Device May Predict Seizure Risk

The NeuroPace RNS System may enable clinicians to identify when patients are at highest risk for seizures, thus allowing patients to plan around these events, according to a study published January 8 in Nature Communications. In 37 subjects with the implanted brain stimulation device, which detected interictal epileptiform activity (IEA) and seizures over years, researchers found that IEA oscillates with circadian and subject-specific multiday periods. Multiday periodicities, most commonly 20–30 days in duration, are robust and relatively stable for as long as 10 years in men and women. Investigators also found that seizures occur preferentially during the rising phase of multiday IEA rhythms. Combining phase information from circadian and multiday IEA rhythms could be a biomarker for determining relative seizure risk with a large effect size in most subjects.

Baud MO, Kleen JK, Mirro EA, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun. 2018;9(1):88.

DBS May Improve Survival in Parkinson’s Disease

Deep brain stimulation (DBS) is associated with a modest survival advantage when compared with medical management alone, according to a study published in the December 2017 issue of Movement Disorders. Investigators conducted a retrospective analysis of Veterans Affairs and Medicare administrative data of veterans with Parkinson’s disease between 2007 and 2013. They used propensity-score matching to pair patients who received DBS with those who received medical management alone. Veterans with Parkinson’s disease who received DBS had a longer survival measured in days than veterans who did not undergo DBS (2,291 days vs 2,064 days). Mean age at death was similar for both groups (76.5 vs 75.9), and the most common cause of death was Parkinson’s disease. The study groups may have differed in ways that are not measured.

Weaver FM, Stroupe KT, Smith B, et al. Survival in patients with Parkinson’s disease after deep brain stimulation or medical management. Mov Disord. 2017;32(12):1756-1763.

Idalopirdine May Not Decrease Cognitive Loss in Alzheimer’s Disease

In patients with mild to moderate Alzheimer’s disease, the use of idalopirdine, compared with placebo, does not improve cognition over 24 weeks of treatment, according to a study published January 9 in JAMA. The study examined three randomized clinical trials with 2,525 patients age 50 or older with mild to moderate Alzheimer’s disease. The 24-week studies were conducted from October 2013 to January 2017. Six months of 10 mg/day, 30 mg/day, or 60 mg/day idalopirdine treatment added to cholinesterase inhibitor therapy did not improve cognition or decrease cognitive loss. There was no requirement for evidence of Alzheimer’s disease biomarker positivity for inclusion in the trials, however, which may have allowed some patients to be included without having Alzheimer’s disease pathology.

Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319(2):130-142.

New Biomarker May Identify Huntington’s Disease

A potential biomarker for Huntington’s disease could mean a more effective way of evaluating treatments for this neurologic disease, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers studied miRNA levels in CSF from 30 asymptomatic carriers of the mutation that causes Huntington’s disease. They also studied CSF from participants diagnosed with Huntington’s disease, and from healthy controls. In all, 2,081 miRNAs were detected, and six were significantly increased in asymptomatic carriers versus controls. When the researchers evaluated the miRNA levels in each of the three patient groups, they found that all six had a pattern of increasing abundance from control to low risk, and from low risk to medium risk. The miRNA levels increase years before symptoms arise.

Reed ER, Latourelle JC, Bockholt JH, et al. MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study. Neurology. 2017 Dec 27 [Epub ahead of print].

Higher Topiramate Dose May Increase Risk of Cleft Lip or Palate

Topiramate increases the risk of cleft lip or cleft palate in offspring in a dose-dependent manner, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers examined Medicaid data and identified approximately 1.4 million women who gave birth to live babies over 10 years. They compared women who filled a prescription for topiramate during their first trimester with women who did not fill a prescription for any antiseizure drug and women who filled a prescription for lamotrigine. The risk of oral clefts at birth was 4.1 per 1,000 in infants born to women exposed to topiramate, compared with 1.1 per 1,000 in the group unexposed to antiseizure drugs, and 1.5 per 1,000 among women exposed to lamotrigine.

Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. Neurology. 2017 Dec 27 [Epub ahead of print].

Genetic Factors That Contribute to Alzheimer’s Disease Identified

Researchers have identified several new genes responsible for Alzheimer’s disease, including genes leading to functional and structural changes in the brain and elevated levels of Alzheimer’s disease proteins in CSF, according to a study published online ahead of print December 20, 2017, in Alzheimer’s & Dementia. Researchers tested the association between Alzheimer’s disease-related brain MRI measures, logical memory test scores, and CSF levels of amyloid beta and tau with millions of single-nucleotide polymorphisms (SNPs) in 1,189 participants in the Alzheimer Disease Neuroimaging Initiative study. Among people with normal cognitive functioning, SRRM4 was associated with total tau, and MTUS1 was associated with hippocampal volume. In participants with mild cognitive impairment, SNPs near ZNF804B were associated with logical memory test of delayed recall scores.

Chung J, Wang X, Maruyama T, et al. Genome-wide association study of Alzheimer’s disease endophenotypes at prediagnosis stages. Alzheimers Dement. 2017 Dec 20 [Epub ahead of print].

Fish Consumption May Improve Intelligence and Sleep

Children who eat fish at least once per week sleep better and have higher IQ scores than children who consume fish less frequently or not at all, according to a study published December 21, 2017, in Scientific Reports. The study included a cohort of 541 children (54% boys) between ages 9 and 11. The children took an IQ test and completed a questionnaire about fish consumption in the previous month. Options ranged from “never” to “at least once per week.” Their parents also answered the standardized Children Sleep Habits Questionnaire. Children who reported eating fish weekly scored 4.8 points higher on the IQ exams than those who said they “seldom” or “never” consumed fish. In addition, increased fish consumption was associated with fewer sleep disturbances.

Liu J, Cui Y, Li L, et al. The mediating role of sleep in the fish consumption - cognitive functioning relationship: a cohort study. Sci Rep. 2017;7(1):17961.

Rating Scales Predict Discharge Destination in Stroke

Outcome measure scores strongly predict discharge destination among patients with stroke and provide an objective means of early discharge planning, according to a study published in the January issue of the Journal of Neurologic Physical Therapy. A systematic review indicated that for every one-point increase on the Functional Independence Measure, a patient was approximately 1.08 times more likely to be discharged home than to institutionalized care. Patients with stroke who performed above average were 12 times more likely to be discharged home. Patients who performed poorly were 3.4 times more likely to be discharged to institutionalized care than home, and skilled nursing facility admission was more likely than admission to an inpatient rehabilitation facility. Patients with average performance were 1.9 times more likely to be discharged to institutionalized care.

Thorpe ER, Garrett KB, Smith AM, et al. Outcome measure scores predict discharge destination in patients with acute and subacute stroke: a systematic review and series of meta-analyses. J Neurol Phys Ther. 2018;42(1):2-11.

Do Green Leafy Vegetables Slow Brain Aging?

Eating about one serving per day of green, leafy vegetables may be linked to a slower rate of brain aging, according to a study published online ahead of print December 20, 2017, in Neurology. Researchers followed 960 cognitively normal people with an average age of 81 for an average of 4.7 years. In a linear mixed model adjusted for age, sex, education, cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green, leafy vegetables was associated with slower cognitive decline. Participants in the highest quintile of vegetable intake were the equivalent of 11 years younger, compared with people who never ate vegetables. Higher intake of phylloquinone, lutein, nitrate, folate, kaempferol, and alpha-tocopherol were associated with slower cognitive decline.

Morris MC, Wang Y, Barnes LL, et al. Nutrients and bioactives in green leafy vegetables and cognitive decline: prospective study. Neurology. 2017 Dec 20 [Epub ahead of print].

Data Clarify the Genetic Profile of Dementia With Lewy Bodies

Research has increased understanding of the unique genetic profile of dementia with Lewy bodies. In a study published January 17 in Lancet Neurology, researchers genotyped 1,743 patients with dementia with Lewy bodies and 4,454 controls. APOE and GBA had the same associations with dementia with Lewy bodies as they do with Alzheimer’s disease and Parkinson’s disease, respectively. SNCA, which is associated with Parkinson’s disease, also was associated with dementia with Lewy bodies, but through a different part of the gene. Evidence suggested that CNTN1 is associated with dementia with Lewy bodies, but the result was not statistically significant. The authors estimated that the heritable component of the disorder is approximately 36%. Common genetic variability has a role in the disease, said the authors.

Guerreiro R, Ross OA, Kun-Rodrigues C, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17(1):64-74.

Preterm Newborns Have Altered Cerebral Perfusion

Altered regional cortical blood flow (CBF) in infants born very preterm at term-equivalent age may reflect early brain dysmaturation despite the absence of cerebral cortical injury, according to a study published online ahead of print November 30, 2017 in the Journal of Pediatrics. In this prospective, cross-sectional study, researchers used noninvasive 3T arterial spin labeling MRI to quantify regional CBF in the cerebral cortex of 202 infants, 98 of whom were born preterm. Analyses were performed controlling for sex, gestational age, and age at MRI. Infants born preterm had greater global CBF and greater absolute regional CBF in all brain regions except the insula. Relative CBF in the insula, anterior cingulate cortex, and auditory cortex were decreased significantly in infants born preterm, compared with infants born at full term.

Bouyssi-Kobar M, Murnick J, Brossard-Racine M, et al. Altered cerebral perfusion in infants born preterm compared with infants born full term. J Pediatr. 2017 Nov 30 [Epub ahead of print].

