Neurodevelopmental Disorders

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Children with autism rely heavily on proprioception, unlike children with other developmental motor impairments or typically developing children.

PROVIDENCE, RI—Children with autism spectrum disorder form a representation of internal models that places an unusually strong reliance on proprioception, according to research presented at the 39th National Meeting of the Child Neurology Society.

“This anomalous motor learning is specific to autism spectrum disorder, rather than a general deficit of all populations with developmental motor impairments, as children with ADHD did not generalize differently than typically developing children,” reported Stewart H. Mostofsky, MD, research scientist at the Kennedy Krieger Institute and Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, and colleagues. “Our results suggest that autism-associated impairment in understanding actions of others may be a consequence of the fact that in learning to perform actions, children with autism place a greater than normal reliance on their own proprioception while discounting the visual consequences of their actions.”

The researchers analyzed 25 children with autism (mean age, 10.31), 16 with ADHD (mean age, 10.66), and 39 typically developing children (mean age, 10.82). As part of a game, each child held the handle of a robotic arm, trying to capture animals that had escaped from a zoo. An animal would appear at a target location 8 cm away; if the child reached the target in time, the animal was captured and the child was given a point.

“Analyses revealed that all groups were able to effectively adapt their arm movement,” stated Dr. Mostofsky’s group. “However, generalization patterns were markedly different. There was a significant interaction between diagnostic group and relative generalization to targets 2 and 3. Posthoc analyses revealed this difference was due to significantly greater generalization of the autism group in the intrinsic (proprioceptive) coordinate system as compared to typically developing children. In contrast, there was no significant difference in generalization between ADHD and typically developing children.”

Regression analyses revealed that among all groups, generalization in the intrinsic (proprioceptive) coordinate system (ie, to target 3) was a significant predictor of social ability, such that greater social impairment was predicted by increased force for target 3, noted Dr. Mostofsky and colleagues. “Further,” the researchers concluded, “for the children with autism, increased force for target 3 predicted impaired social interaction. In addition, increased generalization to target 3 also predicted impaired imitation ability, as assessed on a praxis examination, as well as impairment in motor control.”

Children with autism rely heavily on proprioception, unlike children with other developmental motor impairments or typically developing children.

PROVIDENCE, RI—Children with autism spectrum disorder form a representation of internal models that places an unusually strong reliance on proprioception, according to research presented at the 39th National Meeting of the Child Neurology Society.

“This anomalous motor learning is specific to autism spectrum disorder, rather than a general deficit of all populations with developmental motor impairments, as children with ADHD did not generalize differently than typically developing children,” reported Stewart H. Mostofsky, MD, research scientist at the Kennedy Krieger Institute and Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, and colleagues. “Our results suggest that autism-associated impairment in understanding actions of others may be a consequence of the fact that in learning to perform actions, children with autism place a greater than normal reliance on their own proprioception while discounting the visual consequences of their actions.”

The researchers analyzed 25 children with autism (mean age, 10.31), 16 with ADHD (mean age, 10.66), and 39 typically developing children (mean age, 10.82). As part of a game, each child held the handle of a robotic arm, trying to capture animals that had escaped from a zoo. An animal would appear at a target location 8 cm away; if the child reached the target in time, the animal was captured and the child was given a point.

“Analyses revealed that all groups were able to effectively adapt their arm movement,” stated Dr. Mostofsky’s group. “However, generalization patterns were markedly different. There was a significant interaction between diagnostic group and relative generalization to targets 2 and 3. Posthoc analyses revealed this difference was due to significantly greater generalization of the autism group in the intrinsic (proprioceptive) coordinate system as compared to typically developing children. In contrast, there was no significant difference in generalization between ADHD and typically developing children.”

Regression analyses revealed that among all groups, generalization in the intrinsic (proprioceptive) coordinate system (ie, to target 3) was a significant predictor of social ability, such that greater social impairment was predicted by increased force for target 3, noted Dr. Mostofsky and colleagues. “Further,” the researchers concluded, “for the children with autism, increased force for target 3 predicted impaired social interaction. In addition, increased generalization to target 3 also predicted impaired imitation ability, as assessed on a praxis examination, as well as impairment in motor control.”

Children with autism rely heavily on proprioception, unlike children with other developmental motor impairments or typically developing children.

PROVIDENCE, RI—Children with autism spectrum disorder form a representation of internal models that places an unusually strong reliance on proprioception, according to research presented at the 39th National Meeting of the Child Neurology Society.

“This anomalous motor learning is specific to autism spectrum disorder, rather than a general deficit of all populations with developmental motor impairments, as children with ADHD did not generalize differently than typically developing children,” reported Stewart H. Mostofsky, MD, research scientist at the Kennedy Krieger Institute and Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, and colleagues. “Our results suggest that autism-associated impairment in understanding actions of others may be a consequence of the fact that in learning to perform actions, children with autism place a greater than normal reliance on their own proprioception while discounting the visual consequences of their actions.”

