Literature Review

Many patients with focal epilepsy may have widespread progressive cortical thinning to an extent greater than that associated with normal aging, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.

To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
 

Comparing brain changes in patients and controls

Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.

Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
 

The rate of atrophy was doubled in patients

Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.

Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.

Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.

Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
 

A surrogate marker for neurodegeneration?

“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.

One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.

Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.

The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.

egreb@mdedge.com

SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.

Many patients with focal epilepsy may have widespread progressive cortical thinning to an extent greater than that associated with normal aging, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.

To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
 

Comparing brain changes in patients and controls

Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.

Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
 

The rate of atrophy was doubled in patients

Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.

Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.

Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.

Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
 

A surrogate marker for neurodegeneration?

“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.

One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.

Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.

The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.

egreb@mdedge.com

SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.

Many patients with focal epilepsy may have widespread progressive cortical thinning to an extent greater than that associated with normal aging, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.

To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
 

Comparing brain changes in patients and controls

Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.

Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
 

The rate of atrophy was doubled in patients

Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.

Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.

Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.

Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
 

A surrogate marker for neurodegeneration?

“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.

One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.

Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.

The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.

egreb@mdedge.com

SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.

Decades after undergoing surgery and radiotherapy, survivors of a pediatric CNS tumor may have worse neuropsychologic and socioeconomic outcomes, compared with their unaffected siblings. Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.

“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”

Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.

Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.

After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.

Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.

Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.

The National Cancer Institute supported the study. The authors had no disclosures.

egreb@mdedge.com

SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.

Decades after undergoing surgery and radiotherapy, survivors of a pediatric CNS tumor may have worse neuropsychologic and socioeconomic outcomes, compared with their unaffected siblings. Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.

“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”

Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.

Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.

After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.

Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.

Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.

The National Cancer Institute supported the study. The authors had no disclosures.

egreb@mdedge.com

SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.

Decades after undergoing surgery and radiotherapy, survivors of a pediatric CNS tumor may have worse neuropsychologic and socioeconomic outcomes, compared with their unaffected siblings. Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.

“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”

Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.

Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.

After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.

Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.

Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.

The National Cancer Institute supported the study. The authors had no disclosures.

egreb@mdedge.com

SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.

Measuring plasma amyloid-beta 42 and amyloid-beta 40 using a fully automated immunoassay predicts amyloid-beta status in all stages of Alzheimer’s disease, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.

In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
 

Testing the immunoassay in two cohorts

Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.

Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
 

Automated immunoassay had high predictive accuracy

The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.

Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.

In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.

The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
 

Validation cohort was small

Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.

“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”

Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.

This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.

egreb@mdedge.com

SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.

Measuring plasma amyloid-beta 42 and amyloid-beta 40 using a fully automated immunoassay predicts amyloid-beta status in all stages of Alzheimer’s disease, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.

In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
 

Testing the immunoassay in two cohorts

Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.

Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
 

Automated immunoassay had high predictive accuracy

The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.

Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.

In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.

The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
 

Validation cohort was small

Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.

“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”

Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.

This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.

egreb@mdedge.com

SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.

Measuring plasma amyloid-beta 42 and amyloid-beta 40 using a fully automated immunoassay predicts amyloid-beta status in all stages of Alzheimer’s disease, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.

In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
 

Testing the immunoassay in two cohorts

Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.

Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
 

Automated immunoassay had high predictive accuracy

The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.

Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.

In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.

The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
 

Validation cohort was small

Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.

“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”

Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.

This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.

egreb@mdedge.com

SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.

Patients with mild or moderate Alzheimer’s disease who took nilvadipine experienced increases in cerebral blood flow in the hippocampus, according to a new study.

copyright Radboud University Medical Center

Cerebral blood flow in other regions of the brain did not significantly change in patients who took the antihypertensive drug nilvadipine, according to a report on the trial published in Hypertension. Reduced cerebral blood flow is an early marker of Alzheimer’s disease, and the SPRINT MIND study suggests that intensive blood pressure control may reduce the risk of cognitive impairment.

“These findings [of the new study] not only indicate preserved cerebral autoregulation in Alzheimer’s disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment,” said Jurgen A.H.R. Claassen, MD, PhD of Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. “An important question is whether this observed increase in [cerebral blood flow] translates to clinical benefits. Unfortunately, sample sizes were too small and follow-up time too short to reliably study the effects ... on structural brain measures and cognitive measures.”

