “They also highlight the importance of intervening early to preclude ongoing or further brain injury among these youngsters.”

 

“Most importantly, our findings suggest a much-needed treatment option for clinicians and families of children with sickle cell disease who have had silent strokes,” he added.

 

In addition, children who were treated with regular blood transfusions had less incidence of other complaints related to sickle cell disease, such as sickle cell crises – episodes of acute pain – and respiratory complications.

 

            The researchers recommended that all children with sickle cell disease have at least one MRI brain scan before entering elementary school, in order to look for evidence of a silent stroke. Parents of children who have experienced a silent stroke should discuss the benefits and potential risks of transfusion – which could include adverse immune reactions, infections, or a buildup of excess iron in the child’s blood – with a physician, they wrote.

 

“The data make transfusion the only evidence-based option to prevent stroke recurrence and further brain injury in this vulnerable population,” study author Michael Noetzel, MD, professor of neurology and pediatrics at the Washington University School of medicine, said in a separate news release. “Now that we have identified a viable treatment option, early detection of silent cerebral strokes should become a major focus for clinicians and families of children with sickle cell disease.”

 

Although the exact mechanism by which blood transfusions can reduce the risk of recurrent stroke is unclear, “we think the transfusions are helping because they raise the total amount of circulating blood and lower the percentage of sickle-shaped calls in the patient’s bloodstream,” added study author Allison King, MD, assistant professor of pediatrics and occupational therapy at Washington University School of Medicine. “Keeping the sickled cells to less than 30 percent of total blood cells seems to be ideal.”

 

For more coverage of sickle cell disease and stroke, browse our archives here: http://bit.ly/scd-stroke.


Friday, August 22, 2014

by Rebecca Hiscott

Researchers have identified a new genetic risk factor associated with ischemic stroke, independent of stroke subtype, in a genome-wide association study and meta-analysis published in the August 19 issue of Neurology.

            “Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner,” the authors wrote. They added that the locus was not found to be associated with intracerebral hemorrhage (ICH).

CT scans from children with hemorrhagic and ischemic (arterial and venous) stroke and its mimics.

            The researchers used the Immunochip – a targeted genome-wide array containing approximately 200,000 genetic variants associated with immune-related genes, as well as around 3,000 single nucleotide polymorphisms (SNPs) associated with ischemic stroke – to look at genetic risk factors involved in 3,420 cases of ischemic stroke and 6,821 controls. They then conducted a meta-analysis using data from the Wellcome Trust Case Control Consortium 2 (WTCCC2) genome-wide association study (GWAS) of 3,582 cases of ischemic stroke and 5,972 controls, as well as summary statistics from 8,480 ischemic stroke cases and 56,032 controls analyzed in the METASTROKE consortium. Lastly, they conducted a computer-simulated replication study with additional stroke and control cases from the INTERSTROKE and VISP studies.

            Analysis of the initial 3,420 cases of ischemic stroke and 6,821 controls identified three SNPs on two independent loci on chromosomes 10q26 and 19q13 for all ischemic stroke, as well as five SNPs across 5 loci for large artery ischemic stroke, the authors reported.

            The subsequent meta-analysis confirmed previous findings from the WTCCC2 study associating the histone deacetylase 9 (HDAC9) locus on chromosome 7p21 with large artery ischemic stroke, as well as an association between pituitary homeobox 2 (PITX2) and zinc finger homeobox 3 (ZFHX3) loci at chromosomes 4q25 and 16q22 and cardioembolic stroke.

            Importantly, the meta-analysis also identified a new risk locus at 12q24.12, which was included in the Immunochip because of its association with type 1 diabetes mellitus. It has also been associated with several cardiovascular risk factors, including blood pressure and cholesterol, the authors noted. The association was strengthened by targeted replication with data from the INTERSTROKE and VISP studies. In addition, the replication study showed that the risk locus was not associated with intracerebral hemorrhage.