—Kimberly Williams

Device May Predict Seizure Risk

The NeuroPace RNS System may enable clinicians to identify when patients are at highest risk for seizures, thus allowing patients to plan around these events, according to a study published January 8 in Nature Communications. In 37 subjects with the implanted brain stimulation device, which detected interictal epileptiform activity (IEA) and seizures over years, researchers found that IEA oscillates with circadian and subject-specific multiday periods. Multiday periodicities, most commonly 20–30 days in duration, are robust and relatively stable for as long as 10 years in men and women. Investigators also found that seizures occur preferentially during the rising phase of multiday IEA rhythms. Combining phase information from circadian and multiday IEA rhythms could be a biomarker for determining relative seizure risk with a large effect size in most subjects.

Baud MO, Kleen JK, Mirro EA, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun. 2018;9(1):88.

DBS May Improve Survival in Parkinson’s Disease

Deep brain stimulation (DBS) is associated with a modest survival advantage when compared with medical management alone, according to a study published in the December 2017 issue of Movement Disorders. Investigators conducted a retrospective analysis of Veterans Affairs and Medicare administrative data of veterans with Parkinson’s disease between 2007 and 2013. They used propensity-score matching to pair patients who received DBS with those who received medical management alone. Veterans with Parkinson’s disease who received DBS had a longer survival measured in days than veterans who did not undergo DBS (2,291 days vs 2,064 days). Mean age at death was similar for both groups (76.5 vs 75.9), and the most common cause of death was Parkinson’s disease. The study groups may have differed in ways that are not measured.

Weaver FM, Stroupe KT, Smith B, et al. Survival in patients with Parkinson’s disease after deep brain stimulation or medical management. Mov Disord. 2017;32(12):1756-1763.

Idalopirdine May Not Decrease Cognitive Loss in Alzheimer’s Disease

In patients with mild to moderate Alzheimer’s disease, the use of idalopirdine, compared with placebo, does not improve cognition over 24 weeks of treatment, according to a study published January 9 in JAMA. The study examined three randomized clinical trials with 2,525 patients age 50 or older with mild to moderate Alzheimer’s disease. The 24-week studies were conducted from October 2013 to January 2017. Six months of 10 mg/day, 30 mg/day, or 60 mg/day idalopirdine treatment added to cholinesterase inhibitor therapy did not improve cognition or decrease cognitive loss. There was no requirement for evidence of Alzheimer’s disease biomarker positivity for inclusion in the trials, however, which may have allowed some patients to be included without having Alzheimer’s disease pathology.

Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319(2):130-142.

New Biomarker May Identify Huntington’s Disease

A potential biomarker for Huntington’s disease could mean a more effective way of evaluating treatments for this neurologic disease, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers studied miRNA levels in CSF from 30 asymptomatic carriers of the mutation that causes Huntington’s disease. They also studied CSF from participants diagnosed with Huntington’s disease, and from healthy controls. In all, 2,081 miRNAs were detected, and six were significantly increased in asymptomatic carriers versus controls. When the researchers evaluated the miRNA levels in each of the three patient groups, they found that all six had a pattern of increasing abundance from control to low risk, and from low risk to medium risk. The miRNA levels increase years before symptoms arise.

Reed ER, Latourelle JC, Bockholt JH, et al. MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study. Neurology. 2017 Dec 27 [Epub ahead of print].

Higher Topiramate Dose May Increase Risk of Cleft Lip or Palate

Topiramate increases the risk of cleft lip or cleft palate in offspring in a dose-dependent manner, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers examined Medicaid data and identified approximately 1.4 million women who gave birth to live babies over 10 years. They compared women who filled a prescription for topiramate during their first trimester with women who did not fill a prescription for any antiseizure drug and women who filled a prescription for lamotrigine. The risk of oral clefts at birth was 4.1 per 1,000 in infants born to women exposed to topiramate, compared with 1.1 per 1,000 in the group unexposed to antiseizure drugs, and 1.5 per 1,000 among women exposed to lamotrigine.

Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. Neurology. 2017 Dec 27 [Epub ahead of print].

Genetic Factors That Contribute to Alzheimer’s Disease Identified

Researchers have identified several new genes responsible for Alzheimer’s disease, including genes leading to functional and structural changes in the brain and elevated levels of Alzheimer’s disease proteins in CSF, according to a study published online ahead of print December 20, 2017, in Alzheimer’s & Dementia. Researchers tested the association between Alzheimer’s disease-related brain MRI measures, logical memory test scores, and CSF levels of amyloid beta and tau with millions of single-nucleotide polymorphisms (SNPs) in 1,189 participants in the Alzheimer Disease Neuroimaging Initiative study. Among people with normal cognitive functioning, SRRM4 was associated with total tau, and MTUS1 was associated with hippocampal volume. In participants with mild cognitive impairment, SNPs near ZNF804B were associated with logical memory test of delayed recall scores.

Chung J, Wang X, Maruyama T, et al. Genome-wide association study of Alzheimer’s disease endophenotypes at prediagnosis stages. Alzheimers Dement. 2017 Dec 20 [Epub ahead of print].

Fish Consumption May Improve Intelligence and Sleep

Children who eat fish at least once per week sleep better and have higher IQ scores than children who consume fish less frequently or not at all, according to a study published December 21, 2017, in Scientific Reports. The study included a cohort of 541 children (54% boys) between ages 9 and 11. The children took an IQ test and completed a questionnaire about fish consumption in the previous month. Options ranged from “never” to “at least once per week.” Their parents also answered the standardized Children Sleep Habits Questionnaire. Children who reported eating fish weekly scored 4.8 points higher on the IQ exams than those who said they “seldom” or “never” consumed fish. In addition, increased fish consumption was associated with fewer sleep disturbances.

Liu J, Cui Y, Li L, et al. The mediating role of sleep in the fish consumption - cognitive functioning relationship: a cohort study. Sci Rep. 2017;7(1):17961.

Rating Scales Predict Discharge Destination in Stroke

Outcome measure scores strongly predict discharge destination among patients with stroke and provide an objective means of early discharge planning, according to a study published in the January issue of the Journal of Neurologic Physical Therapy. A systematic review indicated that for every one-point increase on the Functional Independence Measure, a patient was approximately 1.08 times more likely to be discharged home than to institutionalized care. Patients with stroke who performed above average were 12 times more likely to be discharged home. Patients who performed poorly were 3.4 times more likely to be discharged to institutionalized care than home, and skilled nursing facility admission was more likely than admission to an inpatient rehabilitation facility. Patients with average performance were 1.9 times more likely to be discharged to institutionalized care.

Thorpe ER, Garrett KB, Smith AM, et al. Outcome measure scores predict discharge destination in patients with acute and subacute stroke: a systematic review and series of meta-analyses. J Neurol Phys Ther. 2018;42(1):2-11.

Do Green Leafy Vegetables Slow Brain Aging?

Eating about one serving per day of green, leafy vegetables may be linked to a slower rate of brain aging, according to a study published online ahead of print December 20, 2017, in Neurology. Researchers followed 960 cognitively normal people with an average age of 81 for an average of 4.7 years. In a linear mixed model adjusted for age, sex, education, cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green, leafy vegetables was associated with slower cognitive decline. Participants in the highest quintile of vegetable intake were the equivalent of 11 years younger, compared with people who never ate vegetables. Higher intake of phylloquinone, lutein, nitrate, folate, kaempferol, and alpha-tocopherol were associated with slower cognitive decline.

Morris MC, Wang Y, Barnes LL, et al. Nutrients and bioactives in green leafy vegetables and cognitive decline: prospective study. Neurology. 2017 Dec 20 [Epub ahead of print].

Data Clarify the Genetic Profile of Dementia With Lewy Bodies

Research has increased understanding of the unique genetic profile of dementia with Lewy bodies. In a study published January 17 in Lancet Neurology, researchers genotyped 1,743 patients with dementia with Lewy bodies and 4,454 controls. APOE and GBA had the same associations with dementia with Lewy bodies as they do with Alzheimer’s disease and Parkinson’s disease, respectively. SNCA, which is associated with Parkinson’s disease, also was associated with dementia with Lewy bodies, but through a different part of the gene. Evidence suggested that CNTN1 is associated with dementia with Lewy bodies, but the result was not statistically significant. The authors estimated that the heritable component of the disorder is approximately 36%. Common genetic variability has a role in the disease, said the authors.

Guerreiro R, Ross OA, Kun-Rodrigues C, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17(1):64-74.

Preterm Newborns Have Altered Cerebral Perfusion

Altered regional cortical blood flow (CBF) in infants born very preterm at term-equivalent age may reflect early brain dysmaturation despite the absence of cerebral cortical injury, according to a study published online ahead of print November 30, 2017 in the Journal of Pediatrics. In this prospective, cross-sectional study, researchers used noninvasive 3T arterial spin labeling MRI to quantify regional CBF in the cerebral cortex of 202 infants, 98 of whom were born preterm. Analyses were performed controlling for sex, gestational age, and age at MRI. Infants born preterm had greater global CBF and greater absolute regional CBF in all brain regions except the insula. Relative CBF in the insula, anterior cingulate cortex, and auditory cortex were decreased significantly in infants born preterm, compared with infants born at full term.

Bouyssi-Kobar M, Murnick J, Brossard-Racine M, et al. Altered cerebral perfusion in infants born preterm compared with infants born full term. J Pediatr. 2017 Nov 30 [Epub ahead of print].

