Literature Review

Awareness of memory impairment typically begins to decline several years before dementia onset, according to research published online ahead of print August 26 in Neurology. The decline in awareness is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.

An unexpected finding of the study, according to the investigators, is that decline in awareness of memory impairment in dementia begins earlier in younger people, compared with older people. “The reason for this is uncertain, but it likely reflects a general awareness that memory loss is more normative at older ages rather than an age-related difference in awareness of one’s own memory loss,” said Robert S. Wilson, PhD, Professor of Neurological Sciences and Psychology at Rush University Medical Center in Chicago.

Participants Were Cognitively Healthy at Enrollment

It is unclear how common unawareness about one’s memory loss is, as well as when such unawareness develops. Some studies have shown an association between unawareness and dementia severity, but other research has found no such association. Longitudinal studies have not settled the question of whether unawareness changes over time. These studies mainly have focused on patients with prevalent dementia.

Dr. Wilson and colleagues analyzed data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study, three longitudinal clinical–pathologic studies of older persons without cognitive impairment at enrollment. All participants were age 50 or older at baseline. At the time of the analyses, 3,298 people had completed the baseline evaluation and agreed to brain autopsy at death. After the investigators excluded ineligible participants, 2,115 people were eligible for follow-up. Follow-up data were available for 2,092 people.

To track change in memory awareness in dementia, the researchers examined a subset of 239 persons who completed at least four annual evaluations and developed incident dementia before their last evaluation. This population had a mean baseline age of 79.2 and a mean follow-up of 10.8 years.

To investigate the pathologic basis of unawareness of memory impairment, the investigators analyzed a second subset of people who underwent neuropathologic examinations. A total of 662 participants underwent a brain autopsy and neuropathologic examination, and results were available for the first consecutive 627 persons. Dr. Wilson and colleagues analyzed the association of memory awareness with TDP-43 pathology in 585 of these patients. This population died at a mean age of 89.1 with a mean of 9.2 years of follow-up.

All participants had an annual clinical assessment that included a medical history, neurologic examination, and tests of memory and cognition. Participants were asked two questions about their memory that the researchers combined to obtain a subjective memory measure. In addition, participants underwent 19 cognitive tests annually, including tests of episodic, semantic, and working memory. After each evaluation, a clinician blinded to previously collected data diagnosed dementia.

Brain removal occurred at a mean of 8.2 hours after death. The neuropathologic examination included quantification of β-amyloid-immunoreactive plaques and tau-immunoreactive tangles. Researchers also assessed TDP-43 in six brain regions.

Memory Awareness Declined 
Before Dementia Onset

At baseline, subjective memory rating and episodic memory performance had normal distributions in the full study population. Patients did not tend to overestimate or underestimate their memory ability. Objective memory performance and subjective memory rating declined over time. Higher subjective memory at baseline predicted less episodic memory decline.

In the subset of 239 people, loss of memory awareness occurred in nearly all persons who developed dementia. Time of unawareness onset and rate of progression varied, however. Starting at a mean of 2.6 years before dementia onset, episodic memory awareness began to decline sharply at a mean rate of 0.260 units per year, which is nearly half of the baseline standard deviation. Memory awareness began to decline two to three years earlier in younger persons, compared with older persons. Neither sex nor education was related to change in memory awareness.

In the subset of 385 people with postmortem data, the measure of episodic memory awareness declined a mean of 0.035 units per year. In this group, TDP-43 pathology, tangle density, and gross cerebral infarcts were associated with more rapid decline in episodic memory awareness. When the researchers accounted for these associations, they found no change in episodic memory awareness. Dr. Wilson’s group also analyzed the entire study population who died with and without dementia and found that TDP-43 pathology, tangle density, and gross infarcts were each associated with declining awareness of episodic memory impairment in each subgroup, although the associations were stronger in the subgroup with dementia.

Findings Must Be Replicated

“These observations suggest that unawareness of amnestic dysfunction is part of the natural history of late-life dementia and is driven by accumulation of dementia-related pathologies,” said Dr. Wilson. Unawareness of memory impairment typically becomes apparent at the time of dementia diagnosis and may require a history of cognitive decline to be based on expert judgment or a knowledgeable informant, rather than self-report.

One of the study’s strengths, according to the investigators, was that participants were followed at regular intervals for several years and participated in follow-up and brain autopsy at high rates, which minimized the likelihood that selective attrition affected the results. The focus on persons who were cognitively healthy at baseline and later developed dementia enabled the researchers to link the development of memory awareness to the natural history of dementia. The primary limitation, according to the authors, is that participants were selected, which entails that the results need to be replicated in other cohorts. “The extent to which these findings apply to awareness of other dementia signs is also uncertain,” Dr. Wilson concluded.

—Erik Greb

Awareness of memory impairment typically begins to decline several years before dementia onset, according to research published online ahead of print August 26 in Neurology. The decline in awareness is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.

An unexpected finding of the study, according to the investigators, is that decline in awareness of memory impairment in dementia begins earlier in younger people, compared with older people. “The reason for this is uncertain, but it likely reflects a general awareness that memory loss is more normative at older ages rather than an age-related difference in awareness of one’s own memory loss,” said Robert S. Wilson, PhD, Professor of Neurological Sciences and Psychology at Rush University Medical Center in Chicago.

Participants Were Cognitively Healthy at Enrollment

It is unclear how common unawareness about one’s memory loss is, as well as when such unawareness develops. Some studies have shown an association between unawareness and dementia severity, but other research has found no such association. Longitudinal studies have not settled the question of whether unawareness changes over time. These studies mainly have focused on patients with prevalent dementia.

Dr. Wilson and colleagues analyzed data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study, three longitudinal clinical–pathologic studies of older persons without cognitive impairment at enrollment. All participants were age 50 or older at baseline. At the time of the analyses, 3,298 people had completed the baseline evaluation and agreed to brain autopsy at death. After the investigators excluded ineligible participants, 2,115 people were eligible for follow-up. Follow-up data were available for 2,092 people.