Nilvadipine is a dihydropyridine calcium antagonist used to treat hypertension. In the NILVAD trial, investigators assessed the effects of nilvadipine versus placebo in approximately 500 patients with Alzheimer’s disease. The 18-month trial found no beneficial effects of nilvadipine on cognitive function, but subgroup analyses suggested a potential benefit among patients in the early stages of the disease (PLoS Med. 2018 Sep 24;15[9]:e1002660.).

The cerebral blood flow analysis was a preplanned substudy of NILVAD designed to assess how 6 months of treatment with the drug affects cerebral blood flow as measured using MRI arterial spin labeling. The researchers looked at cerebral blood flow in whole-brain gray matter and in specific regions such as the hippocampus.


The substudy analysis included 22 patients who received nilvadipine and 22 who received placebo during the randomized, double-blind study. Participants had a mean age of 72.8 years and a mean Mini-Mental State Examination score of 20.4.

At 6 months, nilvadipine lowered systolic BP by 11.5 mm Hg, and whole-brain gray matter cerebral blood flow remained stable. Blood flow to the hippocampus increased by approximately 20% among patients treated with nilvadipine – by 24.4 mL/100 g per minute to the left hippocampus and by 20.1 mL/100 g per minute to the right hippocampus.

The increased hippocampal cerebral blood flow could be related to nilvadipine’s antihypertensive effects or its effects on amyloid-beta, the authors noted.

“These findings indicate that the known decrease in [cerebral blood flow] in patients with [Alzheimer’s disease] can in some regions be reversed,” they wrote.

“Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer’s disease,” Dr. Claassen said in a statement. “In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer’s disease, especially in earlier states of disease.”

The researchers wrote they lacked biomarkers to confirm Alzheimer’s disease pathology. Most of the study participants were white Europeans, which “limits extrapolation [of the findings] to other populations,” they added.

The Alzheimer’s Drug Discovery Foundation and the Dutch Alzheimer Society funded the NILVAD cerebral blood flow substudy. NILVAD was funded by the European Commission Framework 7 Program Health Theme. Dr. Claassen had no disclosures; one coauthor disclosed a pending patent for nilvadipine.

jremaly@mdedge.com

SOURCE: Claassen JAHR et al. Hypertension. 2019 Jun 17. doi: 10.1161/HYPERTENSIONAHA.119.12892.

Patients with mild or moderate Alzheimer’s disease who took nilvadipine experienced increases in cerebral blood flow in the hippocampus, according to a new study.

copyright Radboud University Medical Center

Cerebral blood flow in other regions of the brain did not significantly change in patients who took the antihypertensive drug nilvadipine, according to a report on the trial published in Hypertension. Reduced cerebral blood flow is an early marker of Alzheimer’s disease, and the SPRINT MIND study suggests that intensive blood pressure control may reduce the risk of cognitive impairment.

“These findings [of the new study] not only indicate preserved cerebral autoregulation in Alzheimer’s disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment,” said Jurgen A.H.R. Claassen, MD, PhD of Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. “An important question is whether this observed increase in [cerebral blood flow] translates to clinical benefits. Unfortunately, sample sizes were too small and follow-up time too short to reliably study the effects ... on structural brain measures and cognitive measures.”

Nilvadipine is a dihydropyridine calcium antagonist used to treat hypertension. In the NILVAD trial, investigators assessed the effects of nilvadipine versus placebo in approximately 500 patients with Alzheimer’s disease. The 18-month trial found no beneficial effects of nilvadipine on cognitive function, but subgroup analyses suggested a potential benefit among patients in the early stages of the disease (PLoS Med. 2018 Sep 24;15[9]:e1002660.).

The cerebral blood flow analysis was a preplanned substudy of NILVAD designed to assess how 6 months of treatment with the drug affects cerebral blood flow as measured using MRI arterial spin labeling. The researchers looked at cerebral blood flow in whole-brain gray matter and in specific regions such as the hippocampus.


The substudy analysis included 22 patients who received nilvadipine and 22 who received placebo during the randomized, double-blind study. Participants had a mean age of 72.8 years and a mean Mini-Mental State Examination score of 20.4.