—Kimberly Williams

Device May Predict Seizure Risk

The NeuroPace RNS System may enable clinicians to identify when patients are at highest risk for seizures, thus allowing patients to plan around these events, according to a study published January 8 in Nature Communications. In 37 subjects with the implanted brain stimulation device, which detected interictal epileptiform activity (IEA) and seizures over years, researchers found that IEA oscillates with circadian and subject-specific multiday periods. Multiday periodicities, most commonly 20–30 days in duration, are robust and relatively stable for as long as 10 years in men and women. Investigators also found that seizures occur preferentially during the rising phase of multiday IEA rhythms. Combining phase information from circadian and multiday IEA rhythms could be a biomarker for determining relative seizure risk with a large effect size in most subjects.

Baud MO, Kleen JK, Mirro EA, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun. 2018;9(1):88.

DBS May Improve Survival in Parkinson’s Disease

Deep brain stimulation (DBS) is associated with a modest survival advantage when compared with medical management alone, according to a study published in the December 2017 issue of Movement Disorders. Investigators conducted a retrospective analysis of Veterans Affairs and Medicare administrative data of veterans with Parkinson’s disease between 2007 and 2013. They used propensity-score matching to pair patients who received DBS with those who received medical management alone. Veterans with Parkinson’s disease who received DBS had a longer survival measured in days than veterans who did not undergo DBS (2,291 days vs 2,064 days). Mean age at death was similar for both groups (76.5 vs 75.9), and the most common cause of death was Parkinson’s disease. The study groups may have differed in ways that are not measured.

Weaver FM, Stroupe KT, Smith B, et al. Survival in patients with Parkinson’s disease after deep brain stimulation or medical management. Mov Disord. 2017;32(12):1756-1763.

Idalopirdine May Not Decrease Cognitive Loss in Alzheimer’s Disease

In patients with mild to moderate Alzheimer’s disease, the use of idalopirdine, compared with placebo, does not improve cognition over 24 weeks of treatment, according to a study published January 9 in JAMA. The study examined three randomized clinical trials with 2,525 patients age 50 or older with mild to moderate Alzheimer’s disease. The 24-week studies were conducted from October 2013 to January 2017. Six months of 10 mg/day, 30 mg/day, or 60 mg/day idalopirdine treatment added to cholinesterase inhibitor therapy did not improve cognition or decrease cognitive loss. There was no requirement for evidence of Alzheimer’s disease biomarker positivity for inclusion in the trials, however, which may have allowed some patients to be included without having Alzheimer’s disease pathology.

Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319(2):130-142.

New Biomarker May Identify Huntington’s Disease

A potential biomarker for Huntington’s disease could mean a more effective way of evaluating treatments for this neurologic disease, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers studied miRNA levels in CSF from 30 asymptomatic carriers of the mutation that causes Huntington’s disease. They also studied CSF from participants diagnosed with Huntington’s disease, and from healthy controls. In all, 2,081 miRNAs were detected, and six were significantly increased in asymptomatic carriers versus controls. When the researchers evaluated the miRNA levels in each of the three patient groups, they found that all six had a pattern of increasing abundance from control to low risk, and from low risk to medium risk. The miRNA levels increase years before symptoms arise.

Reed ER, Latourelle JC, Bockholt JH, et al. MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study. Neurology. 2017 Dec 27 [Epub ahead of print].

Higher Topiramate Dose May Increase Risk of Cleft Lip or Palate

Topiramate increases the risk of cleft lip or cleft palate in offspring in a dose-dependent manner, according to a study published online ahead of print December 27, 2017, in Neurology. Researchers examined Medicaid data and identified approximately 1.4 million women who gave birth to live babies over 10 years. They compared women who filled a prescription for topiramate during their first trimester with women who did not fill a prescription for any antiseizure drug and women who filled a prescription for lamotrigine. The risk of oral clefts at birth was 4.1 per 1,000 in infants born to women exposed to topiramate, compared with 1.1 per 1,000 in the group unexposed to antiseizure drugs, and 1.5 per 1,000 among women exposed to lamotrigine.

Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. Neurology. 2017 Dec 27 [Epub ahead of print].

Genetic Factors That Contribute to Alzheimer’s Disease Identified

Researchers have identified several new genes responsible for Alzheimer’s disease, including genes leading to functional and structural changes in the brain and elevated levels of Alzheimer’s disease proteins in CSF, according to a study published online ahead of print December 20, 2017, in Alzheimer’s & Dementia. Researchers tested the association between Alzheimer’s disease-related brain MRI measures, logical memory test scores, and CSF levels of amyloid beta and tau with millions of single-nucleotide polymorphisms (SNPs) in 1,189 participants in the Alzheimer Disease Neuroimaging Initiative study. Among people with normal cognitive functioning, SRRM4 was associated with total tau, and MTUS1 was associated with hippocampal volume. In participants with mild cognitive impairment, SNPs near ZNF804B were associated with logical memory test of delayed recall scores.

Chung J, Wang X, Maruyama T, et al. Genome-wide association study of Alzheimer’s disease endophenotypes at prediagnosis stages. Alzheimers Dement. 2017 Dec 20 [Epub ahead of print].

Fish Consumption May Improve Intelligence and Sleep

Children who eat fish at least once per week sleep better and have higher IQ scores than children who consume fish less frequently or not at all, according to a study published December 21, 2017, in Scientific Reports. The study included a cohort of 541 children (54% boys) between ages 9 and 11. The children took an IQ test and completed a questionnaire about fish consumption in the previous month. Options ranged from “never” to “at least once per week.” Their parents also answered the standardized Children Sleep Habits Questionnaire. Children who reported eating fish weekly scored 4.8 points higher on the IQ exams than those who said they “seldom” or “never” consumed fish. In addition, increased fish consumption was associated with fewer sleep disturbances.

Liu J, Cui Y, Li L, et al. The mediating role of sleep in the fish consumption - cognitive functioning relationship: a cohort study. Sci Rep. 2017;7(1):17961.

Rating Scales Predict Discharge Destination in Stroke

Outcome measure scores strongly predict discharge destination among patients with stroke and provide an objective means of early discharge planning, according to a study published in the January issue of the Journal of Neurologic Physical Therapy. A systematic review indicated that for every one-point increase on the Functional Independence Measure, a patient was approximately 1.08 times more likely to be discharged home than to institutionalized care. Patients with stroke who performed above average were 12 times more likely to be discharged home. Patients who performed poorly were 3.4 times more likely to be discharged to institutionalized care than home, and skilled nursing facility admission was more likely than admission to an inpatient rehabilitation facility. Patients with average performance were 1.9 times more likely to be discharged to institutionalized care.

Thorpe ER, Garrett KB, Smith AM, et al. Outcome measure scores predict discharge destination in patients with acute and subacute stroke: a systematic review and series of meta-analyses. J Neurol Phys Ther. 2018;42(1):2-11.

Do Green Leafy Vegetables Slow Brain Aging?

Eating about one serving per day of green, leafy vegetables may be linked to a slower rate of brain aging, according to a study published online ahead of print December 20, 2017, in Neurology. Researchers followed 960 cognitively normal people with an average age of 81 for an average of 4.7 years. In a linear mixed model adjusted for age, sex, education, cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green, leafy vegetables was associated with slower cognitive decline. Participants in the highest quintile of vegetable intake were the equivalent of 11 years younger, compared with people who never ate vegetables. Higher intake of phylloquinone, lutein, nitrate, folate, kaempferol, and alpha-tocopherol were associated with slower cognitive decline.

Morris MC, Wang Y, Barnes LL, et al. Nutrients and bioactives in green leafy vegetables and cognitive decline: prospective study. Neurology. 2017 Dec 20 [Epub ahead of print].

Data Clarify the Genetic Profile of Dementia With Lewy Bodies

Research has increased understanding of the unique genetic profile of dementia with Lewy bodies. In a study published January 17 in Lancet Neurology, researchers genotyped 1,743 patients with dementia with Lewy bodies and 4,454 controls. APOE and GBA had the same associations with dementia with Lewy bodies as they do with Alzheimer’s disease and Parkinson’s disease, respectively. SNCA, which is associated with Parkinson’s disease, also was associated with dementia with Lewy bodies, but through a different part of the gene. Evidence suggested that CNTN1 is associated with dementia with Lewy bodies, but the result was not statistically significant. The authors estimated that the heritable component of the disorder is approximately 36%. Common genetic variability has a role in the disease, said the authors.

Guerreiro R, Ross OA, Kun-Rodrigues C, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17(1):64-74.

Preterm Newborns Have Altered Cerebral Perfusion

Altered regional cortical blood flow (CBF) in infants born very preterm at term-equivalent age may reflect early brain dysmaturation despite the absence of cerebral cortical injury, according to a study published online ahead of print November 30, 2017 in the Journal of Pediatrics. In this prospective, cross-sectional study, researchers used noninvasive 3T arterial spin labeling MRI to quantify regional CBF in the cerebral cortex of 202 infants, 98 of whom were born preterm. Analyses were performed controlling for sex, gestational age, and age at MRI. Infants born preterm had greater global CBF and greater absolute regional CBF in all brain regions except the insula. Relative CBF in the insula, anterior cingulate cortex, and auditory cortex were decreased significantly in infants born preterm, compared with infants born at full term.

Bouyssi-Kobar M, Murnick J, Brossard-Racine M, et al. Altered cerebral perfusion in infants born preterm compared with infants born full term. J Pediatr. 2017 Nov 30 [Epub ahead of print].

—Kimberly Williams

The National Institute of Mental Health (NIMH) has announced the creation of a redesigned statistics section on its website that feature data interactive visualization tools.

