Literature Review

The American Academy of Neurology and the American Epilepsy Society have released their guidelines on how to manage an adult patient who has had their first unprovoked seizure. Based on their review of the evidence, they recommend that clinicians base their decision about immediately initiating an antiepileptic drug after a first seizure on an individualized assessment. That evaluation should weigh the risk of a second seizure occurring against the adverse effects of the medication, as well as patient preferences. The risk of a second seizure increases if the patient has already suffered a symptomatic brain insult such as a stroke or head trauma, among other risk factors. The guidelines also point out that immediate treatment with an antiepileptic agent reduces the likelihood of additional seizures for 2 years but does not have an impact on long-term prognosis for seizure remission.

Tao JX, Davis AM. Management of an Unprovoked First Seizure in Adults. JAMA. 2016;316(15):1590-1591.

The American Academy of Neurology and the American Epilepsy Society have released their guidelines on how to manage an adult patient who has had their first unprovoked seizure. Based on their review of the evidence, they recommend that clinicians base their decision about immediately initiating an antiepileptic drug after a first seizure on an individualized assessment. That evaluation should weigh the risk of a second seizure occurring against the adverse effects of the medication, as well as patient preferences. The risk of a second seizure increases if the patient has already suffered a symptomatic brain insult such as a stroke or head trauma, among other risk factors. The guidelines also point out that immediate treatment with an antiepileptic agent reduces the likelihood of additional seizures for 2 years but does not have an impact on long-term prognosis for seizure remission.

Tao JX, Davis AM. Management of an Unprovoked First Seizure in Adults. JAMA. 2016;316(15):1590-1591.

The American Academy of Neurology and the American Epilepsy Society have released their guidelines on how to manage an adult patient who has had their first unprovoked seizure. Based on their review of the evidence, they recommend that clinicians base their decision about immediately initiating an antiepileptic drug after a first seizure on an individualized assessment. That evaluation should weigh the risk of a second seizure occurring against the adverse effects of the medication, as well as patient preferences. The risk of a second seizure increases if the patient has already suffered a symptomatic brain insult such as a stroke or head trauma, among other risk factors. The guidelines also point out that immediate treatment with an antiepileptic agent reduces the likelihood of additional seizures for 2 years but does not have an impact on long-term prognosis for seizure remission.

Tao JX, Davis AM. Management of an Unprovoked First Seizure in Adults. JAMA. 2016;316(15):1590-1591.

Temporal lobe epilepsy (TLE) is believed to disrupt resting state functional connectivity in the brain. To explore this association in more depth, investigators used group independent component analysis (ICA) to identify the brain’s default mode network (DMN). The DMN has been linked to episodic memory, which does not function normally in patients with TLE. The researchers found functional connectivity instability over time among patients with left and right sided TLE, when compared with healthy controls. The instability within the DMN was most consistently detected within the precuneus region of the brain.

Robinson LF, He X, Barnett P et al. The temporal instability of resting state network connectivity in intractable epilepsy. Hum Brain Mapp. 2016; Sept 15 [Epub ahead of print]

Temporal lobe epilepsy (TLE) is believed to disrupt resting state functional connectivity in the brain. To explore this association in more depth, investigators used group independent component analysis (ICA) to identify the brain’s default mode network (DMN). The DMN has been linked to episodic memory, which does not function normally in patients with TLE. The researchers found functional connectivity instability over time among patients with left and right sided TLE, when compared with healthy controls. The instability within the DMN was most consistently detected within the precuneus region of the brain.

Robinson LF, He X, Barnett P et al. The temporal instability of resting state network connectivity in intractable epilepsy. Hum Brain Mapp. 2016; Sept 15 [Epub ahead of print]

Temporal lobe epilepsy (TLE) is believed to disrupt resting state functional connectivity in the brain. To explore this association in more depth, investigators used group independent component analysis (ICA) to identify the brain’s default mode network (DMN). The DMN has been linked to episodic memory, which does not function normally in patients with TLE. The researchers found functional connectivity instability over time among patients with left and right sided TLE, when compared with healthy controls. The instability within the DMN was most consistently detected within the precuneus region of the brain.