The researchers analyzed 25 children with autism (mean age, 10.31), 16 with ADHD (mean age, 10.66), and 39 typically developing children (mean age, 10.82). As part of a game, each child held the handle of a robotic arm, trying to capture animals that had escaped from a zoo. An animal would appear at a target location 8 cm away; if the child reached the target in time, the animal was captured and the child was given a point.

“Analyses revealed that all groups were able to effectively adapt their arm movement,” stated Dr. Mostofsky’s group. “However, generalization patterns were markedly different. There was a significant interaction between diagnostic group and relative generalization to targets 2 and 3. Posthoc analyses revealed this difference was due to significantly greater generalization of the autism group in the intrinsic (proprioceptive) coordinate system as compared to typically developing children. In contrast, there was no significant difference in generalization between ADHD and typically developing children.”

Regression analyses revealed that among all groups, generalization in the intrinsic (proprioceptive) coordinate system (ie, to target 3) was a significant predictor of social ability, such that greater social impairment was predicted by increased force for target 3, noted Dr. Mostofsky and colleagues. “Further,” the researchers concluded, “for the children with autism, increased force for target 3 predicted impaired social interaction. In addition, increased generalization to target 3 also predicted impaired imitation ability, as assessed on a praxis examination, as well as impairment in motor control.”

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

Untreated poor vision may be a contributing factor to late-life dementia and Alzheimer’s disease, a study in the February 11 online American Journal of Epidemiology found. Using data from the Health and Retirement Study and Medicare files from 1992 to 2005, researchers tracked the visual health of 625 elderly subjects with normal cognition for an average span of 8.5 years. Subjects with very good or excellent vision at baseline had a 63% reduced risk of dementia. Those with poorer vision who did not seek ophthalmologic treatment had a 9.5-fold increased risk of developing Alzheimer’s disease and a fivefold greater risk of cognitive impairment without dementia. Poorer vision without a previous eye procedure increased the risk of Alzheimer’s disease fivefold. In study subjects ages 90 years or older, 77.9% who maintained normal cognition had at least one previous eye procedure, compared with 51% of those who developed Alzheimer’s disease.

Behavioral signs of autism are not present from birth to age 6 months, but emerge with significantly declining trajectories over time, according to a study in the March issue of the Journal of the American Academy of Child and Adolescent Psychiatry. In a prospective longitudinal study, researchers compared 25 infants, who were later diagnosed with an autism spectrum disorder (ASD), with 25 gender-matched, low-risk control children, later determined to have typical development. Subjects were evaluated via videos taken at 6, 12, 18, 24, and 36 months. Researchers rated children based on frequency of gaze to faces, social smiles, and directed vocalizations. Both groups were similar at 6 months of age, but those with ASD declined significantly by 12 months of age. “Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development,” the study authors wrote. “More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well.”

Treating children who have intractable epilepsy with a ketogenic diet appears to have no long-term adverse effects, researchers reported in the February 1 online Epilepsia. The investigators recruited questionnaires and laboratory reports from patients who were treated with the diet at Johns Hopkins Hospital between November 1993 and December 2008. Of the 101 responders (median age, 13), 96% would recommend the diet to others; however, just slightly more than half would have started the diet before trying anticonvulsants. The respondents’ mean total cholesterol was normal at 158 mg/dL, although most lipid levels were abnormal during the diet.

Elderly individuals who experience spontaneous alterations in cognition, attention, and arousal are 4.6 times more likely to have dementia, according to research published in the January 19 Neurology. In a study of 511 subjects (mean age, 78.1) at the Washington University Alzheimer Disease Research Center, investigators assessed patients for dementia using the Clinical Dementia Rating (CDR) and a neuropsychologic test battery. Participants also filled out the Mayo Fluctuations Questionnaire to assess cognitive changes and the Mayo Sleep Questionnaire to determine daytime alertness levels. Those presenting with disorganized, illogical thinking were 7.8 times more likely to have a CDR rating greater than 0. The incidence of a CDR rating of 0.5 was 13.4 times greater in patients with fluctuations than in those without, and a CDR 1 rating was associated with a 34-fold increase in patients with fluctuations.

An increase in brain magnesium enhances both short-term synaptic facilitation and longer-term potentiation and improves learning and memory functions, according to data published in the January 28 Neuron. In a study of young and old rats, researchers found that increasing brain magnesium using magnesium-L-threonate (MgT), a novel magnesium compound, enhanced learning ability, working memory, and short- and long-term memory in rats. “MgT treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of the hypocampus that were correlated with memory improvement,” the authors wrote. “Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability.” In addition, the researchers noted that when combined with upregulation of NR2B-containing NMDA receptors, MgT further enhanced synaptic plasticity.

A defect in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling in Cftr-deficient mice can be corrected with rosiglitazone, which helped reduce the severity of the cystic fibrosis phenotype, investigators reported in the February 14 online Nature Medicine. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator. Treatment with the synthetic PPAR-gamma ligand rosiglitazone partially normalized the altered gene expression patterned, reducing disease severity. Although the drug had no effect on chloride secretion in the colon, it increased expression of the genes encoding carbonic anhydrases 4 and 2, increased bicarbonate secretion, and reduced mucus retention.