In addition to providing statistics on mental illness in general, the new section offers data on specific mental illnesses ranging from autism spectrum disorders to schizophrenia. It also includes data on suicide, which is among the country’s top 10 causes of death.

“Each [person with mental illness] has a singular, compelling story that conveys an understanding of the depth of suffering,” said Joshua A. Gordon, MD, PhD, director of the NIMH, in a statement announcing the tool. “Statistics build on this foundation by helping us better understand the broader scope and impact of mental illnesses on society.”

The NIMH said the section would be updated as new data from agencies, such as the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration, are released.

Read the full announcement here

cpnews@frontlinemedcom.com

The National Institute of Mental Health (NIMH) has announced the creation of a redesigned statistics section on its website that feature data interactive visualization tools.

In addition to providing statistics on mental illness in general, the new section offers data on specific mental illnesses ranging from autism spectrum disorders to schizophrenia. It also includes data on suicide, which is among the country’s top 10 causes of death.

“Each [person with mental illness] has a singular, compelling story that conveys an understanding of the depth of suffering,” said Joshua A. Gordon, MD, PhD, director of the NIMH, in a statement announcing the tool. “Statistics build on this foundation by helping us better understand the broader scope and impact of mental illnesses on society.”

The NIMH said the section would be updated as new data from agencies, such as the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration, are released.

Read the full announcement here

cpnews@frontlinemedcom.com

The National Institute of Mental Health (NIMH) has announced the creation of a redesigned statistics section on its website that feature data interactive visualization tools.

In addition to providing statistics on mental illness in general, the new section offers data on specific mental illnesses ranging from autism spectrum disorders to schizophrenia. It also includes data on suicide, which is among the country’s top 10 causes of death.

“Each [person with mental illness] has a singular, compelling story that conveys an understanding of the depth of suffering,” said Joshua A. Gordon, MD, PhD, director of the NIMH, in a statement announcing the tool. “Statistics build on this foundation by helping us better understand the broader scope and impact of mental illnesses on society.”

The NIMH said the section would be updated as new data from agencies, such as the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration, are released.

Read the full announcement here

cpnews@frontlinemedcom.com

DALLAS – Elective inductions at 39 weeks’ gestation were safe for the newborn and conferred dual benefits upon first-time mothers, reducing the risk of cesarean delivery by 16% and pregnancy-related hypertensive disorder by 36%, compared with women managed expectantly.

Infants delivered by elective inductions were smaller than those born to expectantly managed women and experienced a 29% reduction in the need for respiratory support at birth, William A. Grobman, MD, reported at the meeting, sponsored by the Society for Maternal-Fetal Medicine. They were no more likely than infants in the comparator group to experience dangerous perinatal outcomes, including low Apgar scores, meconium inhalation, hypoxia, or birth trauma, said Dr. Grobman, professor of obstetrics and gynecology at Northwestern University, Chicago.

Michele G. Sullivan/Frontline Medical News

msullivan@frontlinemedcom.com

SOURCE: Grobman W. Am J Obstet Gynecol. 2018 Jan;218:S601.

DALLAS – Elective inductions at 39 weeks’ gestation were safe for the newborn and conferred dual benefits upon first-time mothers, reducing the risk of cesarean delivery by 16% and pregnancy-related hypertensive disorder by 36%, compared with women managed expectantly.

Infants delivered by elective inductions were smaller than those born to expectantly managed women and experienced a 29% reduction in the need for respiratory support at birth, William A. Grobman, MD, reported at the meeting, sponsored by the Society for Maternal-Fetal Medicine. They were no more likely than infants in the comparator group to experience dangerous perinatal outcomes, including low Apgar scores, meconium inhalation, hypoxia, or birth trauma, said Dr. Grobman, professor of obstetrics and gynecology at Northwestern University, Chicago.

Michele G. Sullivan/Frontline Medical News

msullivan@frontlinemedcom.com

SOURCE: Grobman W. Am J Obstet Gynecol. 2018 Jan;218:S601.

DALLAS – Elective inductions at 39 weeks’ gestation were safe for the newborn and conferred dual benefits upon first-time mothers, reducing the risk of cesarean delivery by 16% and pregnancy-related hypertensive disorder by 36%, compared with women managed expectantly.

Infants delivered by elective inductions were smaller than those born to expectantly managed women and experienced a 29% reduction in the need for respiratory support at birth, William A. Grobman, MD, reported at the meeting, sponsored by the Society for Maternal-Fetal Medicine. They were no more likely than infants in the comparator group to experience dangerous perinatal outcomes, including low Apgar scores, meconium inhalation, hypoxia, or birth trauma, said Dr. Grobman, professor of obstetrics and gynecology at Northwestern University, Chicago.

Michele G. Sullivan/Frontline Medical News

msullivan@frontlinemedcom.com

SOURCE: Grobman W. Am J Obstet Gynecol. 2018 Jan;218:S601.

KANSAS CITY, MO—Newborn screening for Krabbe disease, also known as globoid-cell leukodystrophy (GLD), may help researchers evaluate potential therapies for this condition, according to an overview presented at the 46th Annual Meeting of the Child Neurology Society. Early diagnosis likely is needed to effectively intervene, especially in rapidly progressive forms of the disease, said Gustavo H. B. Maegawa, MD, PhD, Associate Professor of Neuroscience in the Department of Pediatrics at the University of Florida’s College of Medicine in Gainesville.

A Severe Condition

Krabbe disease is a lysosomal storage disorder caused by mutations in the galactosylceramidase (GALC) gene. The incidence is approximately one in 100,000 births. The carrier frequency is approximately one in 150. Krabbe disease is panethnic, and high incidence has been observed in inbred populations.

In the United States, 85% to 90% of patients with Krabbe disease have the infantile form, with onset of symptoms occuring before age 6 months. Stage I symptoms of infantile Krabbe disease include irritability, stiffness, developmental delay, feeding problems, and seizures. Stage II symptoms include rapid neurodegeneration with hypertonicity of the upper and lower extremities, optic atrophy, wheel-chair bound, hyporeflexia, and worsening of dysphagia requiring tube feeding. During stage III, affected patients become immobile, go blind, and eventually enter a vegetative state. Most cases are infantile and progress “so fast that the child dies before 10 or 12 months of age,” said Dr. Maegawa.

Current Treatment and Newborn Screening

In 2005, Escolar et al reported that hematopoietic stem cell transplantation (HSCT) favorably altered the natural history of the disease in asymptomatic newborns with infantile Krabbe disease, whereas HSCT after symptoms had developed did not result in substantive neurologic improvement. This finding set the stage for newborn screening programs for Krabbe disease.

New York State began screening all newborns for Krabbe disease in 2006. Wasserstein et al examined the clinical outcomes of infants screened for Krabbe disease in the state. Of the nearly two million infants screened, five were diagnosed with early-infantile Krabbe disease, and three died. Two babies died from HSCT-related complications, and one died from untreated disease. In addition, screening identified 92 infants with low risk of the disease, 37 with moderate risk, and 14 with high risk.

Initially, infants with confirmatory residual GALC activities between 0.30 and 0.5 nmol/hour/mg protein were considered to be at low-risk. Later on, with the experience of repeating the GALC activity, infants with activities greater than 0.3 nmol/hour/mg are now considered to not be at risk unless they carry two potentially pathogenic variants, which would classify them as moderate risk. In the moderate-risk category, newborns present confirmatory GALC activity of 0.16 to 0.29 nmol/hour/mg protein or GALC activity in the low-risk range but two known or potentially pathogenic mutations in the GALC gene.

In the high-risk category, newborns show high risk for Krabbe disease based on very low confirmatory GALC activity of 0.0 to 0.15-nmol/hour/mg protein. All infants in this group underwent urgent neurodiagnostic evaluation that included a neurologic exam every month, neuroimaging at 0, four, eight, and 12 months until 12 months. Between 13 and 36 months of age, the neurologic exams are every three months and brain imaging as needed.

The incidence of infantile Krabbe disease in New York, one in 394,000, was lower than anticipated. Researchers also observed significant overlap between risk categories. A few children switched from high to moderate risk groups. Finally, there was low compliance with the Krabbe Consortium protocol.

Seeking Therapies

Researchers are using cell-based high-throughput screening (HTS) assays to discover potential treatments for Krabbe disease. One proposed HTS assay is performed in cell-lines with the human GALC mutated protein with a specific flurogenic substrate also used to measure the GALC activity in dried blood spots in newborn screens for Krabbe disease, said Dr. Maegawa.

Another developed throughput assay is cell-based but uses neurologically relevant brain cells and measures accumulated psychosine, a cytotoxic natural substrate in Krabbe disease. The cell-line was established from the brain of naturally occuring mouse models for Krabbe disease called the Twitcher mouse.

This is an essential component of the myelin, but at nonphysiological high levels, psychosine becomes extremely toxic to myelin-forming cells, such as oligodendrocytes and Schwann cells.

“We are also looking at the manipulation of the biosynthetic psychosine, which is the extremely cytotoxic metabolite in Krabbe disease. If we find a molecule that normalizes the levels of psychosine, we will eventually be able to find a drug that will prevent the cytotoxicity of high levels found in Krabbe disease and to eventually arrest and prevent the demyelination that occurs in this disease,” said Dr. Maegawa.

“Gene therapy and cell therapy trials have shown progress in the Twitcher models by carrying a homozygous nonsense mutation in the GALC murine gene. Hopefully, a combination of these approaches will soon be used in clinical trials.”