Robinson LF, He X, Barnett P et al. The temporal instability of resting state network connectivity in intractable epilepsy. Hum Brain Mapp. 2016; Sept 15 [Epub ahead of print]

Volumetric correlation analysis of the brain can help detect subtle structural changes in patients with temporal lobe epilepsy (TLE). With that in mind, Conrad and associates performed T1 weighted 3T magnetic resonance imaging in 44 drug-resistant patients with unilateral TLE and in 44 healthy controls. They detected increased correlation in the contralateral areas to seizure foci and networks in several areas of the brains of patients with both left-sided and right-sided TLE. The areas, which included limbic, subcortical, and temporal regions, confirmed that there are coordinated volume changes in this population that are not confined to ipsilateral regions.

Conrad BN, Rogers BP, Abou-Khalil B et al. Increased MRI volumetric correlation contralateral to seizure focus in temporal lobe epilepsy. Epilepsy Res. 2016; 126:53-61.

Volumetric correlation analysis of the brain can help detect subtle structural changes in patients with temporal lobe epilepsy (TLE). With that in mind, Conrad and associates performed T1 weighted 3T magnetic resonance imaging in 44 drug-resistant patients with unilateral TLE and in 44 healthy controls. They detected increased correlation in the contralateral areas to seizure foci and networks in several areas of the brains of patients with both left-sided and right-sided TLE. The areas, which included limbic, subcortical, and temporal regions, confirmed that there are coordinated volume changes in this population that are not confined to ipsilateral regions.

Conrad BN, Rogers BP, Abou-Khalil B et al. Increased MRI volumetric correlation contralateral to seizure focus in temporal lobe epilepsy. Epilepsy Res. 2016; 126:53-61.

Volumetric correlation analysis of the brain can help detect subtle structural changes in patients with temporal lobe epilepsy (TLE). With that in mind, Conrad and associates performed T1 weighted 3T magnetic resonance imaging in 44 drug-resistant patients with unilateral TLE and in 44 healthy controls. They detected increased correlation in the contralateral areas to seizure foci and networks in several areas of the brains of patients with both left-sided and right-sided TLE. The areas, which included limbic, subcortical, and temporal regions, confirmed that there are coordinated volume changes in this population that are not confined to ipsilateral regions.

Conrad BN, Rogers BP, Abou-Khalil B et al. Increased MRI volumetric correlation contralateral to seizure focus in temporal lobe epilepsy. Epilepsy Res. 2016; 126:53-61.

Patients with epilepsy who also have intellectual disabilities seem to fare better when they adhere to a self-management program suggests this pilot study. Since individuals with intellectual disabilities are 20 times more likely to have epilepsy, researchers wanted to determine if a self-management program could make a difference. Their review of pilot and randomized controlled feasibility studies suggests that patients find this type of intervention acceptable and that the programs improve seizure frequency and may improve their quality of life.  Although their analysis highlights the potential for self-management programs, the investigators are currently conducting a randomized controlled trial to obtain more definitive results.

Dannenberg M, Mengoni SE, Gates B, Durand M. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review.  Seizure. 2016;41:16-25.

Patients with epilepsy who also have intellectual disabilities seem to fare better when they adhere to a self-management program suggests this pilot study. Since individuals with intellectual disabilities are 20 times more likely to have epilepsy, researchers wanted to determine if a self-management program could make a difference. Their review of pilot and randomized controlled feasibility studies suggests that patients find this type of intervention acceptable and that the programs improve seizure frequency and may improve their quality of life.  Although their analysis highlights the potential for self-management programs, the investigators are currently conducting a randomized controlled trial to obtain more definitive results.

Dannenberg M, Mengoni SE, Gates B, Durand M. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review.  Seizure. 2016;41:16-25.

Patients with epilepsy who also have intellectual disabilities seem to fare better when they adhere to a self-management program suggests this pilot study. Since individuals with intellectual disabilities are 20 times more likely to have epilepsy, researchers wanted to determine if a self-management program could make a difference. Their review of pilot and randomized controlled feasibility studies suggests that patients find this type of intervention acceptable and that the programs improve seizure frequency and may improve their quality of life.  Although their analysis highlights the potential for self-management programs, the investigators are currently conducting a randomized controlled trial to obtain more definitive results.