Untreated poor vision may be a contributing factor to late-life dementia and Alzheimer’s disease, a study in the February 11 online American Journal of Epidemiology found. Using data from the Health and Retirement Study and Medicare files from 1992 to 2005, researchers tracked the visual health of 625 elderly subjects with normal cognition for an average span of 8.5 years. Subjects with very good or excellent vision at baseline had a 63% reduced risk of dementia. Those with poorer vision who did not seek ophthalmologic treatment had a 9.5-fold increased risk of developing Alzheimer’s disease and a fivefold greater risk of cognitive impairment without dementia. Poorer vision without a previous eye procedure increased the risk of Alzheimer’s disease fivefold. In study subjects ages 90 years or older, 77.9% who maintained normal cognition had at least one previous eye procedure, compared with 51% of those who developed Alzheimer’s disease.

Behavioral signs of autism are not present from birth to age 6 months, but emerge with significantly declining trajectories over time, according to a study in the March issue of the Journal of the American Academy of Child and Adolescent Psychiatry. In a prospective longitudinal study, researchers compared 25 infants, who were later diagnosed with an autism spectrum disorder (ASD), with 25 gender-matched, low-risk control children, later determined to have typical development. Subjects were evaluated via videos taken at 6, 12, 18, 24, and 36 months. Researchers rated children based on frequency of gaze to faces, social smiles, and directed vocalizations. Both groups were similar at 6 months of age, but those with ASD declined significantly by 12 months of age. “Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development,” the study authors wrote. “More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well.”

Treating children who have intractable epilepsy with a ketogenic diet appears to have no long-term adverse effects, researchers reported in the February 1 online Epilepsia. The investigators recruited questionnaires and laboratory reports from patients who were treated with the diet at Johns Hopkins Hospital between November 1993 and December 2008. Of the 101 responders (median age, 13), 96% would recommend the diet to others; however, just slightly more than half would have started the diet before trying anticonvulsants. The respondents’ mean total cholesterol was normal at 158 mg/dL, although most lipid levels were abnormal during the diet.

Elderly individuals who experience spontaneous alterations in cognition, attention, and arousal are 4.6 times more likely to have dementia, according to research published in the January 19 Neurology. In a study of 511 subjects (mean age, 78.1) at the Washington University Alzheimer Disease Research Center, investigators assessed patients for dementia using the Clinical Dementia Rating (CDR) and a neuropsychologic test battery. Participants also filled out the Mayo Fluctuations Questionnaire to assess cognitive changes and the Mayo Sleep Questionnaire to determine daytime alertness levels. Those presenting with disorganized, illogical thinking were 7.8 times more likely to have a CDR rating greater than 0. The incidence of a CDR rating of 0.5 was 13.4 times greater in patients with fluctuations than in those without, and a CDR 1 rating was associated with a 34-fold increase in patients with fluctuations.

An increase in brain magnesium enhances both short-term synaptic facilitation and longer-term potentiation and improves learning and memory functions, according to data published in the January 28 Neuron. In a study of young and old rats, researchers found that increasing brain magnesium using magnesium-L-threonate (MgT), a novel magnesium compound, enhanced learning ability, working memory, and short- and long-term memory in rats. “MgT treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of the hypocampus that were correlated with memory improvement,” the authors wrote. “Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability.” In addition, the researchers noted that when combined with upregulation of NR2B-containing NMDA receptors, MgT further enhanced synaptic plasticity.

A defect in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling in Cftr-deficient mice can be corrected with rosiglitazone, which helped reduce the severity of the cystic fibrosis phenotype, investigators reported in the February 14 online Nature Medicine. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator. Treatment with the synthetic PPAR-gamma ligand rosiglitazone partially normalized the altered gene expression patterned, reducing disease severity. Although the drug had no effect on chloride secretion in the colon, it increased expression of the genes encoding carbonic anhydrases 4 and 2, increased bicarbonate secretion, and reduced mucus retention.

Untreated poor vision may be a contributing factor to late-life dementia and Alzheimer’s disease, a study in the February 11 online American Journal of Epidemiology found. Using data from the Health and Retirement Study and Medicare files from 1992 to 2005, researchers tracked the visual health of 625 elderly subjects with normal cognition for an average span of 8.5 years. Subjects with very good or excellent vision at baseline had a 63% reduced risk of dementia. Those with poorer vision who did not seek ophthalmologic treatment had a 9.5-fold increased risk of developing Alzheimer’s disease and a fivefold greater risk of cognitive impairment without dementia. Poorer vision without a previous eye procedure increased the risk of Alzheimer’s disease fivefold. In study subjects ages 90 years or older, 77.9% who maintained normal cognition had at least one previous eye procedure, compared with 51% of those who developed Alzheimer’s disease.