—Erica Tricarico

Suggested Reading

Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Eng J Med. 2005;352(20):2069-2081.

Jang DS, Ye W, Guimei T, et al. Cell-based high-throughput screening identifies galactocerebrosidase enhancers as potential small-molecule therapies for Krabbe disease. J Neurosci Res. 2016;94(11):1231-1245.

Ribbens J, Whiteley G, Furuya F, et al. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013;434(1):15-25.

Ribbens JJ, Moser AB, Hubbard WC, et al. Characterization and application of a disease-cell model for neurodegenerative lysosomal disease. Mol Genet Metab. 2014;111(2):172-183.

Wasserstein M, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1243.

KANSAS CITY, MO—Newborn screening for Krabbe disease, also known as globoid-cell leukodystrophy (GLD), may help researchers evaluate potential therapies for this condition, according to an overview presented at the 46th Annual Meeting of the Child Neurology Society. Early diagnosis likely is needed to effectively intervene, especially in rapidly progressive forms of the disease, said Gustavo H. B. Maegawa, MD, PhD, Associate Professor of Neuroscience in the Department of Pediatrics at the University of Florida’s College of Medicine in Gainesville.

A Severe Condition

Krabbe disease is a lysosomal storage disorder caused by mutations in the galactosylceramidase (GALC) gene. The incidence is approximately one in 100,000 births. The carrier frequency is approximately one in 150. Krabbe disease is panethnic, and high incidence has been observed in inbred populations.

In the United States, 85% to 90% of patients with Krabbe disease have the infantile form, with onset of symptoms occuring before age 6 months. Stage I symptoms of infantile Krabbe disease include irritability, stiffness, developmental delay, feeding problems, and seizures. Stage II symptoms include rapid neurodegeneration with hypertonicity of the upper and lower extremities, optic atrophy, wheel-chair bound, hyporeflexia, and worsening of dysphagia requiring tube feeding. During stage III, affected patients become immobile, go blind, and eventually enter a vegetative state. Most cases are infantile and progress “so fast that the child dies before 10 or 12 months of age,” said Dr. Maegawa.

Current Treatment and Newborn Screening

In 2005, Escolar et al reported that hematopoietic stem cell transplantation (HSCT) favorably altered the natural history of the disease in asymptomatic newborns with infantile Krabbe disease, whereas HSCT after symptoms had developed did not result in substantive neurologic improvement. This finding set the stage for newborn screening programs for Krabbe disease.

New York State began screening all newborns for Krabbe disease in 2006. Wasserstein et al examined the clinical outcomes of infants screened for Krabbe disease in the state. Of the nearly two million infants screened, five were diagnosed with early-infantile Krabbe disease, and three died. Two babies died from HSCT-related complications, and one died from untreated disease. In addition, screening identified 92 infants with low risk of the disease, 37 with moderate risk, and 14 with high risk.

Initially, infants with confirmatory residual GALC activities between 0.30 and 0.5 nmol/hour/mg protein were considered to be at low-risk. Later on, with the experience of repeating the GALC activity, infants with activities greater than 0.3 nmol/hour/mg are now considered to not be at risk unless they carry two potentially pathogenic variants, which would classify them as moderate risk. In the moderate-risk category, newborns present confirmatory GALC activity of 0.16 to 0.29 nmol/hour/mg protein or GALC activity in the low-risk range but two known or potentially pathogenic mutations in the GALC gene.

In the high-risk category, newborns show high risk for Krabbe disease based on very low confirmatory GALC activity of 0.0 to 0.15-nmol/hour/mg protein. All infants in this group underwent urgent neurodiagnostic evaluation that included a neurologic exam every month, neuroimaging at 0, four, eight, and 12 months until 12 months. Between 13 and 36 months of age, the neurologic exams are every three months and brain imaging as needed.

The incidence of infantile Krabbe disease in New York, one in 394,000, was lower than anticipated. Researchers also observed significant overlap between risk categories. A few children switched from high to moderate risk groups. Finally, there was low compliance with the Krabbe Consortium protocol.

Seeking Therapies

Researchers are using cell-based high-throughput screening (HTS) assays to discover potential treatments for Krabbe disease. One proposed HTS assay is performed in cell-lines with the human GALC mutated protein with a specific flurogenic substrate also used to measure the GALC activity in dried blood spots in newborn screens for Krabbe disease, said Dr. Maegawa.

Another developed throughput assay is cell-based but uses neurologically relevant brain cells and measures accumulated psychosine, a cytotoxic natural substrate in Krabbe disease. The cell-line was established from the brain of naturally occuring mouse models for Krabbe disease called the Twitcher mouse.

This is an essential component of the myelin, but at nonphysiological high levels, psychosine becomes extremely toxic to myelin-forming cells, such as oligodendrocytes and Schwann cells.

“We are also looking at the manipulation of the biosynthetic psychosine, which is the extremely cytotoxic metabolite in Krabbe disease. If we find a molecule that normalizes the levels of psychosine, we will eventually be able to find a drug that will prevent the cytotoxicity of high levels found in Krabbe disease and to eventually arrest and prevent the demyelination that occurs in this disease,” said Dr. Maegawa.

“Gene therapy and cell therapy trials have shown progress in the Twitcher models by carrying a homozygous nonsense mutation in the GALC murine gene. Hopefully, a combination of these approaches will soon be used in clinical trials.”

—Erica Tricarico

Suggested Reading

Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Eng J Med. 2005;352(20):2069-2081.

Jang DS, Ye W, Guimei T, et al. Cell-based high-throughput screening identifies galactocerebrosidase enhancers as potential small-molecule therapies for Krabbe disease. J Neurosci Res. 2016;94(11):1231-1245.

Ribbens J, Whiteley G, Furuya F, et al. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013;434(1):15-25.

Ribbens JJ, Moser AB, Hubbard WC, et al. Characterization and application of a disease-cell model for neurodegenerative lysosomal disease. Mol Genet Metab. 2014;111(2):172-183.

Wasserstein M, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1243.

KANSAS CITY, MO—Newborn screening for Krabbe disease, also known as globoid-cell leukodystrophy (GLD), may help researchers evaluate potential therapies for this condition, according to an overview presented at the 46th Annual Meeting of the Child Neurology Society. Early diagnosis likely is needed to effectively intervene, especially in rapidly progressive forms of the disease, said Gustavo H. B. Maegawa, MD, PhD, Associate Professor of Neuroscience in the Department of Pediatrics at the University of Florida’s College of Medicine in Gainesville.

A Severe Condition

Krabbe disease is a lysosomal storage disorder caused by mutations in the galactosylceramidase (GALC) gene. The incidence is approximately one in 100,000 births. The carrier frequency is approximately one in 150. Krabbe disease is panethnic, and high incidence has been observed in inbred populations.

In the United States, 85% to 90% of patients with Krabbe disease have the infantile form, with onset of symptoms occuring before age 6 months. Stage I symptoms of infantile Krabbe disease include irritability, stiffness, developmental delay, feeding problems, and seizures. Stage II symptoms include rapid neurodegeneration with hypertonicity of the upper and lower extremities, optic atrophy, wheel-chair bound, hyporeflexia, and worsening of dysphagia requiring tube feeding. During stage III, affected patients become immobile, go blind, and eventually enter a vegetative state. Most cases are infantile and progress “so fast that the child dies before 10 or 12 months of age,” said Dr. Maegawa.

Current Treatment and Newborn Screening

In 2005, Escolar et al reported that hematopoietic stem cell transplantation (HSCT) favorably altered the natural history of the disease in asymptomatic newborns with infantile Krabbe disease, whereas HSCT after symptoms had developed did not result in substantive neurologic improvement. This finding set the stage for newborn screening programs for Krabbe disease.

New York State began screening all newborns for Krabbe disease in 2006. Wasserstein et al examined the clinical outcomes of infants screened for Krabbe disease in the state. Of the nearly two million infants screened, five were diagnosed with early-infantile Krabbe disease, and three died. Two babies died from HSCT-related complications, and one died from untreated disease. In addition, screening identified 92 infants with low risk of the disease, 37 with moderate risk, and 14 with high risk.

Initially, infants with confirmatory residual GALC activities between 0.30 and 0.5 nmol/hour/mg protein were considered to be at low-risk. Later on, with the experience of repeating the GALC activity, infants with activities greater than 0.3 nmol/hour/mg are now considered to not be at risk unless they carry two potentially pathogenic variants, which would classify them as moderate risk. In the moderate-risk category, newborns present confirmatory GALC activity of 0.16 to 0.29 nmol/hour/mg protein or GALC activity in the low-risk range but two known or potentially pathogenic mutations in the GALC gene.

In the high-risk category, newborns show high risk for Krabbe disease based on very low confirmatory GALC activity of 0.0 to 0.15-nmol/hour/mg protein. All infants in this group underwent urgent neurodiagnostic evaluation that included a neurologic exam every month, neuroimaging at 0, four, eight, and 12 months until 12 months. Between 13 and 36 months of age, the neurologic exams are every three months and brain imaging as needed.

The incidence of infantile Krabbe disease in New York, one in 394,000, was lower than anticipated. Researchers also observed significant overlap between risk categories. A few children switched from high to moderate risk groups. Finally, there was low compliance with the Krabbe Consortium protocol.

Seeking Therapies

Researchers are using cell-based high-throughput screening (HTS) assays to discover potential treatments for Krabbe disease. One proposed HTS assay is performed in cell-lines with the human GALC mutated protein with a specific flurogenic substrate also used to measure the GALC activity in dried blood spots in newborn screens for Krabbe disease, said Dr. Maegawa.