At 6 months, nilvadipine lowered systolic BP by 11.5 mm Hg, and whole-brain gray matter cerebral blood flow remained stable. Blood flow to the hippocampus increased by approximately 20% among patients treated with nilvadipine – by 24.4 mL/100 g per minute to the left hippocampus and by 20.1 mL/100 g per minute to the right hippocampus.

The increased hippocampal cerebral blood flow could be related to nilvadipine’s antihypertensive effects or its effects on amyloid-beta, the authors noted.

“These findings indicate that the known decrease in [cerebral blood flow] in patients with [Alzheimer’s disease] can in some regions be reversed,” they wrote.

“Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer’s disease,” Dr. Claassen said in a statement. “In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer’s disease, especially in earlier states of disease.”

The researchers wrote they lacked biomarkers to confirm Alzheimer’s disease pathology. Most of the study participants were white Europeans, which “limits extrapolation [of the findings] to other populations,” they added.

The Alzheimer’s Drug Discovery Foundation and the Dutch Alzheimer Society funded the NILVAD cerebral blood flow substudy. NILVAD was funded by the European Commission Framework 7 Program Health Theme. Dr. Claassen had no disclosures; one coauthor disclosed a pending patent for nilvadipine.

jremaly@mdedge.com

SOURCE: Claassen JAHR et al. Hypertension. 2019 Jun 17. doi: 10.1161/HYPERTENSIONAHA.119.12892.

Patients with mild or moderate Alzheimer’s disease who took nilvadipine experienced increases in cerebral blood flow in the hippocampus, according to a new study.

copyright Radboud University Medical Center

Cerebral blood flow in other regions of the brain did not significantly change in patients who took the antihypertensive drug nilvadipine, according to a report on the trial published in Hypertension. Reduced cerebral blood flow is an early marker of Alzheimer’s disease, and the SPRINT MIND study suggests that intensive blood pressure control may reduce the risk of cognitive impairment.

“These findings [of the new study] not only indicate preserved cerebral autoregulation in Alzheimer’s disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment,” said Jurgen A.H.R. Claassen, MD, PhD of Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. “An important question is whether this observed increase in [cerebral blood flow] translates to clinical benefits. Unfortunately, sample sizes were too small and follow-up time too short to reliably study the effects ... on structural brain measures and cognitive measures.”

Nilvadipine is a dihydropyridine calcium antagonist used to treat hypertension. In the NILVAD trial, investigators assessed the effects of nilvadipine versus placebo in approximately 500 patients with Alzheimer’s disease. The 18-month trial found no beneficial effects of nilvadipine on cognitive function, but subgroup analyses suggested a potential benefit among patients in the early stages of the disease (PLoS Med. 2018 Sep 24;15[9]:e1002660.).

The cerebral blood flow analysis was a preplanned substudy of NILVAD designed to assess how 6 months of treatment with the drug affects cerebral blood flow as measured using MRI arterial spin labeling. The researchers looked at cerebral blood flow in whole-brain gray matter and in specific regions such as the hippocampus.


The substudy analysis included 22 patients who received nilvadipine and 22 who received placebo during the randomized, double-blind study. Participants had a mean age of 72.8 years and a mean Mini-Mental State Examination score of 20.4.

At 6 months, nilvadipine lowered systolic BP by 11.5 mm Hg, and whole-brain gray matter cerebral blood flow remained stable. Blood flow to the hippocampus increased by approximately 20% among patients treated with nilvadipine – by 24.4 mL/100 g per minute to the left hippocampus and by 20.1 mL/100 g per minute to the right hippocampus.

The increased hippocampal cerebral blood flow could be related to nilvadipine’s antihypertensive effects or its effects on amyloid-beta, the authors noted.

“These findings indicate that the known decrease in [cerebral blood flow] in patients with [Alzheimer’s disease] can in some regions be reversed,” they wrote.

“Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer’s disease,” Dr. Claassen said in a statement. “In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer’s disease, especially in earlier states of disease.”

The researchers wrote they lacked biomarkers to confirm Alzheimer’s disease pathology. Most of the study participants were white Europeans, which “limits extrapolation [of the findings] to other populations,” they added.