To track change in memory awareness in dementia, the researchers examined a subset of 239 persons who completed at least four annual evaluations and developed incident dementia before their last evaluation. This population had a mean baseline age of 79.2 and a mean follow-up of 10.8 years.

To investigate the pathologic basis of unawareness of memory impairment, the investigators analyzed a second subset of people who underwent neuropathologic examinations. A total of 662 participants underwent a brain autopsy and neuropathologic examination, and results were available for the first consecutive 627 persons. Dr. Wilson and colleagues analyzed the association of memory awareness with TDP-43 pathology in 585 of these patients. This population died at a mean age of 89.1 with a mean of 9.2 years of follow-up.

All participants had an annual clinical assessment that included a medical history, neurologic examination, and tests of memory and cognition. Participants were asked two questions about their memory that the researchers combined to obtain a subjective memory measure. In addition, participants underwent 19 cognitive tests annually, including tests of episodic, semantic, and working memory. After each evaluation, a clinician blinded to previously collected data diagnosed dementia.

Brain removal occurred at a mean of 8.2 hours after death. The neuropathologic examination included quantification of β-amyloid-immunoreactive plaques and tau-immunoreactive tangles. Researchers also assessed TDP-43 in six brain regions.

Memory Awareness Declined 
Before Dementia Onset

At baseline, subjective memory rating and episodic memory performance had normal distributions in the full study population. Patients did not tend to overestimate or underestimate their memory ability. Objective memory performance and subjective memory rating declined over time. Higher subjective memory at baseline predicted less episodic memory decline.

In the subset of 239 people, loss of memory awareness occurred in nearly all persons who developed dementia. Time of unawareness onset and rate of progression varied, however. Starting at a mean of 2.6 years before dementia onset, episodic memory awareness began to decline sharply at a mean rate of 0.260 units per year, which is nearly half of the baseline standard deviation. Memory awareness began to decline two to three years earlier in younger persons, compared with older persons. Neither sex nor education was related to change in memory awareness.

In the subset of 385 people with postmortem data, the measure of episodic memory awareness declined a mean of 0.035 units per year. In this group, TDP-43 pathology, tangle density, and gross cerebral infarcts were associated with more rapid decline in episodic memory awareness. When the researchers accounted for these associations, they found no change in episodic memory awareness. Dr. Wilson’s group also analyzed the entire study population who died with and without dementia and found that TDP-43 pathology, tangle density, and gross infarcts were each associated with declining awareness of episodic memory impairment in each subgroup, although the associations were stronger in the subgroup with dementia.

Findings Must Be Replicated

“These observations suggest that unawareness of amnestic dysfunction is part of the natural history of late-life dementia and is driven by accumulation of dementia-related pathologies,” said Dr. Wilson. Unawareness of memory impairment typically becomes apparent at the time of dementia diagnosis and may require a history of cognitive decline to be based on expert judgment or a knowledgeable informant, rather than self-report.

One of the study’s strengths, according to the investigators, was that participants were followed at regular intervals for several years and participated in follow-up and brain autopsy at high rates, which minimized the likelihood that selective attrition affected the results. The focus on persons who were cognitively healthy at baseline and later developed dementia enabled the researchers to link the development of memory awareness to the natural history of dementia. The primary limitation, according to the authors, is that participants were selected, which entails that the results need to be replicated in other cohorts. “The extent to which these findings apply to awareness of other dementia signs is also uncertain,” Dr. Wilson concluded.

—Erik Greb

Awareness of memory impairment typically begins to decline several years before dementia onset, according to research published online ahead of print August 26 in Neurology. The decline in awareness is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.

An unexpected finding of the study, according to the investigators, is that decline in awareness of memory impairment in dementia begins earlier in younger people, compared with older people. “The reason for this is uncertain, but it likely reflects a general awareness that memory loss is more normative at older ages rather than an age-related difference in awareness of one’s own memory loss,” said Robert S. Wilson, PhD, Professor of Neurological Sciences and Psychology at Rush University Medical Center in Chicago.

Participants Were Cognitively Healthy at Enrollment

It is unclear how common unawareness about one’s memory loss is, as well as when such unawareness develops. Some studies have shown an association between unawareness and dementia severity, but other research has found no such association. Longitudinal studies have not settled the question of whether unawareness changes over time. These studies mainly have focused on patients with prevalent dementia.

Dr. Wilson and colleagues analyzed data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study, three longitudinal clinical–pathologic studies of older persons without cognitive impairment at enrollment. All participants were age 50 or older at baseline. At the time of the analyses, 3,298 people had completed the baseline evaluation and agreed to brain autopsy at death. After the investigators excluded ineligible participants, 2,115 people were eligible for follow-up. Follow-up data were available for 2,092 people.

To track change in memory awareness in dementia, the researchers examined a subset of 239 persons who completed at least four annual evaluations and developed incident dementia before their last evaluation. This population had a mean baseline age of 79.2 and a mean follow-up of 10.8 years.

To investigate the pathologic basis of unawareness of memory impairment, the investigators analyzed a second subset of people who underwent neuropathologic examinations. A total of 662 participants underwent a brain autopsy and neuropathologic examination, and results were available for the first consecutive 627 persons. Dr. Wilson and colleagues analyzed the association of memory awareness with TDP-43 pathology in 585 of these patients. This population died at a mean age of 89.1 with a mean of 9.2 years of follow-up.

All participants had an annual clinical assessment that included a medical history, neurologic examination, and tests of memory and cognition. Participants were asked two questions about their memory that the researchers combined to obtain a subjective memory measure. In addition, participants underwent 19 cognitive tests annually, including tests of episodic, semantic, and working memory. After each evaluation, a clinician blinded to previously collected data diagnosed dementia.

Brain removal occurred at a mean of 8.2 hours after death. The neuropathologic examination included quantification of β-amyloid-immunoreactive plaques and tau-immunoreactive tangles. Researchers also assessed TDP-43 in six brain regions.