Behavioral signs of autism are not present from birth to age 6 months, but emerge with significantly declining trajectories over time, according to a study in the March issue of the Journal of the American Academy of Child and Adolescent Psychiatry. In a prospective longitudinal study, researchers compared 25 infants, who were later diagnosed with an autism spectrum disorder (ASD), with 25 gender-matched, low-risk control children, later determined to have typical development. Subjects were evaluated via videos taken at 6, 12, 18, 24, and 36 months. Researchers rated children based on frequency of gaze to faces, social smiles, and directed vocalizations. Both groups were similar at 6 months of age, but those with ASD declined significantly by 12 months of age. “Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development,” the study authors wrote. “More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well.”

Treating children who have intractable epilepsy with a ketogenic diet appears to have no long-term adverse effects, researchers reported in the February 1 online Epilepsia. The investigators recruited questionnaires and laboratory reports from patients who were treated with the diet at Johns Hopkins Hospital between November 1993 and December 2008. Of the 101 responders (median age, 13), 96% would recommend the diet to others; however, just slightly more than half would have started the diet before trying anticonvulsants. The respondents’ mean total cholesterol was normal at 158 mg/dL, although most lipid levels were abnormal during the diet.

Elderly individuals who experience spontaneous alterations in cognition, attention, and arousal are 4.6 times more likely to have dementia, according to research published in the January 19 Neurology. In a study of 511 subjects (mean age, 78.1) at the Washington University Alzheimer Disease Research Center, investigators assessed patients for dementia using the Clinical Dementia Rating (CDR) and a neuropsychologic test battery. Participants also filled out the Mayo Fluctuations Questionnaire to assess cognitive changes and the Mayo Sleep Questionnaire to determine daytime alertness levels. Those presenting with disorganized, illogical thinking were 7.8 times more likely to have a CDR rating greater than 0. The incidence of a CDR rating of 0.5 was 13.4 times greater in patients with fluctuations than in those without, and a CDR 1 rating was associated with a 34-fold increase in patients with fluctuations.

An increase in brain magnesium enhances both short-term synaptic facilitation and longer-term potentiation and improves learning and memory functions, according to data published in the January 28 Neuron. In a study of young and old rats, researchers found that increasing brain magnesium using magnesium-L-threonate (MgT), a novel magnesium compound, enhanced learning ability, working memory, and short- and long-term memory in rats. “MgT treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of the hypocampus that were correlated with memory improvement,” the authors wrote. “Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability.” In addition, the researchers noted that when combined with upregulation of NR2B-containing NMDA receptors, MgT further enhanced synaptic plasticity.

A defect in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling in Cftr-deficient mice can be corrected with rosiglitazone, which helped reduce the severity of the cystic fibrosis phenotype, investigators reported in the February 14 online Nature Medicine. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator. Treatment with the synthetic PPAR-gamma ligand rosiglitazone partially normalized the altered gene expression patterned, reducing disease severity. Although the drug had no effect on chloride secretion in the colon, it increased expression of the genes encoding carbonic anhydrases 4 and 2, increased bicarbonate secretion, and reduced mucus retention.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”

Oligonucleotide microarray analysis reveals a higher yield of abnormalities in children with autism than previously seen with other techniques.

LOUISVILLE—Microarray analysis and testing for fragile X syndrome revealed genetic abnormalities in 10% of children with autism, according to research presented at the 38th National Meeting of the Child Neurology Society. Christa Lese Martin, PhD, and colleagues studied 93 children (79 males) with autism spectrum disorders (ASD) between ages 2 and 7 who were enrolled in an ongoing, comprehensive project aimed at finding meaningful subtypes of autism.

The children underwent a panel of genetic testing, including high-resolution karyotype and fluorescence in situ hybridization (FISH) for 15q, fragile X testing, and array comparative genomic hybridization using the EmArray Cyto array, a custom array of 44,000 oligos designed by Emory Genetics Laboratory in Atlanta, to detect copy number imbalances across the genome.

“Our study demonstrates that clinical microarray—ie, cytogenetic array—testing to look for genome-wide deletions or duplications and fragile X testing is strongly indicated in individuals with ASD,” Dr. Martin, Associate Professor of Human Genetics, Emory University School of Medicine in Atlanta, told Neurology Reviews. “The combination of these two tests identifies a cause for ASD in approximately 10% of individuals. The identification of a cause for ASD not only provides a clinical diagnosis, but also provides the opportunity for accurate genetic counseling for the families.”

New ASD Loci Identified
The pathogenic abnormalities identified included fragile X syndrome, a 17p deletion of the Smith-Magenis region, an unbalanced translocation resulting in duplication of 2p and deletion of 9p, and 16p11.2 duplication syndrome. The children with imbalances had similar cognitive and behavioral profiles as the remainder of the sample and had no obvious clues suggesting any underlying genetic abnormalities, the investigators noted.

“Karyotype alone is not sensitive, and multiple FISH probes would be needed to identify the most common autism loci, greatly increasing cost while still missing the important opportunity to examine the rest of the genome,” reported Dr. Martin’s group. “Our results also demonstrate that genome-wide microarray technology has increased yield and provides more cost-effective testing.”