The Alzheimer’s Drug Discovery Foundation and the Dutch Alzheimer Society funded the NILVAD cerebral blood flow substudy. NILVAD was funded by the European Commission Framework 7 Program Health Theme. Dr. Claassen had no disclosures; one coauthor disclosed a pending patent for nilvadipine.

jremaly@mdedge.com

SOURCE: Claassen JAHR et al. Hypertension. 2019 Jun 17. doi: 10.1161/HYPERTENSIONAHA.119.12892.

CSF levels of neurofilament light (NfL) are elevated in most neurologic conditions, according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.

Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
 

A meta-analysis of CSF samples

Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.

The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
 

NfL increased with age

Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.

CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).

In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
 

Many factors influence NfL level in CSF

The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.

Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.

Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.

One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.

The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.

egreb@mdedge.com

SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.

CSF levels of neurofilament light (NfL) are elevated in most neurologic conditions, according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.

Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
 

A meta-analysis of CSF samples

Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.

The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
 

NfL increased with age

Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.

CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).

In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
 

Many factors influence NfL level in CSF

The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.

Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.

Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.

One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.

The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.

egreb@mdedge.com

SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.

CSF levels of neurofilament light (NfL) are elevated in most neurologic conditions, according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.

Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
 

A meta-analysis of CSF samples

Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.

The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
 

NfL increased with age

Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.

CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).

In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
 

Many factors influence NfL level in CSF

The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.

Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.

Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.

One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.

The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.

egreb@mdedge.com

SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.

In a trial of a novel gene-silencing therapy, patients with early Huntington’s disease had dose-dependent reductions of the mutant protein characteristic of their disease and no serious adverse events, according to a study published in the New England Journal of Medicine.

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTT_Rx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTT_Rx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.

For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTT_Rx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.

The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.

Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.

The median peak plasma concentrations of HTT_Rx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.

Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.

An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.

The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
 

SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.

In a trial of a novel gene-silencing therapy, patients with early Huntington’s disease had dose-dependent reductions of the mutant protein characteristic of their disease and no serious adverse events, according to a study published in the New England Journal of Medicine.

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTT_Rx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTT_Rx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.

For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTT_Rx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.

The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.

Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.

The median peak plasma concentrations of HTT_Rx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.

Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.

An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.

The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
 

SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.

In a trial of a novel gene-silencing therapy, patients with early Huntington’s disease had dose-dependent reductions of the mutant protein characteristic of their disease and no serious adverse events, according to a study published in the New England Journal of Medicine.

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTT_Rx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTT_Rx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.

For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTT_Rx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.

The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.

Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.

The median peak plasma concentrations of HTT_Rx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.

Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.

An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.

The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
 

SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.

Seizures induced by cortical stimulation are as effective as spontaneous seizures in identifying the epileptogenic zone, according to a study of patients with focal drug-resistant epilepsy.

“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.

To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.

Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.

The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.

The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.

Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.

SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.

Seizures induced by cortical stimulation are as effective as spontaneous seizures in identifying the epileptogenic zone, according to a study of patients with focal drug-resistant epilepsy.

“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.

To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.

Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.

The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.

The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.

Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.

SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.

Seizures induced by cortical stimulation are as effective as spontaneous seizures in identifying the epileptogenic zone, according to a study of patients with focal drug-resistant epilepsy.

“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.

To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.

Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.

The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.

The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.

Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.

SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.

Among patients with hepatitis C virus, antiviral treatment is associated with a reduced risk of Parkinson’s disease, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.

In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.

Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.

The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.

The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.

To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.

Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.

The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.

“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.

Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.

The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.

egreb@mdedge.com

SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.

Among patients with hepatitis C virus, antiviral treatment is associated with a reduced risk of Parkinson’s disease, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.

In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.

Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.

The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.

The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.

To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.

Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.

The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.

“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.

Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.

The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.

egreb@mdedge.com

SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.

Among patients with hepatitis C virus, antiviral treatment is associated with a reduced risk of Parkinson’s disease, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.

In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.

Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.

The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.

The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.

To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.

Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.

The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.

“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.

Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.

The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.

egreb@mdedge.com

SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.

Levels of tau in cerebrospinal fluid (CSF) and plasma are significantly associated with survival time in patients with sporadic Creutzfeldt-Jakob disease, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.

The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
 

Evaluating fluid and nonfluid biomarkers

Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.

Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.

The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.

Plasma total tau was associated with survival

In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.

Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.

Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.

Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
 

Plasma tau could be a diagnostic biomarker

“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”

Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”

Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.

Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.

egreb@mdedge.com

SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.

Levels of tau in cerebrospinal fluid (CSF) and plasma are significantly associated with survival time in patients with sporadic Creutzfeldt-Jakob disease, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.

The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
 

Evaluating fluid and nonfluid biomarkers

Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.

Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.

The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.

Plasma total tau was associated with survival

In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.

Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.

Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.

Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
 

Plasma tau could be a diagnostic biomarker

“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”

Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”

Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.

Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.

egreb@mdedge.com

SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.

Levels of tau in cerebrospinal fluid (CSF) and plasma are significantly associated with survival time in patients with sporadic Creutzfeldt-Jakob disease, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.

The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
 

Evaluating fluid and nonfluid biomarkers

Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.

Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.

The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.

Plasma total tau was associated with survival

In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.

Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.

Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.

Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
 

Plasma tau could be a diagnostic biomarker

“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”

Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”

Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.

Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.

egreb@mdedge.com

SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.

A migraine preventive with improved efficacy and adverse event profile and a favorable mode of administration would be valuable to patients with migraine, according to the results of a study published in Headache. When offered hypothetical preventive migraine medicines with a wide array of attributes, patients leaned toward those with a reduction in migraine days and an avoidance of weight gain, according to an analysis of responses to a discrete-choice experiment survey.

“We found that respondents had a significant willingness to pay for medicines with higher efficacy and less-severe adverse events,” wrote Carol Mansfield, PhD, of RTI Health Solutions in North Carolina, and coauthors.

To evaluate patient preferences for theoretical migraine medicine, the researchers conducted a discrete-choice experiment via a web-based survey. Respondents met eligibility criteria if they were adults aged 18 years or older who self-reported 6 or more migraine days per month and completed the survey in full. They were asked to choose between options defined by six attributes: reduction in headache days per month, frequency of limitations with physical activities, cognition problems, weight gain, how the medicine is taken, and monthly out-of-pocket cost.

Of the 300 respondents included in the analysis, 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription migraine preventive in the last 6 months. Respondents reported, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of adverse events – defined as memory problems and 10% weight gain – but were willing to trade off efficacy for less-severe adverse events. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once-monthly injection or daily pill to twice-monthly injections. Respondents, on average, were willing to pay $116 per month for an improvement from 10% to 50% in reduced headache days (95% confidence interval [CI], $91-$141) and $43 for an improvement from 10% to 25% (95% CI, $34-$53). They were also willing to pay $84 per month to avoid a 10% weight gain (95% CI, $64-$103), $59 per month to avoid memory problems (95% CI, $42-$76), and $32 per month to avoid thinking problems (95% CI, $18-$46).

The coauthors acknowledged their study’s limitations, including all migraine diagnoses being self-reported and the study sample not necessarily being representative of patients with migraine overall. In addition, though the potential medicinal attributes used were prominent in clinical literature and focus groups, they could choose only a limited amount and so their analysis “did not address other attributes that may be important to patients.”

Given their findings, the researchers recommended that “clinicians should work with patients to select treatments that meet each patient’s needs.”

Amgen and Novartis funded the study. The authors reported numerous conflicts of interest, including receiving grants, consulting fees, and royalties from pharmaceutical companies and organizations. During the study, three of the authors were employed at RTI Health Solutions, a non-for-profit organization that conducts research with pharmaceutical companies such as the study’s sponsor.

SOURCE: Mansfield C et al. Headache. 2019 May;59(5):715-26. doi: 10.1111/head.13498.

A migraine preventive with improved efficacy and adverse event profile and a favorable mode of administration would be valuable to patients with migraine, according to the results of a study published in Headache. When offered hypothetical preventive migraine medicines with a wide array of attributes, patients leaned toward those with a reduction in migraine days and an avoidance of weight gain, according to an analysis of responses to a discrete-choice experiment survey.

“We found that respondents had a significant willingness to pay for medicines with higher efficacy and less-severe adverse events,” wrote Carol Mansfield, PhD, of RTI Health Solutions in North Carolina, and coauthors.

To evaluate patient preferences for theoretical migraine medicine, the researchers conducted a discrete-choice experiment via a web-based survey. Respondents met eligibility criteria if they were adults aged 18 years or older who self-reported 6 or more migraine days per month and completed the survey in full. They were asked to choose between options defined by six attributes: reduction in headache days per month, frequency of limitations with physical activities, cognition problems, weight gain, how the medicine is taken, and monthly out-of-pocket cost.