Memory Awareness Declined 
Before Dementia Onset

At baseline, subjective memory rating and episodic memory performance had normal distributions in the full study population. Patients did not tend to overestimate or underestimate their memory ability. Objective memory performance and subjective memory rating declined over time. Higher subjective memory at baseline predicted less episodic memory decline.

In the subset of 239 people, loss of memory awareness occurred in nearly all persons who developed dementia. Time of unawareness onset and rate of progression varied, however. Starting at a mean of 2.6 years before dementia onset, episodic memory awareness began to decline sharply at a mean rate of 0.260 units per year, which is nearly half of the baseline standard deviation. Memory awareness began to decline two to three years earlier in younger persons, compared with older persons. Neither sex nor education was related to change in memory awareness.

In the subset of 385 people with postmortem data, the measure of episodic memory awareness declined a mean of 0.035 units per year. In this group, TDP-43 pathology, tangle density, and gross cerebral infarcts were associated with more rapid decline in episodic memory awareness. When the researchers accounted for these associations, they found no change in episodic memory awareness. Dr. Wilson’s group also analyzed the entire study population who died with and without dementia and found that TDP-43 pathology, tangle density, and gross infarcts were each associated with declining awareness of episodic memory impairment in each subgroup, although the associations were stronger in the subgroup with dementia.

Findings Must Be Replicated

“These observations suggest that unawareness of amnestic dysfunction is part of the natural history of late-life dementia and is driven by accumulation of dementia-related pathologies,” said Dr. Wilson. Unawareness of memory impairment typically becomes apparent at the time of dementia diagnosis and may require a history of cognitive decline to be based on expert judgment or a knowledgeable informant, rather than self-report.

One of the study’s strengths, according to the investigators, was that participants were followed at regular intervals for several years and participated in follow-up and brain autopsy at high rates, which minimized the likelihood that selective attrition affected the results. The focus on persons who were cognitively healthy at baseline and later developed dementia enabled the researchers to link the development of memory awareness to the natural history of dementia. The primary limitation, according to the authors, is that participants were selected, which entails that the results need to be replicated in other cohorts. “The extent to which these findings apply to awareness of other dementia signs is also uncertain,” Dr. Wilson concluded.

—Erik Greb

Childhood brain tumor survivors are susceptible to seizures, according to a study published online ahead of print August 31 in Epilepsia. Among 298 survivors of pediatric brain tumors, seizures were seen in 24% at presentation and were ongoing in 14%. “Seizures are one of the most significant neurologic complications of childhood brain tumors, as they can occur frequently at any time from diagnosis to years after completion of treatment,” said Nicole J. Ullrich, MD, PhD, Director of Neurologic Neuro-Oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Dr. Ullrich and colleagues conducted a retrospective, longitudinal review of consecutive patients examined during a 12-month period who were at least two years post initial diagnosis of a brain tumor. Data collected included age at diagnosis, length of follow-up, extent of initial resection, tumor histology, and treatment modalities. The timing and frequency of seizures, seizure semiology, EEG results, and anticonvulsant use also were recorded. Average duration of follow-up was 7.6 years.

The study cohort included 298 patients; nearly half (140) were female. Initial surgical resection was gross-total in 109 patients and subtotal in 143. Twenty-nine patients underwent biopsy alone, and 17 had no surgical intervention. Tumor location included posterior fossa in 104 (36%), midline in 98 (34%), cortical in 85 (29%), and other in 11 (3%). The most frequent diagnoses were low-grade glioma, medulloblastoma, and ependyoma.

Thirty patients had seizures at the time of tumor diagnosis (10% of the entire cohort, 42% of those with seizures), whereas seizure onset occurred during treatment in 12 patients (3% of entire cohort, 17% of those with seizures) and more than two years after completion of treatment in 16 patients (5.3% of entire cohort, 22% of those with seizures). Ongoing seizures at the time of most recent follow-up were present in 43 patients (14% of entire cohort, 58% of those with seizures).

Factors predisposing to seizures included tumor pathology (low- or high-grade glioma, glioneuronal tumor), cortical location, and subtotal initial resection of the tumor. Seizures were mostly well controlled by antiepileptic drugs.

Dr. Ullrich and colleagues proposed that earlier identification of seizure-eliciting factors in tumor survivors could help in weaning the patients from anticonvulsant medication to reduce the probability of continuing seizures sooner after treatment.

—Ashley Payton

Childhood brain tumor survivors are susceptible to seizures, according to a study published online ahead of print August 31 in Epilepsia. Among 298 survivors of pediatric brain tumors, seizures were seen in 24% at presentation and were ongoing in 14%. “Seizures are one of the most significant neurologic complications of childhood brain tumors, as they can occur frequently at any time from diagnosis to years after completion of treatment,” said Nicole J. Ullrich, MD, PhD, Director of Neurologic Neuro-Oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Dr. Ullrich and colleagues conducted a retrospective, longitudinal review of consecutive patients examined during a 12-month period who were at least two years post initial diagnosis of a brain tumor. Data collected included age at diagnosis, length of follow-up, extent of initial resection, tumor histology, and treatment modalities. The timing and frequency of seizures, seizure semiology, EEG results, and anticonvulsant use also were recorded. Average duration of follow-up was 7.6 years.

The study cohort included 298 patients; nearly half (140) were female. Initial surgical resection was gross-total in 109 patients and subtotal in 143. Twenty-nine patients underwent biopsy alone, and 17 had no surgical intervention. Tumor location included posterior fossa in 104 (36%), midline in 98 (34%), cortical in 85 (29%), and other in 11 (3%). The most frequent diagnoses were low-grade glioma, medulloblastoma, and ependyoma.

Thirty patients had seizures at the time of tumor diagnosis (10% of the entire cohort, 42% of those with seizures), whereas seizure onset occurred during treatment in 12 patients (3% of entire cohort, 17% of those with seizures) and more than two years after completion of treatment in 16 patients (5.3% of entire cohort, 22% of those with seizures). Ongoing seizures at the time of most recent follow-up were present in 43 patients (14% of entire cohort, 58% of those with seizures).