Another developed throughput assay is cell-based but uses neurologically relevant brain cells and measures accumulated psychosine, a cytotoxic natural substrate in Krabbe disease. The cell-line was established from the brain of naturally occuring mouse models for Krabbe disease called the Twitcher mouse.

This is an essential component of the myelin, but at nonphysiological high levels, psychosine becomes extremely toxic to myelin-forming cells, such as oligodendrocytes and Schwann cells.

“We are also looking at the manipulation of the biosynthetic psychosine, which is the extremely cytotoxic metabolite in Krabbe disease. If we find a molecule that normalizes the levels of psychosine, we will eventually be able to find a drug that will prevent the cytotoxicity of high levels found in Krabbe disease and to eventually arrest and prevent the demyelination that occurs in this disease,” said Dr. Maegawa.

“Gene therapy and cell therapy trials have shown progress in the Twitcher models by carrying a homozygous nonsense mutation in the GALC murine gene. Hopefully, a combination of these approaches will soon be used in clinical trials.”

—Erica Tricarico

Suggested Reading

Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Eng J Med. 2005;352(20):2069-2081.

Jang DS, Ye W, Guimei T, et al. Cell-based high-throughput screening identifies galactocerebrosidase enhancers as potential small-molecule therapies for Krabbe disease. J Neurosci Res. 2016;94(11):1231-1245.

Ribbens J, Whiteley G, Furuya F, et al. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013;434(1):15-25.

Ribbens JJ, Moser AB, Hubbard WC, et al. Characterization and application of a disease-cell model for neurodegenerative lysosomal disease. Mol Genet Metab. 2014;111(2):172-183.

Wasserstein M, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1243.

The Food and Drug Administration announced Dec. 22, 2017, that it has approved an implantable system for treprostinil to treat adult patients with New York Heart Association (NYHA) Class I, II and III pulmonary arterial hypertension.

This infusion system is implanted into a patient for intravenous delivery of treprostinil (Remodulin) and is designed to help supply blood to the lungs and keep a patient’s blood pressure within a healthy range. The system comprises three parts: the pump, the programmer, and the catheter.

The implant should not be used for patients with NYHA Class IV heart failure, a known or suspected infection, bacteremia, or sepsis requiring antibiotics; vasculature that is inadequate for an 8 French introducer or catheter advancement without stylet guidance; implanted leads or catheters (active or abandoned) in the superior vena cava that cannot be removed prior to or at system implant; a body size not sufficient to accept the pump; or skin or soft tissue that would heal poorly or increase susceptibility to infections. Patients who are unable to tolerate a sudden cessation of treprostinil therapy also would not be able to receive the implantable device.

Read the full approval on the FDA’s website.

llaubach@frontlinemedcom.com

The Food and Drug Administration announced Dec. 22, 2017, that it has approved an implantable system for treprostinil to treat adult patients with New York Heart Association (NYHA) Class I, II and III pulmonary arterial hypertension.

This infusion system is implanted into a patient for intravenous delivery of treprostinil (Remodulin) and is designed to help supply blood to the lungs and keep a patient’s blood pressure within a healthy range. The system comprises three parts: the pump, the programmer, and the catheter.

The implant should not be used for patients with NYHA Class IV heart failure, a known or suspected infection, bacteremia, or sepsis requiring antibiotics; vasculature that is inadequate for an 8 French introducer or catheter advancement without stylet guidance; implanted leads or catheters (active or abandoned) in the superior vena cava that cannot be removed prior to or at system implant; a body size not sufficient to accept the pump; or skin or soft tissue that would heal poorly or increase susceptibility to infections. Patients who are unable to tolerate a sudden cessation of treprostinil therapy also would not be able to receive the implantable device.

Read the full approval on the FDA’s website.

llaubach@frontlinemedcom.com

The Food and Drug Administration announced Dec. 22, 2017, that it has approved an implantable system for treprostinil to treat adult patients with New York Heart Association (NYHA) Class I, II and III pulmonary arterial hypertension.

This infusion system is implanted into a patient for intravenous delivery of treprostinil (Remodulin) and is designed to help supply blood to the lungs and keep a patient’s blood pressure within a healthy range. The system comprises three parts: the pump, the programmer, and the catheter.

The implant should not be used for patients with NYHA Class IV heart failure, a known or suspected infection, bacteremia, or sepsis requiring antibiotics; vasculature that is inadequate for an 8 French introducer or catheter advancement without stylet guidance; implanted leads or catheters (active or abandoned) in the superior vena cava that cannot be removed prior to or at system implant; a body size not sufficient to accept the pump; or skin or soft tissue that would heal poorly or increase susceptibility to infections. Patients who are unable to tolerate a sudden cessation of treprostinil therapy also would not be able to receive the implantable device.

Read the full approval on the FDA’s website.

llaubach@frontlinemedcom.com

JACKSONVILLE, FLA. – The American Medical Association and National Institutes of Health recommend that patient instructions should be written at a sixth-grade level, and the Centers for Disease Control and Prevention recommend an eighth-grade level so patients and caregivers can easily understand them, but a study of education materials that patients get for surgery finds that they typically overshoot that mark – in some cases considerably.

A study of patient education materials distributed at the University of Alabama at Birmingham has revealed that the materials patients received in 12 different surgical specialties were, on average, written above an eighth-grade level, second-year medical student Callie Perkins reported at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

Ingram Publishing/Thinkstock.com

SOURCE: Perkins, C et al. Abstract 67.08

JACKSONVILLE, FLA. – The American Medical Association and National Institutes of Health recommend that patient instructions should be written at a sixth-grade level, and the Centers for Disease Control and Prevention recommend an eighth-grade level so patients and caregivers can easily understand them, but a study of education materials that patients get for surgery finds that they typically overshoot that mark – in some cases considerably.

A study of patient education materials distributed at the University of Alabama at Birmingham has revealed that the materials patients received in 12 different surgical specialties were, on average, written above an eighth-grade level, second-year medical student Callie Perkins reported at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

Ingram Publishing/Thinkstock.com

SOURCE: Perkins, C et al. Abstract 67.08

JACKSONVILLE, FLA. – The American Medical Association and National Institutes of Health recommend that patient instructions should be written at a sixth-grade level, and the Centers for Disease Control and Prevention recommend an eighth-grade level so patients and caregivers can easily understand them, but a study of education materials that patients get for surgery finds that they typically overshoot that mark – in some cases considerably.

A study of patient education materials distributed at the University of Alabama at Birmingham has revealed that the materials patients received in 12 different surgical specialties were, on average, written above an eighth-grade level, second-year medical student Callie Perkins reported at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

Ingram Publishing/Thinkstock.com

SOURCE: Perkins, C et al. Abstract 67.08

Antihistamines are still widely prescribed for atopic dermatitis across specialties, despite lack of evidence of their effectiveness, said Alice He, MD, at the Center for Dermatology Research, Wake Forest University, Winston-Salem, N.C., and her associates.

Results of double-blind, randomized trials have found that oral antihistamines do not effectively treat itch associated with atopic dermatitis (AD), and American Academy of Dermatology guidelines state that intermittent short-term use of sedating antihistamines may help insomnia secondary to itch, but should not be substituted for topical treatments in atopic dermatitis management (J Am Acad Dermatol. 2014;71[2]:327-49), the investigators said. Nonetheless, physicians continue to prescribe antihistamines to AD patients.

aniaostudio/Thinkstock.com

SOURCE: He A et al. J Amer Acad of Dermatol. 2008. doi: 10.1016/j.jaad.2017.12.077.

Antihistamines are still widely prescribed for atopic dermatitis across specialties, despite lack of evidence of their effectiveness, said Alice He, MD, at the Center for Dermatology Research, Wake Forest University, Winston-Salem, N.C., and her associates.

Results of double-blind, randomized trials have found that oral antihistamines do not effectively treat itch associated with atopic dermatitis (AD), and American Academy of Dermatology guidelines state that intermittent short-term use of sedating antihistamines may help insomnia secondary to itch, but should not be substituted for topical treatments in atopic dermatitis management (J Am Acad Dermatol. 2014;71[2]:327-49), the investigators said. Nonetheless, physicians continue to prescribe antihistamines to AD patients.

aniaostudio/Thinkstock.com

SOURCE: He A et al. J Amer Acad of Dermatol. 2008. doi: 10.1016/j.jaad.2017.12.077.

Antihistamines are still widely prescribed for atopic dermatitis across specialties, despite lack of evidence of their effectiveness, said Alice He, MD, at the Center for Dermatology Research, Wake Forest University, Winston-Salem, N.C., and her associates.

Results of double-blind, randomized trials have found that oral antihistamines do not effectively treat itch associated with atopic dermatitis (AD), and American Academy of Dermatology guidelines state that intermittent short-term use of sedating antihistamines may help insomnia secondary to itch, but should not be substituted for topical treatments in atopic dermatitis management (J Am Acad Dermatol. 2014;71[2]:327-49), the investigators said. Nonetheless, physicians continue to prescribe antihistamines to AD patients.

aniaostudio/Thinkstock.com

SOURCE: He A et al. J Amer Acad of Dermatol. 2008. doi: 10.1016/j.jaad.2017.12.077.

Physician specialists are calling on Congress to isolate Medicare Part B drug reimbursements from payment adjustments under the Merit-Based Incentive Payment System (MIPS).