In addition, four subjects had fragile X mutations; one was a full mutation, one was a premutation, and two were grey zone mutations. “Full mutation fragile X is a relatively rare finding in autism samples,” the researchers noted. “But premutation and grey zone mutations are more common than would be expected in a general population sample.”

Array Analysis in Diagnosing ASD
“Cytogenetic array analysis and fragile X testing are currently offered in many clinical genetic laboratories and should be offered as part of the diagnostic workup in the evaluation of ASD,” asserted Dr. Martin, who co-leads the array services at Emory Genetics Laboratory. “In addition, since all of the cases examined in our study had normal G-banded chromosome analysis, but several clinically significant abnormalities were identified by array analysis, these data provide further support that the array should be used as the first-line cytogenetic test since this analysis can identify imbalances that are below the resolution of a routine karyotype.

“The yield of cytogenetic array testing in individuals with ASD is quite high—8% to 10% has now been reported from various studies,” she added. “This information is invaluable to families to alleviate their search for a cause in their children and counsel them appropriately on recurrence risks in their family.”

LOUISVILLE—The autistic brain builds a stronger-than-normal association between motor commands and proprioceptive feedback, which may account for why children with autism have difficulty forming the models necessary to engage not only in motor behavior, but in social and communicative behaviors, according to research presented at the 38th National Meeting of the Child Neurology Society.

Stewart H. Mostofsky, MD, Associate Professor of Neurology at Kennedy Krieger Institute and the Johns Hopkins University School of Medicine in Baltimore, and colleagues, observed 14 children with autism spectrum disorders and 13 typically developing children as they learned to control a robotic arm. Subjects attempted to reach a target of interest while the robotic arm produced a force perpendicular to that location.

To test this hypothesis, children engaged in a second experiment in which Dr. Mostofsky’s group observed and assessed generalization, the signature of activation fields of neurons. “Generalization can tell you about how [children] learn, because you can look at the way they are able to transfer what they learn in one particular state to another,” Dr. Mostofsky said.

“The generalization patterns were strikingly different,” Dr. Mostofsky and colleagues reported. Typically developing children generalized in both proprioceptive and visual coordinates when generating models of behavior; whereas, children with autism spectrum disorders only generalized in proprioceptive coordinates, and approximately twice as strong as the typically developing children. Furthermore, the tendency to generalize in proprioceptive coordinates was highly predictive of autism-associated impairments in performance in skilled motor gestures to imitation, as well as performance of these gestures to command, and with actual tool use (often referred to as “dyspraxia”).

“[Moreover], notions of feed-forward hypotheses would suggest that these same internal models that are the basis of learning skilled movements might also be the basis for which our brain learns to understand and recognize the actions of others,” Dr. Mostofsky stated. Therefore, impaired acquisition of skill movements may contribute to the social deficits associated with autism.

Serum IL-6 Levels

Consistent with this hypothesis, generalization in intrinsic proprioceptive coordinates was highly predictive of higher (more impaired) Autism Diagnostic Observation Schedule scores for children with autism, and predictive of higher (more impaired) Social Responsiveness Scale scores for children with autism and in typically developing children, according to Dr. Mostofsky.

Dr. Mostofsky and colleagues are now examining whether these findings are specific to autism. In addition, they want to determine whether the formation of internal models of action are associated with abnormal patterns of neural connectivity. “Our preliminary diffusion tensor imaging findings do suggest that disorganization of white matter in the primary sensorimotor cortex may be associated with this increased proprioceptive bias,” Dr. Mostofsky commented.

The researchers also want to determine whether these observations can be used to modify the learning patterns in autism, either on a behavioral level, or as cortical stimulation methods used to upregulate visual-premotor connections.

—Laura Sassano

LOUISVILLE—The autistic brain builds a stronger-than-normal association between motor commands and proprioceptive feedback, which may account for why children with autism have difficulty forming the models necessary to engage not only in motor behavior, but in social and communicative behaviors, according to research presented at the 38th National Meeting of the Child Neurology Society.

Stewart H. Mostofsky, MD, Associate Professor of Neurology at Kennedy Krieger Institute and the Johns Hopkins University School of Medicine in Baltimore, and colleagues, observed 14 children with autism spectrum disorders and 13 typically developing children as they learned to control a robotic arm. Subjects attempted to reach a target of interest while the robotic arm produced a force perpendicular to that location.

To test this hypothesis, children engaged in a second experiment in which Dr. Mostofsky’s group observed and assessed generalization, the signature of activation fields of neurons. “Generalization can tell you about how [children] learn, because you can look at the way they are able to transfer what they learn in one particular state to another,” Dr. Mostofsky said.

“The generalization patterns were strikingly different,” Dr. Mostofsky and colleagues reported. Typically developing children generalized in both proprioceptive and visual coordinates when generating models of behavior; whereas, children with autism spectrum disorders only generalized in proprioceptive coordinates, and approximately twice as strong as the typically developing children. Furthermore, the tendency to generalize in proprioceptive coordinates was highly predictive of autism-associated impairments in performance in skilled motor gestures to imitation, as well as performance of these gestures to command, and with actual tool use (often referred to as “dyspraxia”).