Factors predisposing to seizures included tumor pathology (low- or high-grade glioma, glioneuronal tumor), cortical location, and subtotal initial resection of the tumor. Seizures were mostly well controlled by antiepileptic drugs.

Dr. Ullrich and colleagues proposed that earlier identification of seizure-eliciting factors in tumor survivors could help in weaning the patients from anticonvulsant medication to reduce the probability of continuing seizures sooner after treatment.

—Ashley Payton

Childhood brain tumor survivors are susceptible to seizures, according to a study published online ahead of print August 31 in Epilepsia. Among 298 survivors of pediatric brain tumors, seizures were seen in 24% at presentation and were ongoing in 14%. “Seizures are one of the most significant neurologic complications of childhood brain tumors, as they can occur frequently at any time from diagnosis to years after completion of treatment,” said Nicole J. Ullrich, MD, PhD, Director of Neurologic Neuro-Oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Dr. Ullrich and colleagues conducted a retrospective, longitudinal review of consecutive patients examined during a 12-month period who were at least two years post initial diagnosis of a brain tumor. Data collected included age at diagnosis, length of follow-up, extent of initial resection, tumor histology, and treatment modalities. The timing and frequency of seizures, seizure semiology, EEG results, and anticonvulsant use also were recorded. Average duration of follow-up was 7.6 years.

The study cohort included 298 patients; nearly half (140) were female. Initial surgical resection was gross-total in 109 patients and subtotal in 143. Twenty-nine patients underwent biopsy alone, and 17 had no surgical intervention. Tumor location included posterior fossa in 104 (36%), midline in 98 (34%), cortical in 85 (29%), and other in 11 (3%). The most frequent diagnoses were low-grade glioma, medulloblastoma, and ependyoma.

Thirty patients had seizures at the time of tumor diagnosis (10% of the entire cohort, 42% of those with seizures), whereas seizure onset occurred during treatment in 12 patients (3% of entire cohort, 17% of those with seizures) and more than two years after completion of treatment in 16 patients (5.3% of entire cohort, 22% of those with seizures). Ongoing seizures at the time of most recent follow-up were present in 43 patients (14% of entire cohort, 58% of those with seizures).

Factors predisposing to seizures included tumor pathology (low- or high-grade glioma, glioneuronal tumor), cortical location, and subtotal initial resection of the tumor. Seizures were mostly well controlled by antiepileptic drugs.

Dr. Ullrich and colleagues proposed that earlier identification of seizure-eliciting factors in tumor survivors could help in weaning the patients from anticonvulsant medication to reduce the probability of continuing seizures sooner after treatment.

—Ashley Payton

Certain CSF biomarkers may help differentiate Parkinson’s disease from other causes of parkinsonism and predict which patients will later develop Parkinson’s disease-related dementia, according to research published online ahead of print August 10 in JAMA Neurology.

In a prospective, population-based, longitudinal study, David C. Bäckström, MD, of Umeå University in Sweden, and his coinvestigators examined several biomarkers in CSF samples from 128 patients with new-onset, treatment-naïve parkinsonism who resided in Sweden. These patients agreed to CSF collection by lumbar puncture at baseline, and some agreed to serial sampling. Patients were followed yearly for five to nine years and underwent periodic comprehensive neuropsychologic testing. At their most recent follow-up visit, 104 of these participants had been diagnosed with Parkinson’s disease, 11 with multiple system atrophy (MSA), and 13 with progressive supranuclear palsy (PSP). For reference, researchers obtained CSF samples from 30 healthy control subjects.

High levels of neurofilament light chain protein (NFL) together with low levels of amyloid-beta1-42 distinguished PSP from Parkinson’s disease at baseline as well as one year later, after patients had been receiving dopaminergic therapy for months. Even elevated NFL alone was useful for differentiating PSP from Parkinson’s disease: a baseline NFL exceeding 2,020 ng/L had a sensitivity of 75% and a specificity of 83% in distinguishing the two disorders. The tendency of NFL to gradually increase in PSP was even more indicative of the disease. At one year, NFL levels exceeding 2,916 ng/L had a sensitivity of 89% and a specificity of 93% for identifying PSP. CSF samples at baseline could not distinguish MSA from Parkinson’s disease, however.

In addition, an early pattern of high NFL, low amyloid-beta1-42, and high heart fatty-acid-binding protein (HFABP) predicted Parkinson’s disease-related dementia with 90% sensitivity and 71% specificity. Patients whose baseline NFL exceeded 1,100 ng/L, whose amyloid-beta1-42 was less than 626 ng/L, and whose HFABP exceeded 500 ng/L were at 2.6, 2.8, and 2.8 times higher risk of future Parkinson’s disease-related dementia, respectively, than other patients with parkinsonism.

—Mary Ann Moon

Certain CSF biomarkers may help differentiate Parkinson’s disease from other causes of parkinsonism and predict which patients will later develop Parkinson’s disease-related dementia, according to research published online ahead of print August 10 in JAMA Neurology.

In a prospective, population-based, longitudinal study, David C. Bäckström, MD, of Umeå University in Sweden, and his coinvestigators examined several biomarkers in CSF samples from 128 patients with new-onset, treatment-naïve parkinsonism who resided in Sweden. These patients agreed to CSF collection by lumbar puncture at baseline, and some agreed to serial sampling. Patients were followed yearly for five to nine years and underwent periodic comprehensive neuropsychologic testing. At their most recent follow-up visit, 104 of these participants had been diagnosed with Parkinson’s disease, 11 with multiple system atrophy (MSA), and 13 with progressive supranuclear palsy (PSP). For reference, researchers obtained CSF samples from 30 healthy control subjects.