A coalition of medical societies, large group practices, and patient advocacy groups has asked for an “intervention this year with a technical correction that ensures the [MIPS] score adjustment is not applied to Part B drug payments,” according to Jan. 18 letter sent to the leaders of the Senate Finance Committee, House Energy and Commerce Committee, and the House Ways and Means Committee. “Since the 2018 MIPS year has begun, it is imperative that Congress acts quickly to ensure that patient access to critical treatments is not negatively impacted.”

Pradit_Ph/thinkstock

gtwachtman@frontlinemedcom.com

Physician specialists are calling on Congress to isolate Medicare Part B drug reimbursements from payment adjustments under the Merit-Based Incentive Payment System (MIPS).

A coalition of medical societies, large group practices, and patient advocacy groups has asked for an “intervention this year with a technical correction that ensures the [MIPS] score adjustment is not applied to Part B drug payments,” according to Jan. 18 letter sent to the leaders of the Senate Finance Committee, House Energy and Commerce Committee, and the House Ways and Means Committee. “Since the 2018 MIPS year has begun, it is imperative that Congress acts quickly to ensure that patient access to critical treatments is not negatively impacted.”

Pradit_Ph/thinkstock

gtwachtman@frontlinemedcom.com

Physician specialists are calling on Congress to isolate Medicare Part B drug reimbursements from payment adjustments under the Merit-Based Incentive Payment System (MIPS).

A coalition of medical societies, large group practices, and patient advocacy groups has asked for an “intervention this year with a technical correction that ensures the [MIPS] score adjustment is not applied to Part B drug payments,” according to Jan. 18 letter sent to the leaders of the Senate Finance Committee, House Energy and Commerce Committee, and the House Ways and Means Committee. “Since the 2018 MIPS year has begun, it is imperative that Congress acts quickly to ensure that patient access to critical treatments is not negatively impacted.”

Pradit_Ph/thinkstock

gtwachtman@frontlinemedcom.com

SAN DIEGO—Cross-species genetic screens are helping researchers find molecules that modulate the proteins that cause adult neurodegenerative disease, according to a lecture delivered at the 142nd Annual Meeting of the American Neurological Association. Such screening thus reveals potential therapeutic targets and augments scientific understanding of the biology of these proteins.

The research raises the possibility that clinicians will be able to delay or prevent neurodegenerative disease in the future through the early administration of molecules that target these proteins. “We need to identify those at risk and begin the therapy … before the symptoms develop, just like you would treat somebody with statins if they have high cholesterol before they have a heart attack,” said Huda Y. Zoghbi, MD, an investigator with the Howard Hughes Medical Institute; Professor of Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology at Baylor College of Medicine; and Director of the Jan and Dan Duncan Neurological Research Institute in Houston.

Research Into a Rare Disorder

Studying the rare disorder spinocerebellar ataxia type 1 (SCA1) has yielded information that could be applicable to more common neurodegenerative diseases, said Dr. Zoghbi. SCA1 is characterized by a loss of Purkinje cells and brainstem neurons that impairs balance and coordination and increases the risk of premature death. In 1993, Dr. Zoghbi; Harry Orr, PhD, Professor and Tulloch Chair in Genetics at the University of Minnesota in Minneapolis; and colleagues discovered that a CAG repeat expansion in ATXN1 causes SCA1 by producing an abnormally long version of the ataxin-1 protein. They also found that neurodegeneration results if levels of normal ataxin-1 are increased by 20% or 30%. The brain thus is highly sensitive to ataxin-1 levels, said Dr. Zoghbi.

Borrowing a technique from cancer research, the investigators performed genetic screening using fruit fly and human cells to find targets that would reduce ataxin-1 levels when inhibited. They found approximately 30 relevant genes in each organism, and about 12 were common to both organisms. All of the shared genes operate in the mitogen-activated protein (MAP) kinase pathway, and inhibiting each gene lowered ataxin-1 in cells and flies.

Inhibiting Enzymes

The researchers also observed that the enzymes MSK1 and MSK2 intervene in the pathway and promote ataxin-1 accumulation. Inhibiting MSK1 produced clinical improvement in SCA1 mouse models, and inhibiting MSK1 and MSK2 together produced still more improvement. A small molecule that inhibited MSK1 therefore could help patients with SCA1, said Dr. Zoghbi.

Inhibiting enzymes such as MSK1 and MSK2 for years at a time could raise safety concerns, however. The investigators thus decided to look for other modulators of ataxin-1, on the theory that targeting modulators that function in different pathways could reduce the amount of inhibition required and decrease the risk of adverse events.

Further screening revealed that PKA1 appeared to modulate ataxin-1 by a mechanism similar to that of MSK1. An animal study indicated that inhibiting MSK1 and inhibiting PKA1 produced equivalent reductions on ataxin-1, but that inhibiting both in tandem yielded a greater reduction. The investigators then found that the PAK1 enzyme promoted ataxin-1 accumulation through a pathway different from that of MSK1 and PKA1. Inhibiting PAK1 reduced ataxin-1 levels, and inhibiting PAK1 and MSK1 simultaneously had a still greater effect.

Targeting Tauopathies

Their research into kinases and enzymes prompted Dr. Zoghbi and colleagues to consider whole genome screening as a method of targeting proteins that cause neurodegenerative diseases other than SCA1. Overexpression of tau, for example, causes neurodegeneration, regardless of whether the overexpression results from a mutation in tau-encoding genes. “Tau is a true culprit in dementias, and we thought that if we could find something to lower it, we could help patients with these disorders,” said Dr. Zoghbi.

Another genetic screen suggested that the enzyme Nuak1 stabilizes tau by phosphorylating it at Ser356. The investigators observed that inhibiting Nuak1 reduced tau levels and suppressed neurodegeneration in human cells and in fruit flies. Tau accumulation decreases fruit flies’ climbing ability, and inhibiting Nuak1 improved this ability in flies with tau accumulation.

In a subsequent mouse study, Dr. Zoghbi and colleagues found that inhibiting Nuak1 significantly reduced levels of phosphorylated tau and provided smaller reductions in total tau and endogenous tau. They also observed that mice with tauopathy took longer than wild-type mice to complete a water maze task. Inhibiting Nuak1 in mice with tauopathy improved their performance on this task. Nuak1 inhibition also restored synaptic plasticity in these mice to a level similar to that of wild-type mice. Finally, Nuak1 inhibition reduced tau tangle pathology and increased survival. Dr. Zoghbi and colleagues are now searching for small-molecule Nuak1 inhibitors that could provide protection against tauopathy.

In Search of More Targets

The investigators next looked for genes that influence tau. Successive levels of genetic screening identified 59 genes that “robustly lower tau levels,” said Dr. Zoghbi. She and her colleagues prioritized 12 of the genes for investigation.

They used adenoassociated viral vectors to deliver therapies that can knock out mouse genes for as long as a year. With this technique, the investigators confirmed that all of the initial 12 genes decreased tau levels. In principle, this strategy could enable researchers to scan the whole genome for genes that modulate tau, said Dr. Zoghbi.

—Erik Greb

Suggested Reading

Lasagna-Reeves CA, de Haro M, Hao S, et al. Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron. 2016; 92(2):407-418.

Park J, Al-Ramahi I, Tan Q, et al. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature. 2013;498(7454):325-331.

Rousseaux MW, de Haro M, Lasagna-Reeves CA, et al. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. Elife. 2016 Oct 25;5. pii: e19809

SAN DIEGO—Cross-species genetic screens are helping researchers find molecules that modulate the proteins that cause adult neurodegenerative disease, according to a lecture delivered at the 142nd Annual Meeting of the American Neurological Association. Such screening thus reveals potential therapeutic targets and augments scientific understanding of the biology of these proteins.

The research raises the possibility that clinicians will be able to delay or prevent neurodegenerative disease in the future through the early administration of molecules that target these proteins. “We need to identify those at risk and begin the therapy … before the symptoms develop, just like you would treat somebody with statins if they have high cholesterol before they have a heart attack,” said Huda Y. Zoghbi, MD, an investigator with the Howard Hughes Medical Institute; Professor of Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology at Baylor College of Medicine; and Director of the Jan and Dan Duncan Neurological Research Institute in Houston.

Research Into a Rare Disorder

Studying the rare disorder spinocerebellar ataxia type 1 (SCA1) has yielded information that could be applicable to more common neurodegenerative diseases, said Dr. Zoghbi. SCA1 is characterized by a loss of Purkinje cells and brainstem neurons that impairs balance and coordination and increases the risk of premature death. In 1993, Dr. Zoghbi; Harry Orr, PhD, Professor and Tulloch Chair in Genetics at the University of Minnesota in Minneapolis; and colleagues discovered that a CAG repeat expansion in ATXN1 causes SCA1 by producing an abnormally long version of the ataxin-1 protein. They also found that neurodegeneration results if levels of normal ataxin-1 are increased by 20% or 30%. The brain thus is highly sensitive to ataxin-1 levels, said Dr. Zoghbi.

Borrowing a technique from cancer research, the investigators performed genetic screening using fruit fly and human cells to find targets that would reduce ataxin-1 levels when inhibited. They found approximately 30 relevant genes in each organism, and about 12 were common to both organisms. All of the shared genes operate in the mitogen-activated protein (MAP) kinase pathway, and inhibiting each gene lowered ataxin-1 in cells and flies.