“[Moreover], notions of feed-forward hypotheses would suggest that these same internal models that are the basis of learning skilled movements might also be the basis for which our brain learns to understand and recognize the actions of others,” Dr. Mostofsky stated. Therefore, impaired acquisition of skill movements may contribute to the social deficits associated with autism.

Serum IL-6 Levels

Consistent with this hypothesis, generalization in intrinsic proprioceptive coordinates was highly predictive of higher (more impaired) Autism Diagnostic Observation Schedule scores for children with autism, and predictive of higher (more impaired) Social Responsiveness Scale scores for children with autism and in typically developing children, according to Dr. Mostofsky.

Dr. Mostofsky and colleagues are now examining whether these findings are specific to autism. In addition, they want to determine whether the formation of internal models of action are associated with abnormal patterns of neural connectivity. “Our preliminary diffusion tensor imaging findings do suggest that disorganization of white matter in the primary sensorimotor cortex may be associated with this increased proprioceptive bias,” Dr. Mostofsky commented.

The researchers also want to determine whether these observations can be used to modify the learning patterns in autism, either on a behavioral level, or as cortical stimulation methods used to upregulate visual-premotor connections.

—Laura Sassano

LOUISVILLE—The autistic brain builds a stronger-than-normal association between motor commands and proprioceptive feedback, which may account for why children with autism have difficulty forming the models necessary to engage not only in motor behavior, but in social and communicative behaviors, according to research presented at the 38th National Meeting of the Child Neurology Society.

Stewart H. Mostofsky, MD, Associate Professor of Neurology at Kennedy Krieger Institute and the Johns Hopkins University School of Medicine in Baltimore, and colleagues, observed 14 children with autism spectrum disorders and 13 typically developing children as they learned to control a robotic arm. Subjects attempted to reach a target of interest while the robotic arm produced a force perpendicular to that location.

To test this hypothesis, children engaged in a second experiment in which Dr. Mostofsky’s group observed and assessed generalization, the signature of activation fields of neurons. “Generalization can tell you about how [children] learn, because you can look at the way they are able to transfer what they learn in one particular state to another,” Dr. Mostofsky said.

“The generalization patterns were strikingly different,” Dr. Mostofsky and colleagues reported. Typically developing children generalized in both proprioceptive and visual coordinates when generating models of behavior; whereas, children with autism spectrum disorders only generalized in proprioceptive coordinates, and approximately twice as strong as the typically developing children. Furthermore, the tendency to generalize in proprioceptive coordinates was highly predictive of autism-associated impairments in performance in skilled motor gestures to imitation, as well as performance of these gestures to command, and with actual tool use (often referred to as “dyspraxia”).

“[Moreover], notions of feed-forward hypotheses would suggest that these same internal models that are the basis of learning skilled movements might also be the basis for which our brain learns to understand and recognize the actions of others,” Dr. Mostofsky stated. Therefore, impaired acquisition of skill movements may contribute to the social deficits associated with autism.

Serum IL-6 Levels

Consistent with this hypothesis, generalization in intrinsic proprioceptive coordinates was highly predictive of higher (more impaired) Autism Diagnostic Observation Schedule scores for children with autism, and predictive of higher (more impaired) Social Responsiveness Scale scores for children with autism and in typically developing children, according to Dr. Mostofsky.

Dr. Mostofsky and colleagues are now examining whether these findings are specific to autism. In addition, they want to determine whether the formation of internal models of action are associated with abnormal patterns of neural connectivity. “Our preliminary diffusion tensor imaging findings do suggest that disorganization of white matter in the primary sensorimotor cortex may be associated with this increased proprioceptive bias,” Dr. Mostofsky commented.

The researchers also want to determine whether these observations can be used to modify the learning patterns in autism, either on a behavioral level, or as cortical stimulation methods used to upregulate visual-premotor connections.