“Unlike all previous GWAS-identified ischemic stroke loci, this locus does not appear to be associated with a single subtype but rather is associated with ischemic stroke as a whole,” the authors wrote.

            They also found that 12q24’s association with stroke was independent of cardiovascular risk factors such as hypertension, hypercholesterolemia, smoking history, history of symptomatic coronary artery disease and ischemic heart disease, or diabetes mellitus. However, “the lack of risk factor data in all controls prevented a more conventional stratified analysis,” they wrote.

            The authors noted that they could not identify the exact mechanism by which the 12q24 variant might increase the risk of ischemic stroke without increasing risk of intracerebral hemorrhage. However, the study is valuable because it furthers understanding of the biological factors that may contribute to stroke risk, Geoffrey L. Heyer, MD, attending pediatric neurologist at the Nationwide Children’s Hospital and assistant professor of clinical pediatrics at the Ohio State University College of Medicine, and Paul Nyquist, MD, MPH, associate professor in the departments of anesthesiology/critical care medicine and neurological surgery at the Johns Hopkins University School of Medicine, wrote in an editorial published in the same issue of Neurology.

            “The greatest value of such discoveries lies not in the calculation of attributable risk but in the identification of underlying biological pathways that confer risk and provide targets for intervention in this dreaded disease,” they wrote.

            For more coverage of risk factors associated with ischemic stroke, browse our archives here: http://bit.ly/ischemic-stroke-risk.


Thursday, August 21, 2014

by Rebecca Hiscott

 

Depression is the most common non-motor symptom associated with Parkinson’s disease (PD), but the illness remains undertreated in PD patients, a new study reports.

 

 

            Researchers from Northwestern University, the University of Florida, and the National Parkinson Foundation (NPF) looked at 7,031 PD patients from the NPF’s quality improvement initiative database, which contains longitudinal data on PD patients, including demographics, disease severity, quality of life, pharmacological treatment, and utilization of mental health services. Their findings, published in the July 17 issue of the Journal of Parkinson’s Disease, confirmed past research suggesting that depression is common among PD patients.

 

“This is important because previous research has determined that depression is a major determinant of overall quality of life,” study author Danny Bega, MD, instructor in the Ken and Ruth Davee Department of Neurology at Northwestern University, said in a news release.

 

The researchers used the emotional wellbeing domain of the Parkinson’s Disease Questionnaire – a self-completed evaluation of a patient’s motor functioning and wellbeing – as a screening tool for depression in this cohort. They found that 23 percent of PD patients exhibited symptoms of depression, 33 percent had been prescribed antidepressants, 6 percent were receiving counseling, and 14 percent were using both mental health services (MHS) and antidepressants.

 

Overall, 46 percent of patients screening positive for depression at baseline remained untreated. “Whether this can be blamed on poor recognition by physicians, personal preferences, or other factors unaccounted for cannot be easily determined by this retrospective study,” the authors wrote.

 

Dr. Bega sounded a hopeful note in the news release, remarking that “the physician recognition of depression in this population was actually better than previous reports suggested.”

 

 However, the study authors also cautioned that recognition of depression may be lower in the general population, because “this cohort is obtained from NPF Centers of Excellence (COE), where awareness of PD related depression is expected to be higher.”

 

            The researchers conducted a second analysis of the remaining 4,653 patients who were not using antidepressants. After 12 months, 2.4 percent of patients not being treated for depression at the outset were prescribed an antidepressant, 1 percent were referred to MHS, and 0.3 percent were prescribed both.

 

“A significantly higher percentage of those with greater severity of depressive symptoms were started on antidepressants and/or MHS during the study…confirming that physicians do recognize some depressive symptoms in this population,” the authors noted. However, 90.7 percent of patients screening positive for depression in this cohort remained untreated.

 

As a result of these findings, the authors advised that “physicians should be vigilant about systematic screening for depression as part of the routine assessment of all PD patients.”

 

For more coverage of depression in Parkinson’s disease, browse our archives here: http://bit.ly/pd-depression.