High levels of neurofilament light chain protein (NFL) together with low levels of amyloid-beta1-42 distinguished PSP from Parkinson’s disease at baseline as well as one year later, after patients had been receiving dopaminergic therapy for months. Even elevated NFL alone was useful for differentiating PSP from Parkinson’s disease: a baseline NFL exceeding 2,020 ng/L had a sensitivity of 75% and a specificity of 83% in distinguishing the two disorders. The tendency of NFL to gradually increase in PSP was even more indicative of the disease. At one year, NFL levels exceeding 2,916 ng/L had a sensitivity of 89% and a specificity of 93% for identifying PSP. CSF samples at baseline could not distinguish MSA from Parkinson’s disease, however.

In addition, an early pattern of high NFL, low amyloid-beta1-42, and high heart fatty-acid-binding protein (HFABP) predicted Parkinson’s disease-related dementia with 90% sensitivity and 71% specificity. Patients whose baseline NFL exceeded 1,100 ng/L, whose amyloid-beta1-42 was less than 626 ng/L, and whose HFABP exceeded 500 ng/L were at 2.6, 2.8, and 2.8 times higher risk of future Parkinson’s disease-related dementia, respectively, than other patients with parkinsonism.

—Mary Ann Moon

Certain CSF biomarkers may help differentiate Parkinson’s disease from other causes of parkinsonism and predict which patients will later develop Parkinson’s disease-related dementia, according to research published online ahead of print August 10 in JAMA Neurology.

In a prospective, population-based, longitudinal study, David C. Bäckström, MD, of Umeå University in Sweden, and his coinvestigators examined several biomarkers in CSF samples from 128 patients with new-onset, treatment-naïve parkinsonism who resided in Sweden. These patients agreed to CSF collection by lumbar puncture at baseline, and some agreed to serial sampling. Patients were followed yearly for five to nine years and underwent periodic comprehensive neuropsychologic testing. At their most recent follow-up visit, 104 of these participants had been diagnosed with Parkinson’s disease, 11 with multiple system atrophy (MSA), and 13 with progressive supranuclear palsy (PSP). For reference, researchers obtained CSF samples from 30 healthy control subjects.

High levels of neurofilament light chain protein (NFL) together with low levels of amyloid-beta1-42 distinguished PSP from Parkinson’s disease at baseline as well as one year later, after patients had been receiving dopaminergic therapy for months. Even elevated NFL alone was useful for differentiating PSP from Parkinson’s disease: a baseline NFL exceeding 2,020 ng/L had a sensitivity of 75% and a specificity of 83% in distinguishing the two disorders. The tendency of NFL to gradually increase in PSP was even more indicative of the disease. At one year, NFL levels exceeding 2,916 ng/L had a sensitivity of 89% and a specificity of 93% for identifying PSP. CSF samples at baseline could not distinguish MSA from Parkinson’s disease, however.

In addition, an early pattern of high NFL, low amyloid-beta1-42, and high heart fatty-acid-binding protein (HFABP) predicted Parkinson’s disease-related dementia with 90% sensitivity and 71% specificity. Patients whose baseline NFL exceeded 1,100 ng/L, whose amyloid-beta1-42 was less than 626 ng/L, and whose HFABP exceeded 500 ng/L were at 2.6, 2.8, and 2.8 times higher risk of future Parkinson’s disease-related dementia, respectively, than other patients with parkinsonism.

—Mary Ann Moon

Researchers learned that in a survey population of patients with epilepsy who required surgical treatment, 68% of patients returned to regular driving post-surgery. Of the 148 patients in the survey population, 78 patients returned the questionnaire. A pre-surgical history of driving on a regular basis and Engel Class I outcome post-surgery were associated with significantly higher rates of good driving outcomes. Intracranial electroencephalography prior to resection was associated with worse driving outcomes.

Dawkins RL, Omar NB, Agee BS, Walters BC, Riley KO. Assessment of driving outcomes after epilepsy surgery. Epilepsy Behav. 2015;52(A):25-30.

Researchers learned that in a survey population of patients with epilepsy who required surgical treatment, 68% of patients returned to regular driving post-surgery. Of the 148 patients in the survey population, 78 patients returned the questionnaire. A pre-surgical history of driving on a regular basis and Engel Class I outcome post-surgery were associated with significantly higher rates of good driving outcomes. Intracranial electroencephalography prior to resection was associated with worse driving outcomes.

Dawkins RL, Omar NB, Agee BS, Walters BC, Riley KO. Assessment of driving outcomes after epilepsy surgery. Epilepsy Behav. 2015;52(A):25-30.

Researchers learned that in a survey population of patients with epilepsy who required surgical treatment, 68% of patients returned to regular driving post-surgery. Of the 148 patients in the survey population, 78 patients returned the questionnaire. A pre-surgical history of driving on a regular basis and Engel Class I outcome post-surgery were associated with significantly higher rates of good driving outcomes. Intracranial electroencephalography prior to resection was associated with worse driving outcomes.

Dawkins RL, Omar NB, Agee BS, Walters BC, Riley KO. Assessment of driving outcomes after epilepsy surgery. Epilepsy Behav. 2015;52(A):25-30.

Researchers identified 215 cases in the Multicenter Study of Epilepsy Surgery database who reported having seizure(s) while driving—141 were involved in a motor vehicle accident (MVA), 74 were not. There was no difference in the presence and length of auras between the 2 groups. The results question auras as a protective role against MVAs in patients with epilepsy.

Punia V, Farooque P, Chen W, Hirsch LJ, Berg A, Blumenfeld H; the Multicenter Study of Epilepsy Surgery. Epileptic auras and their role in driving safety in people with epilepsy. Epilepsia. 2015; doi:10.1111/epi.13189.

Researchers identified 215 cases in the Multicenter Study of Epilepsy Surgery database who reported having seizure(s) while driving—141 were involved in a motor vehicle accident (MVA), 74 were not. There was no difference in the presence and length of auras between the 2 groups. The results question auras as a protective role against MVAs in patients with epilepsy.