Dannenberg M, Mengoni SE, Gates B, Durand M. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review.  Seizure. 2016;41:16-25.

Although ectopic tissue in certain regions of the brain has been linked to epilepsy, a recent review of the literature concluded that periventricular nodular heterotopia rarely causes clinical seizures. The review evaluated chronic invasive EEG recordings and found that nodules alone are rarely responsible for seizures. Their onset is more likely to be connected with overlying neocortex or mesial temporal structures. However, the analysis did find that substantial or complete ablation of nodules usually results in more favorable surgical outcomes.

Thompson SA, Kalamangalam GP, Tandon N. Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia. Seizure. 2016;41:211-216.

Although ectopic tissue in certain regions of the brain has been linked to epilepsy, a recent review of the literature concluded that periventricular nodular heterotopia rarely causes clinical seizures. The review evaluated chronic invasive EEG recordings and found that nodules alone are rarely responsible for seizures. Their onset is more likely to be connected with overlying neocortex or mesial temporal structures. However, the analysis did find that substantial or complete ablation of nodules usually results in more favorable surgical outcomes.

Thompson SA, Kalamangalam GP, Tandon N. Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia. Seizure. 2016;41:211-216.

Although ectopic tissue in certain regions of the brain has been linked to epilepsy, a recent review of the literature concluded that periventricular nodular heterotopia rarely causes clinical seizures. The review evaluated chronic invasive EEG recordings and found that nodules alone are rarely responsible for seizures. Their onset is more likely to be connected with overlying neocortex or mesial temporal structures. However, the analysis did find that substantial or complete ablation of nodules usually results in more favorable surgical outcomes.

Thompson SA, Kalamangalam GP, Tandon N. Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia. Seizure. 2016;41:211-216.

Patients experiencing different types of seizures tend to present with distinct hand gestures during the attacks, according to a recent retrospective analysis published in Neurology. To reach that conclusion, researchers analyzed videotaped hand postures in patients with genetic generalized epilepsy, localization-related epilepsy, and non-epileptic attacks. They found that 96% of patients with localized epilepsy presented with index-finger pointing while 91.3% of patients with genetic generalized epilepsy presented with hand fanning, which only occurred at the onset of the seizures. The investigators also discovered that making a fist, fanning and index-finger pointing was more common among patients who were having epileptic seizures, when compared to those who were having non-epileptic attacks (74% vs 32%).  

Siegel J, Tatum, WO. Hand postures in primary and secondary generalized tonic-clonic seizures. Neurology. 2016; Published online Sept 24.

Patients experiencing different types of seizures tend to present with distinct hand gestures during the attacks, according to a recent retrospective analysis published in Neurology. To reach that conclusion, researchers analyzed videotaped hand postures in patients with genetic generalized epilepsy, localization-related epilepsy, and non-epileptic attacks. They found that 96% of patients with localized epilepsy presented with index-finger pointing while 91.3% of patients with genetic generalized epilepsy presented with hand fanning, which only occurred at the onset of the seizures. The investigators also discovered that making a fist, fanning and index-finger pointing was more common among patients who were having epileptic seizures, when compared to those who were having non-epileptic attacks (74% vs 32%).  

Siegel J, Tatum, WO. Hand postures in primary and secondary generalized tonic-clonic seizures. Neurology. 2016; Published online Sept 24.

Patients experiencing different types of seizures tend to present with distinct hand gestures during the attacks, according to a recent retrospective analysis published in Neurology. To reach that conclusion, researchers analyzed videotaped hand postures in patients with genetic generalized epilepsy, localization-related epilepsy, and non-epileptic attacks. They found that 96% of patients with localized epilepsy presented with index-finger pointing while 91.3% of patients with genetic generalized epilepsy presented with hand fanning, which only occurred at the onset of the seizures. The investigators also discovered that making a fist, fanning and index-finger pointing was more common among patients who were having epileptic seizures, when compared to those who were having non-epileptic attacks (74% vs 32%).  

Siegel J, Tatum, WO. Hand postures in primary and secondary generalized tonic-clonic seizures. Neurology. 2016; Published online Sept 24.

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].