—Laura Sassano

Seemingly diverse autism mutations may share the same underlying mechanism, according to Eric M. Morrow, MD, PhD, Instructor in Psychiatry at Harvard Medical School in Boston, and colleagues.
“The regulation of expression of some autism candidate genes by neuronal membrane depolarization suggests the appealing hypothesis that neural activity–dependent regulation of synapse development may be a mechanism common to several autism mutations,” stated Dr. Morrow and colleagues in the July 11 Science. “Therefore, disruption of activity-regulated synaptic development may be one mechanism common to at least a subset of seemingly heterogeneous autism-associated mutations.”
The researchers studied 88 large families—in which both parents shared recent ancestors—to find inherited causes of autism spectrum disorders. The families, who came from Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates, were selected to emphasize the role of inherited genetic mutations.
The investigators gathered data with use of homozygosity mapping and compared the DNA of family members with and without autism to identify recessive mutations. Most individuals exhibited different genetic causes with little overlap between families, but a few exceptions were observed.
“Although the large size of linked loci precluded systemic gene sequencing in most cases, we were surprised to see that several consanguineous pedigrees showed large, rare, inherited homozygous deletions within linked regions, some of which are very likely causative mutations,” Dr. Morrow and colleagues said. Specifically, such deletions linked to autism were found in five families, or 6.4% of the study sample. Family members with one remaining functional copy of their genome segments did not have autism, while those with both copies missing did have autism.
The investigators found six gene disruptions that contributed to autism spectrum disorders. The largest of these gene disruptions involved genes essential for learning in the brain, as they are regulated either directly or indirectly by neuronal activity triggered by experience. Not all the genes were deleted—the remaining genes were simply turned off, leaving room for therapies to possibly turn these genes back on.
“Early brain development is driven largely by intrinsic patterns of gene expression that do not depend on experience-driven synaptic activity,” the investigators stated. “In contrast, postnatal brain development requires input from the environment that triggers the release of neurotransmitter and promotes critical aspects of synaptic maturation.... The connection between experience-dependent neural activity and gene expression in the postnatal period forms the basis of learning and memory, and autism symptoms typically emerge during these later stages of development.”
The researchers’ findings also pointed to potential genetic similarities, such as inherited recessive causes, between autism and other neurologic disorders. Among families in the present study who had one member with autism, there was a relatively equivalent male/female ratio compared with other families with autism, indicating that parents who shared a common recent ancestor was a determining factor. In families with more than one member with autism, the male/female ratio was even more balanced.
“The accumulating number of distinct, individually rare genetic causes in autism suggests that the genetic architecture of autism resembles that of mental retardation and epilepsy, with many syndromes, each individually rare, as well as other cases potentially reflecting complex interactions between inherited changes,” Dr. Morrow and colleagues elaborated. “The relatively reduced male/female ratio of affected children and the reduced rate of linked de novo copy number variants in the consanguineous sample [of the present study] ... both suggest that consanguineous pedigrees with autism are enriched for autosomal recessive causes similar to other congenital neurological disorders in consanguineous populations.”
The research team stated that although their findings support recent studies that suggest autism is highly heterogeneous genetically, homozygosity mapping appears to be an effective way to find underlying shared mechanisms. Understanding these genetic underpinnings could eventually help direct various therapies for the different clinical manifestations of autism.
“Our finding that deletions of genes regulated by neuronal activity or regions potentially involved in regulation of gene expression in autism suggests that defects in activity-dependent gene expression may be a cause of cognitive deficits in patients with autism,” the researchers concluded. In addition, their “data implicating noncoding elements in patients with shared ancestry, as well as the heterozygous nonsense changes in patients without shared ancestry, suggest that loss of proper regulation of gene dosage may be an important genetic mechanism in autism.”

Seemingly diverse autism mutations may share the same underlying mechanism, according to Eric M. Morrow, MD, PhD, Instructor in Psychiatry at Harvard Medical School in Boston, and colleagues.
“The regulation of expression of some autism candidate genes by neuronal membrane depolarization suggests the appealing hypothesis that neural activity–dependent regulation of synapse development may be a mechanism common to several autism mutations,” stated Dr. Morrow and colleagues in the July 11 Science. “Therefore, disruption of activity-regulated synaptic development may be one mechanism common to at least a subset of seemingly heterogeneous autism-associated mutations.”
The researchers studied 88 large families—in which both parents shared recent ancestors—to find inherited causes of autism spectrum disorders. The families, who came from Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates, were selected to emphasize the role of inherited genetic mutations.
The investigators gathered data with use of homozygosity mapping and compared the DNA of family members with and without autism to identify recessive mutations. Most individuals exhibited different genetic causes with little overlap between families, but a few exceptions were observed.
“Although the large size of linked loci precluded systemic gene sequencing in most cases, we were surprised to see that several consanguineous pedigrees showed large, rare, inherited homozygous deletions within linked regions, some of which are very likely causative mutations,” Dr. Morrow and colleagues said. Specifically, such deletions linked to autism were found in five families, or 6.4% of the study sample. Family members with one remaining functional copy of their genome segments did not have autism, while those with both copies missing did have autism.
The investigators found six gene disruptions that contributed to autism spectrum disorders. The largest of these gene disruptions involved genes essential for learning in the brain, as they are regulated either directly or indirectly by neuronal activity triggered by experience. Not all the genes were deleted—the remaining genes were simply turned off, leaving room for therapies to possibly turn these genes back on.
“Early brain development is driven largely by intrinsic patterns of gene expression that do not depend on experience-driven synaptic activity,” the investigators stated. “In contrast, postnatal brain development requires input from the environment that triggers the release of neurotransmitter and promotes critical aspects of synaptic maturation.... The connection between experience-dependent neural activity and gene expression in the postnatal period forms the basis of learning and memory, and autism symptoms typically emerge during these later stages of development.”
The researchers’ findings also pointed to potential genetic similarities, such as inherited recessive causes, between autism and other neurologic disorders. Among families in the present study who had one member with autism, there was a relatively equivalent male/female ratio compared with other families with autism, indicating that parents who shared a common recent ancestor was a determining factor. In families with more than one member with autism, the male/female ratio was even more balanced.
“The accumulating number of distinct, individually rare genetic causes in autism suggests that the genetic architecture of autism resembles that of mental retardation and epilepsy, with many syndromes, each individually rare, as well as other cases potentially reflecting complex interactions between inherited changes,” Dr. Morrow and colleagues elaborated. “The relatively reduced male/female ratio of affected children and the reduced rate of linked de novo copy number variants in the consanguineous sample [of the present study] ... both suggest that consanguineous pedigrees with autism are enriched for autosomal recessive causes similar to other congenital neurological disorders in consanguineous populations.”
The research team stated that although their findings support recent studies that suggest autism is highly heterogeneous genetically, homozygosity mapping appears to be an effective way to find underlying shared mechanisms. Understanding these genetic underpinnings could eventually help direct various therapies for the different clinical manifestations of autism.
“Our finding that deletions of genes regulated by neuronal activity or regions potentially involved in regulation of gene expression in autism suggests that defects in activity-dependent gene expression may be a cause of cognitive deficits in patients with autism,” the researchers concluded. In addition, their “data implicating noncoding elements in patients with shared ancestry, as well as the heterozygous nonsense changes in patients without shared ancestry, suggest that loss of proper regulation of gene dosage may be an important genetic mechanism in autism.”