Punia V, Farooque P, Chen W, Hirsch LJ, Berg A, Blumenfeld H; the Multicenter Study of Epilepsy Surgery. Epileptic auras and their role in driving safety in people with epilepsy. Epilepsia. 2015; doi:10.1111/epi.13189.

Researchers identified 215 cases in the Multicenter Study of Epilepsy Surgery database who reported having seizure(s) while driving—141 were involved in a motor vehicle accident (MVA), 74 were not. There was no difference in the presence and length of auras between the 2 groups. The results question auras as a protective role against MVAs in patients with epilepsy.

Punia V, Farooque P, Chen W, Hirsch LJ, Berg A, Blumenfeld H; the Multicenter Study of Epilepsy Surgery. Epileptic auras and their role in driving safety in people with epilepsy. Epilepsia. 2015; doi:10.1111/epi.13189.

A 2-year study of 175 patients with partial-onset seizures showed that responsive neurostimulation using the RNS^® System was not associated with cognitive decline. There was modest cognitive improvement in response to neurostimulation. The areas of improvement were related to the region of the brain from which seizures arose and where neurostimulation was delivered.

Loring DW, Kapur R, Meador KJ, Morrell MJ. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia. 2015; doi:10.111/epi.13191.

A 2-year study of 175 patients with partial-onset seizures showed that responsive neurostimulation using the RNS^® System was not associated with cognitive decline. There was modest cognitive improvement in response to neurostimulation. The areas of improvement were related to the region of the brain from which seizures arose and where neurostimulation was delivered.

Loring DW, Kapur R, Meador KJ, Morrell MJ. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia. 2015; doi:10.111/epi.13191.

A 2-year study of 175 patients with partial-onset seizures showed that responsive neurostimulation using the RNS^® System was not associated with cognitive decline. There was modest cognitive improvement in response to neurostimulation. The areas of improvement were related to the region of the brain from which seizures arose and where neurostimulation was delivered.

Loring DW, Kapur R, Meador KJ, Morrell MJ. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia. 2015; doi:10.111/epi.13191.

A Taskforce for the Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) has proposed a new definition of status epilepticus: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.

The Taskforce also proposed a new diagnostic classification system for status epilepticus that consists of 4 axes: Semiology, Etiology, Electroencephalography (EEG) correlates; and Age.  Each axis is further divided into subcategories, providing a framework for clinical diagnosis, investigation, and therapeutic approaches for patients.

Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015; doi:10.111/epi.13121.

A Taskforce for the Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) has proposed a new definition of status epilepticus: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.

The Taskforce also proposed a new diagnostic classification system for status epilepticus that consists of 4 axes: Semiology, Etiology, Electroencephalography (EEG) correlates; and Age.  Each axis is further divided into subcategories, providing a framework for clinical diagnosis, investigation, and therapeutic approaches for patients.

Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015; doi:10.111/epi.13121.

A Taskforce for the Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) has proposed a new definition of status epilepticus: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.

The Taskforce also proposed a new diagnostic classification system for status epilepticus that consists of 4 axes: Semiology, Etiology, Electroencephalography (EEG) correlates; and Age.  Each axis is further divided into subcategories, providing a framework for clinical diagnosis, investigation, and therapeutic approaches for patients.

Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015; doi:10.111/epi.13121.

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Multiple system atrophy (MSA) is a prion disorder, according to data published online ahead of print August 31 in Proceedings of the National Academy of Sciences of the United States of America. A unique strain of α-synuclein prions causes MSA, and these prions are different from the prions believed to cause Parkinson’s disease.

In addition, α-synuclein is the first new human prion to be identified since the discovery 50 years ago that Creutzfeldt–Jakob disease was transmissible, said Stanley B. Prusiner, MD, Professor of Neurology and Director of the Institute for Neurodegenerative Diseases at University of California, San Francisco. “Establishing that MSA is an α-synuclein prion disorder sets the stage for a new therapeutic campaign,” he added.

Inoculating Mice With 
Brain Specimens

In 2013, Dr. Prusiner and colleagues intracerebrally injected brain homogenates prepared from two people with MSA into TgM83^+/− mice. After 120 days, the mice had progressive CNS dysfunction, and extensive phosphorylated α-synuclein deposits were evident in the cytoplasm and axons of neurons in the mice’s brains.

Dr. Prusiner and colleagues conducted an experiment to determine whether the transmission of MSA in the earlier study was anomalous. First, the researchers obtained brain specimens from 12 deceased patients with a clinical and neuropathologic diagnosis of MSA and from six patients with a diagnosis of Parkinson’s disease. The specimens were obtained from the Parkinson’s UK Brain Bank at Imperial College London, the Sydney Brain Bank in Australia, and the Massachusetts General Hospital Alzheimer’s Disease Research Center in Boston. The researchers confirmed the diagnoses of MSA through postmortem neuropathologic microscopic examination.

The investigators then intracerebrally inoculated TgM83^+/− mice with samples from the 12 deceased patients with MSA. Inoculation with all of the MSA samples caused CNS dysfunction with mean incubation periods of between 100 and 150 days. The mice’s most common clinical signs were dysmetria and circling behavior.

When the researchers intracerebrally inoculated TgM83^+/− mice with brain homogenates from six patients with Parkinson’s disease or a control, however, the intervention did not produce signs of neurologic dysfunction in more than 360 days. Dr. Prusiner and colleagues had had similar results when they bioassayed these samples in human embryonic kidney (HEK) cells expressing α-syn140*A53T–YFP fusion protein.

Distinct Patterns of 
Protein Deposition

During a neuropathologic examination of the brains of the mice inoculated with MSA brain homogenates, the investigators found large aggregates of phosphorylated α-synuclein and widespread astrocytic gliosis. The aggregated α-synuclein primarily took the form of neuronal cytoplasmic inclusions. These mice developed phosphorylated α-synuclein deposits in several brain regions, mostly in the brainstem. The deposits were notably absent from cortical regions.