Of the 300 respondents included in the analysis, 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription migraine preventive in the last 6 months. Respondents reported, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of adverse events – defined as memory problems and 10% weight gain – but were willing to trade off efficacy for less-severe adverse events. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once-monthly injection or daily pill to twice-monthly injections. Respondents, on average, were willing to pay $116 per month for an improvement from 10% to 50% in reduced headache days (95% confidence interval [CI], $91-$141) and $43 for an improvement from 10% to 25% (95% CI, $34-$53). They were also willing to pay $84 per month to avoid a 10% weight gain (95% CI, $64-$103), $59 per month to avoid memory problems (95% CI, $42-$76), and $32 per month to avoid thinking problems (95% CI, $18-$46).

The coauthors acknowledged their study’s limitations, including all migraine diagnoses being self-reported and the study sample not necessarily being representative of patients with migraine overall. In addition, though the potential medicinal attributes used were prominent in clinical literature and focus groups, they could choose only a limited amount and so their analysis “did not address other attributes that may be important to patients.”

Given their findings, the researchers recommended that “clinicians should work with patients to select treatments that meet each patient’s needs.”

Amgen and Novartis funded the study. The authors reported numerous conflicts of interest, including receiving grants, consulting fees, and royalties from pharmaceutical companies and organizations. During the study, three of the authors were employed at RTI Health Solutions, a non-for-profit organization that conducts research with pharmaceutical companies such as the study’s sponsor.

SOURCE: Mansfield C et al. Headache. 2019 May;59(5):715-26. doi: 10.1111/head.13498.

A migraine preventive with improved efficacy and adverse event profile and a favorable mode of administration would be valuable to patients with migraine, according to the results of a study published in Headache. When offered hypothetical preventive migraine medicines with a wide array of attributes, patients leaned toward those with a reduction in migraine days and an avoidance of weight gain, according to an analysis of responses to a discrete-choice experiment survey.

“We found that respondents had a significant willingness to pay for medicines with higher efficacy and less-severe adverse events,” wrote Carol Mansfield, PhD, of RTI Health Solutions in North Carolina, and coauthors.

To evaluate patient preferences for theoretical migraine medicine, the researchers conducted a discrete-choice experiment via a web-based survey. Respondents met eligibility criteria if they were adults aged 18 years or older who self-reported 6 or more migraine days per month and completed the survey in full. They were asked to choose between options defined by six attributes: reduction in headache days per month, frequency of limitations with physical activities, cognition problems, weight gain, how the medicine is taken, and monthly out-of-pocket cost.

Of the 300 respondents included in the analysis, 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription migraine preventive in the last 6 months. Respondents reported, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of adverse events – defined as memory problems and 10% weight gain – but were willing to trade off efficacy for less-severe adverse events. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once-monthly injection or daily pill to twice-monthly injections. Respondents, on average, were willing to pay $116 per month for an improvement from 10% to 50% in reduced headache days (95% confidence interval [CI], $91-$141) and $43 for an improvement from 10% to 25% (95% CI, $34-$53). They were also willing to pay $84 per month to avoid a 10% weight gain (95% CI, $64-$103), $59 per month to avoid memory problems (95% CI, $42-$76), and $32 per month to avoid thinking problems (95% CI, $18-$46).

The coauthors acknowledged their study’s limitations, including all migraine diagnoses being self-reported and the study sample not necessarily being representative of patients with migraine overall. In addition, though the potential medicinal attributes used were prominent in clinical literature and focus groups, they could choose only a limited amount and so their analysis “did not address other attributes that may be important to patients.”

Given their findings, the researchers recommended that “clinicians should work with patients to select treatments that meet each patient’s needs.”

Amgen and Novartis funded the study. The authors reported numerous conflicts of interest, including receiving grants, consulting fees, and royalties from pharmaceutical companies and organizations. During the study, three of the authors were employed at RTI Health Solutions, a non-for-profit organization that conducts research with pharmaceutical companies such as the study’s sponsor.

SOURCE: Mansfield C et al. Headache. 2019 May;59(5):715-26. doi: 10.1111/head.13498.