Seemingly diverse autism mutations may share the same underlying mechanism, according to Eric M. Morrow, MD, PhD, Instructor in Psychiatry at Harvard Medical School in Boston, and colleagues.
“The regulation of expression of some autism candidate genes by neuronal membrane depolarization suggests the appealing hypothesis that neural activity–dependent regulation of synapse development may be a mechanism common to several autism mutations,” stated Dr. Morrow and colleagues in the July 11 Science. “Therefore, disruption of activity-regulated synaptic development may be one mechanism common to at least a subset of seemingly heterogeneous autism-associated mutations.”
The researchers studied 88 large families—in which both parents shared recent ancestors—to find inherited causes of autism spectrum disorders. The families, who came from Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates, were selected to emphasize the role of inherited genetic mutations.
The investigators gathered data with use of homozygosity mapping and compared the DNA of family members with and without autism to identify recessive mutations. Most individuals exhibited different genetic causes with little overlap between families, but a few exceptions were observed.
“Although the large size of linked loci precluded systemic gene sequencing in most cases, we were surprised to see that several consanguineous pedigrees showed large, rare, inherited homozygous deletions within linked regions, some of which are very likely causative mutations,” Dr. Morrow and colleagues said. Specifically, such deletions linked to autism were found in five families, or 6.4% of the study sample. Family members with one remaining functional copy of their genome segments did not have autism, while those with both copies missing did have autism.
The investigators found six gene disruptions that contributed to autism spectrum disorders. The largest of these gene disruptions involved genes essential for learning in the brain, as they are regulated either directly or indirectly by neuronal activity triggered by experience. Not all the genes were deleted—the remaining genes were simply turned off, leaving room for therapies to possibly turn these genes back on.
“Early brain development is driven largely by intrinsic patterns of gene expression that do not depend on experience-driven synaptic activity,” the investigators stated. “In contrast, postnatal brain development requires input from the environment that triggers the release of neurotransmitter and promotes critical aspects of synaptic maturation.... The connection between experience-dependent neural activity and gene expression in the postnatal period forms the basis of learning and memory, and autism symptoms typically emerge during these later stages of development.”
The researchers’ findings also pointed to potential genetic similarities, such as inherited recessive causes, between autism and other neurologic disorders. Among families in the present study who had one member with autism, there was a relatively equivalent male/female ratio compared with other families with autism, indicating that parents who shared a common recent ancestor was a determining factor. In families with more than one member with autism, the male/female ratio was even more balanced.
“The accumulating number of distinct, individually rare genetic causes in autism suggests that the genetic architecture of autism resembles that of mental retardation and epilepsy, with many syndromes, each individually rare, as well as other cases potentially reflecting complex interactions between inherited changes,” Dr. Morrow and colleagues elaborated. “The relatively reduced male/female ratio of affected children and the reduced rate of linked de novo copy number variants in the consanguineous sample [of the present study] ... both suggest that consanguineous pedigrees with autism are enriched for autosomal recessive causes similar to other congenital neurological disorders in consanguineous populations.”
The research team stated that although their findings support recent studies that suggest autism is highly heterogeneous genetically, homozygosity mapping appears to be an effective way to find underlying shared mechanisms. Understanding these genetic underpinnings could eventually help direct various therapies for the different clinical manifestations of autism.
“Our finding that deletions of genes regulated by neuronal activity or regions potentially involved in regulation of gene expression in autism suggests that defects in activity-dependent gene expression may be a cause of cognitive deficits in patients with autism,” the researchers concluded. In addition, their “data implicating noncoding elements in patients with shared ancestry, as well as the heterozygous nonsense changes in patients without shared ancestry, suggest that loss of proper regulation of gene dosage may be an important genetic mechanism in autism.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”