The brains of TgM83^+/− mice inoculated with Parkinson’s disease brain, on the other hand, had a low and unspecific background signal of phosphorylated α-synuclein after more than 360 days, similar to that seen in the control. Inoculation with either control or Parkinson’s disease brain homogenate did not lead to deposition of appreciable phosphorylated α-synuclein in any brain region.

A Call for Heightened Vigilance

“Critical to the interpretation of our results is that TgM83^+/− mice that were hemizygous for the human 
α-synuclein^*A53T transgene did not develop CNS dysfunction spontaneously,” said Dr. Prusiner. “In addition, the brains of these mice did not infect cultured HEK cells expressing α-syn140*A53T fused to yellow fluorescent protein. In contrast, mouse brain homogenates from both the primary and secondary MSA prion transmissions did infect the cultured HEK cells.”

MSA prions can spread from cell to cell along the entire neuraxis, just like PrPSc prions, which cause Creutzfeldt–Jakob disease, do, according to the study. “Importantly, the ability of MSA to induce progressive neurologic disease in TgM83^+/− mice represents the only other human prion disease apart from that caused by PrPSc to induce a lethal phenotype in an animal model,” said Dr. Prusiner.

The unique clinical presentations of the two disorders and the distinct locations in the CNS where they deposit α-synuclein support the hypothesis that the α-synuclein prions that putatively cause Parkinson’s disease may be different from those that cause MSA, said the investigators. Furthermore, the transmission of MSA prions requires Tg mice expressing the A53T mutation found in familial Parkinson’s disease, because mice expressing wild-type mouse or human α-synuclein could not support MSA prion propagation.

The study results suggest that electrodes used for deep brain stimulation and any other equipment that comes into contact with CNS tissue should not be reused. “You can’t kill a protein,” said Kurt Giles, DPhil, Associate Professor of Neurology at University of California, San Francisco and a coauthor of the study. “It can stick tightly to stainless steel, even when the surgical instrument is cleaned. We’re advocating a precautionary approach.” The extent to which MSA prions resist standard decontamination and sterilization procedures is unknown. Therefore, the increased vigilance used in brain biopsies of patients with suspected Creutzfeldt–Jakob disease should be applied to all patients with synucleinopathies, said the authors.

—Erik Greb

Multiple system atrophy (MSA) is a prion disorder, according to data published online ahead of print August 31 in Proceedings of the National Academy of Sciences of the United States of America. A unique strain of α-synuclein prions causes MSA, and these prions are different from the prions believed to cause Parkinson’s disease.

In addition, α-synuclein is the first new human prion to be identified since the discovery 50 years ago that Creutzfeldt–Jakob disease was transmissible, said Stanley B. Prusiner, MD, Professor of Neurology and Director of the Institute for Neurodegenerative Diseases at University of California, San Francisco. “Establishing that MSA is an α-synuclein prion disorder sets the stage for a new therapeutic campaign,” he added.

Inoculating Mice With 
Brain Specimens

In 2013, Dr. Prusiner and colleagues intracerebrally injected brain homogenates prepared from two people with MSA into TgM83^+/− mice. After 120 days, the mice had progressive CNS dysfunction, and extensive phosphorylated α-synuclein deposits were evident in the cytoplasm and axons of neurons in the mice’s brains.

Dr. Prusiner and colleagues conducted an experiment to determine whether the transmission of MSA in the earlier study was anomalous. First, the researchers obtained brain specimens from 12 deceased patients with a clinical and neuropathologic diagnosis of MSA and from six patients with a diagnosis of Parkinson’s disease. The specimens were obtained from the Parkinson’s UK Brain Bank at Imperial College London, the Sydney Brain Bank in Australia, and the Massachusetts General Hospital Alzheimer’s Disease Research Center in Boston. The researchers confirmed the diagnoses of MSA through postmortem neuropathologic microscopic examination.

The investigators then intracerebrally inoculated TgM83^+/− mice with samples from the 12 deceased patients with MSA. Inoculation with all of the MSA samples caused CNS dysfunction with mean incubation periods of between 100 and 150 days. The mice’s most common clinical signs were dysmetria and circling behavior.

When the researchers intracerebrally inoculated TgM83^+/− mice with brain homogenates from six patients with Parkinson’s disease or a control, however, the intervention did not produce signs of neurologic dysfunction in more than 360 days. Dr. Prusiner and colleagues had had similar results when they bioassayed these samples in human embryonic kidney (HEK) cells expressing α-syn140*A53T–YFP fusion protein.

Distinct Patterns of 
Protein Deposition

During a neuropathologic examination of the brains of the mice inoculated with MSA brain homogenates, the investigators found large aggregates of phosphorylated α-synuclein and widespread astrocytic gliosis. The aggregated α-synuclein primarily took the form of neuronal cytoplasmic inclusions. These mice developed phosphorylated α-synuclein deposits in several brain regions, mostly in the brainstem. The deposits were notably absent from cortical regions.

The brains of TgM83^+/− mice inoculated with Parkinson’s disease brain, on the other hand, had a low and unspecific background signal of phosphorylated α-synuclein after more than 360 days, similar to that seen in the control. Inoculation with either control or Parkinson’s disease brain homogenate did not lead to deposition of appreciable phosphorylated α-synuclein in any brain region.

A Call for Heightened Vigilance

“Critical to the interpretation of our results is that TgM83^+/− mice that were hemizygous for the human 
α-synuclein^*A53T transgene did not develop CNS dysfunction spontaneously,” said Dr. Prusiner. “In addition, the brains of these mice did not infect cultured HEK cells expressing α-syn140*A53T fused to yellow fluorescent protein. In contrast, mouse brain homogenates from both the primary and secondary MSA prion transmissions did infect the cultured HEK cells.”

MSA prions can spread from cell to cell along the entire neuraxis, just like PrPSc prions, which cause Creutzfeldt–Jakob disease, do, according to the study. “Importantly, the ability of MSA to induce progressive neurologic disease in TgM83^+/− mice represents the only other human prion disease apart from that caused by PrPSc to induce a lethal phenotype in an animal model,” said Dr. Prusiner.