Inhibiting Enzymes

The researchers also observed that the enzymes MSK1 and MSK2 intervene in the pathway and promote ataxin-1 accumulation. Inhibiting MSK1 produced clinical improvement in SCA1 mouse models, and inhibiting MSK1 and MSK2 together produced still more improvement. A small molecule that inhibited MSK1 therefore could help patients with SCA1, said Dr. Zoghbi.

Inhibiting enzymes such as MSK1 and MSK2 for years at a time could raise safety concerns, however. The investigators thus decided to look for other modulators of ataxin-1, on the theory that targeting modulators that function in different pathways could reduce the amount of inhibition required and decrease the risk of adverse events.

Further screening revealed that PKA1 appeared to modulate ataxin-1 by a mechanism similar to that of MSK1. An animal study indicated that inhibiting MSK1 and inhibiting PKA1 produced equivalent reductions on ataxin-1, but that inhibiting both in tandem yielded a greater reduction. The investigators then found that the PAK1 enzyme promoted ataxin-1 accumulation through a pathway different from that of MSK1 and PKA1. Inhibiting PAK1 reduced ataxin-1 levels, and inhibiting PAK1 and MSK1 simultaneously had a still greater effect.

Targeting Tauopathies

Their research into kinases and enzymes prompted Dr. Zoghbi and colleagues to consider whole genome screening as a method of targeting proteins that cause neurodegenerative diseases other than SCA1. Overexpression of tau, for example, causes neurodegeneration, regardless of whether the overexpression results from a mutation in tau-encoding genes. “Tau is a true culprit in dementias, and we thought that if we could find something to lower it, we could help patients with these disorders,” said Dr. Zoghbi.

Another genetic screen suggested that the enzyme Nuak1 stabilizes tau by phosphorylating it at Ser356. The investigators observed that inhibiting Nuak1 reduced tau levels and suppressed neurodegeneration in human cells and in fruit flies. Tau accumulation decreases fruit flies’ climbing ability, and inhibiting Nuak1 improved this ability in flies with tau accumulation.

In a subsequent mouse study, Dr. Zoghbi and colleagues found that inhibiting Nuak1 significantly reduced levels of phosphorylated tau and provided smaller reductions in total tau and endogenous tau. They also observed that mice with tauopathy took longer than wild-type mice to complete a water maze task. Inhibiting Nuak1 in mice with tauopathy improved their performance on this task. Nuak1 inhibition also restored synaptic plasticity in these mice to a level similar to that of wild-type mice. Finally, Nuak1 inhibition reduced tau tangle pathology and increased survival. Dr. Zoghbi and colleagues are now searching for small-molecule Nuak1 inhibitors that could provide protection against tauopathy.

In Search of More Targets

The investigators next looked for genes that influence tau. Successive levels of genetic screening identified 59 genes that “robustly lower tau levels,” said Dr. Zoghbi. She and her colleagues prioritized 12 of the genes for investigation.

They used adenoassociated viral vectors to deliver therapies that can knock out mouse genes for as long as a year. With this technique, the investigators confirmed that all of the initial 12 genes decreased tau levels. In principle, this strategy could enable researchers to scan the whole genome for genes that modulate tau, said Dr. Zoghbi.

—Erik Greb

Suggested Reading

Lasagna-Reeves CA, de Haro M, Hao S, et al. Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron. 2016; 92(2):407-418.

Park J, Al-Ramahi I, Tan Q, et al. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature. 2013;498(7454):325-331.

Rousseaux MW, de Haro M, Lasagna-Reeves CA, et al. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. Elife. 2016 Oct 25;5. pii: e19809

SAN DIEGO—Cross-species genetic screens are helping researchers find molecules that modulate the proteins that cause adult neurodegenerative disease, according to a lecture delivered at the 142nd Annual Meeting of the American Neurological Association. Such screening thus reveals potential therapeutic targets and augments scientific understanding of the biology of these proteins.

The research raises the possibility that clinicians will be able to delay or prevent neurodegenerative disease in the future through the early administration of molecules that target these proteins. “We need to identify those at risk and begin the therapy … before the symptoms develop, just like you would treat somebody with statins if they have high cholesterol before they have a heart attack,” said Huda Y. Zoghbi, MD, an investigator with the Howard Hughes Medical Institute; Professor of Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology at Baylor College of Medicine; and Director of the Jan and Dan Duncan Neurological Research Institute in Houston.

Research Into a Rare Disorder

Studying the rare disorder spinocerebellar ataxia type 1 (SCA1) has yielded information that could be applicable to more common neurodegenerative diseases, said Dr. Zoghbi. SCA1 is characterized by a loss of Purkinje cells and brainstem neurons that impairs balance and coordination and increases the risk of premature death. In 1993, Dr. Zoghbi; Harry Orr, PhD, Professor and Tulloch Chair in Genetics at the University of Minnesota in Minneapolis; and colleagues discovered that a CAG repeat expansion in ATXN1 causes SCA1 by producing an abnormally long version of the ataxin-1 protein. They also found that neurodegeneration results if levels of normal ataxin-1 are increased by 20% or 30%. The brain thus is highly sensitive to ataxin-1 levels, said Dr. Zoghbi.

Borrowing a technique from cancer research, the investigators performed genetic screening using fruit fly and human cells to find targets that would reduce ataxin-1 levels when inhibited. They found approximately 30 relevant genes in each organism, and about 12 were common to both organisms. All of the shared genes operate in the mitogen-activated protein (MAP) kinase pathway, and inhibiting each gene lowered ataxin-1 in cells and flies.

Inhibiting Enzymes

The researchers also observed that the enzymes MSK1 and MSK2 intervene in the pathway and promote ataxin-1 accumulation. Inhibiting MSK1 produced clinical improvement in SCA1 mouse models, and inhibiting MSK1 and MSK2 together produced still more improvement. A small molecule that inhibited MSK1 therefore could help patients with SCA1, said Dr. Zoghbi.

Inhibiting enzymes such as MSK1 and MSK2 for years at a time could raise safety concerns, however. The investigators thus decided to look for other modulators of ataxin-1, on the theory that targeting modulators that function in different pathways could reduce the amount of inhibition required and decrease the risk of adverse events.

Further screening revealed that PKA1 appeared to modulate ataxin-1 by a mechanism similar to that of MSK1. An animal study indicated that inhibiting MSK1 and inhibiting PKA1 produced equivalent reductions on ataxin-1, but that inhibiting both in tandem yielded a greater reduction. The investigators then found that the PAK1 enzyme promoted ataxin-1 accumulation through a pathway different from that of MSK1 and PKA1. Inhibiting PAK1 reduced ataxin-1 levels, and inhibiting PAK1 and MSK1 simultaneously had a still greater effect.

Targeting Tauopathies

Their research into kinases and enzymes prompted Dr. Zoghbi and colleagues to consider whole genome screening as a method of targeting proteins that cause neurodegenerative diseases other than SCA1. Overexpression of tau, for example, causes neurodegeneration, regardless of whether the overexpression results from a mutation in tau-encoding genes. “Tau is a true culprit in dementias, and we thought that if we could find something to lower it, we could help patients with these disorders,” said Dr. Zoghbi.

Another genetic screen suggested that the enzyme Nuak1 stabilizes tau by phosphorylating it at Ser356. The investigators observed that inhibiting Nuak1 reduced tau levels and suppressed neurodegeneration in human cells and in fruit flies. Tau accumulation decreases fruit flies’ climbing ability, and inhibiting Nuak1 improved this ability in flies with tau accumulation.

In a subsequent mouse study, Dr. Zoghbi and colleagues found that inhibiting Nuak1 significantly reduced levels of phosphorylated tau and provided smaller reductions in total tau and endogenous tau. They also observed that mice with tauopathy took longer than wild-type mice to complete a water maze task. Inhibiting Nuak1 in mice with tauopathy improved their performance on this task. Nuak1 inhibition also restored synaptic plasticity in these mice to a level similar to that of wild-type mice. Finally, Nuak1 inhibition reduced tau tangle pathology and increased survival. Dr. Zoghbi and colleagues are now searching for small-molecule Nuak1 inhibitors that could provide protection against tauopathy.

In Search of More Targets

The investigators next looked for genes that influence tau. Successive levels of genetic screening identified 59 genes that “robustly lower tau levels,” said Dr. Zoghbi. She and her colleagues prioritized 12 of the genes for investigation.

They used adenoassociated viral vectors to deliver therapies that can knock out mouse genes for as long as a year. With this technique, the investigators confirmed that all of the initial 12 genes decreased tau levels. In principle, this strategy could enable researchers to scan the whole genome for genes that modulate tau, said Dr. Zoghbi.

—Erik Greb

Suggested Reading

Lasagna-Reeves CA, de Haro M, Hao S, et al. Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron. 2016; 92(2):407-418.

Park J, Al-Ramahi I, Tan Q, et al. RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature. 2013;498(7454):325-331.

Rousseaux MW, de Haro M, Lasagna-Reeves CA, et al. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. Elife. 2016 Oct 25;5. pii: e19809

San Diego – In a phase 2 trial, the investigational agent ibudilast slowed the rate of brain atrophy by nearly 50% in patients with progressive multiple sclerosis.

“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”

In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.

For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).

“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”

The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.

San Diego – In a phase 2 trial, the investigational agent ibudilast slowed the rate of brain atrophy by nearly 50% in patients with progressive multiple sclerosis.

“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”

In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.

For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).

“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”

The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.

San Diego – In a phase 2 trial, the investigational agent ibudilast slowed the rate of brain atrophy by nearly 50% in patients with progressive multiple sclerosis.

“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”

In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.

For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).

“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”

The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.