The unique clinical presentations of the two disorders and the distinct locations in the CNS where they deposit α-synuclein support the hypothesis that the α-synuclein prions that putatively cause Parkinson’s disease may be different from those that cause MSA, said the investigators. Furthermore, the transmission of MSA prions requires Tg mice expressing the A53T mutation found in familial Parkinson’s disease, because mice expressing wild-type mouse or human α-synuclein could not support MSA prion propagation.

The study results suggest that electrodes used for deep brain stimulation and any other equipment that comes into contact with CNS tissue should not be reused. “You can’t kill a protein,” said Kurt Giles, DPhil, Associate Professor of Neurology at University of California, San Francisco and a coauthor of the study. “It can stick tightly to stainless steel, even when the surgical instrument is cleaned. We’re advocating a precautionary approach.” The extent to which MSA prions resist standard decontamination and sterilization procedures is unknown. Therefore, the increased vigilance used in brain biopsies of patients with suspected Creutzfeldt–Jakob disease should be applied to all patients with synucleinopathies, said the authors.

—Erik Greb

Multiple system atrophy (MSA) is a prion disorder, according to data published online ahead of print August 31 in Proceedings of the National Academy of Sciences of the United States of America. A unique strain of α-synuclein prions causes MSA, and these prions are different from the prions believed to cause Parkinson’s disease.

In addition, α-synuclein is the first new human prion to be identified since the discovery 50 years ago that Creutzfeldt–Jakob disease was transmissible, said Stanley B. Prusiner, MD, Professor of Neurology and Director of the Institute for Neurodegenerative Diseases at University of California, San Francisco. “Establishing that MSA is an α-synuclein prion disorder sets the stage for a new therapeutic campaign,” he added.

Inoculating Mice With 
Brain Specimens

In 2013, Dr. Prusiner and colleagues intracerebrally injected brain homogenates prepared from two people with MSA into TgM83^+/− mice. After 120 days, the mice had progressive CNS dysfunction, and extensive phosphorylated α-synuclein deposits were evident in the cytoplasm and axons of neurons in the mice’s brains.

Dr. Prusiner and colleagues conducted an experiment to determine whether the transmission of MSA in the earlier study was anomalous. First, the researchers obtained brain specimens from 12 deceased patients with a clinical and neuropathologic diagnosis of MSA and from six patients with a diagnosis of Parkinson’s disease. The specimens were obtained from the Parkinson’s UK Brain Bank at Imperial College London, the Sydney Brain Bank in Australia, and the Massachusetts General Hospital Alzheimer’s Disease Research Center in Boston. The researchers confirmed the diagnoses of MSA through postmortem neuropathologic microscopic examination.

The investigators then intracerebrally inoculated TgM83^+/− mice with samples from the 12 deceased patients with MSA. Inoculation with all of the MSA samples caused CNS dysfunction with mean incubation periods of between 100 and 150 days. The mice’s most common clinical signs were dysmetria and circling behavior.

When the researchers intracerebrally inoculated TgM83^+/− mice with brain homogenates from six patients with Parkinson’s disease or a control, however, the intervention did not produce signs of neurologic dysfunction in more than 360 days. Dr. Prusiner and colleagues had had similar results when they bioassayed these samples in human embryonic kidney (HEK) cells expressing α-syn140*A53T–YFP fusion protein.

Distinct Patterns of 
Protein Deposition

During a neuropathologic examination of the brains of the mice inoculated with MSA brain homogenates, the investigators found large aggregates of phosphorylated α-synuclein and widespread astrocytic gliosis. The aggregated α-synuclein primarily took the form of neuronal cytoplasmic inclusions. These mice developed phosphorylated α-synuclein deposits in several brain regions, mostly in the brainstem. The deposits were notably absent from cortical regions.

The brains of TgM83^+/− mice inoculated with Parkinson’s disease brain, on the other hand, had a low and unspecific background signal of phosphorylated α-synuclein after more than 360 days, similar to that seen in the control. Inoculation with either control or Parkinson’s disease brain homogenate did not lead to deposition of appreciable phosphorylated α-synuclein in any brain region.

A Call for Heightened Vigilance

“Critical to the interpretation of our results is that TgM83^+/− mice that were hemizygous for the human 
α-synuclein^*A53T transgene did not develop CNS dysfunction spontaneously,” said Dr. Prusiner. “In addition, the brains of these mice did not infect cultured HEK cells expressing α-syn140*A53T fused to yellow fluorescent protein. In contrast, mouse brain homogenates from both the primary and secondary MSA prion transmissions did infect the cultured HEK cells.”

MSA prions can spread from cell to cell along the entire neuraxis, just like PrPSc prions, which cause Creutzfeldt–Jakob disease, do, according to the study. “Importantly, the ability of MSA to induce progressive neurologic disease in TgM83^+/− mice represents the only other human prion disease apart from that caused by PrPSc to induce a lethal phenotype in an animal model,” said Dr. Prusiner.

The unique clinical presentations of the two disorders and the distinct locations in the CNS where they deposit α-synuclein support the hypothesis that the α-synuclein prions that putatively cause Parkinson’s disease may be different from those that cause MSA, said the investigators. Furthermore, the transmission of MSA prions requires Tg mice expressing the A53T mutation found in familial Parkinson’s disease, because mice expressing wild-type mouse or human α-synuclein could not support MSA prion propagation.

The study results suggest that electrodes used for deep brain stimulation and any other equipment that comes into contact with CNS tissue should not be reused. “You can’t kill a protein,” said Kurt Giles, DPhil, Associate Professor of Neurology at University of California, San Francisco and a coauthor of the study. “It can stick tightly to stainless steel, even when the surgical instrument is cleaned. We’re advocating a precautionary approach.” The extent to which MSA prions resist standard decontamination and sterilization procedures is unknown. Therefore, the increased vigilance used in brain biopsies of patients with suspected Creutzfeldt–Jakob disease should be applied to all patients with synucleinopathies, said the authors.

—Erik Greb