The session titled “The biliary tree and pancreas” provided an overview of the most important pancreaticobiliary diseases, allowing experts to delineate their approaches to challenging aspects of these conditions.

Timothy Gardner, MD, MS, focused on the management and treatment of sequelae in patients with acute pancreatitis. He provided support for the use of lactated Ringer’s as the fluid of choice, cautioning against over-resuscitation. He advised early oral feeds, without clear preference for nasogastric or nasojejunal administration. Dr. Gardner emphasized the importance of classifying type of fluid collection to optimize clinical decision making. Endoscopic techniques appear to be safer and as efficacious as surgical approaches. Regarding thrombosis, anticoagulation was recommended unless an absolute contraindication exists. He also recommended addressing symptomatic ductal disruptions.

Dr. Kim is an assistant professor of gastroenterology at Mount Sinai Hospital, acting director of endoscopy, and director of endoscopic ultrasound at Mount Sinai Hospital, New York. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

The session titled “The biliary tree and pancreas” provided an overview of the most important pancreaticobiliary diseases, allowing experts to delineate their approaches to challenging aspects of these conditions.

Timothy Gardner, MD, MS, focused on the management and treatment of sequelae in patients with acute pancreatitis. He provided support for the use of lactated Ringer’s as the fluid of choice, cautioning against over-resuscitation. He advised early oral feeds, without clear preference for nasogastric or nasojejunal administration. Dr. Gardner emphasized the importance of classifying type of fluid collection to optimize clinical decision making. Endoscopic techniques appear to be safer and as efficacious as surgical approaches. Regarding thrombosis, anticoagulation was recommended unless an absolute contraindication exists. He also recommended addressing symptomatic ductal disruptions.

Dr. Kim is an assistant professor of gastroenterology at Mount Sinai Hospital, acting director of endoscopy, and director of endoscopic ultrasound at Mount Sinai Hospital, New York. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

The session titled “The biliary tree and pancreas” provided an overview of the most important pancreaticobiliary diseases, allowing experts to delineate their approaches to challenging aspects of these conditions.

Timothy Gardner, MD, MS, focused on the management and treatment of sequelae in patients with acute pancreatitis. He provided support for the use of lactated Ringer’s as the fluid of choice, cautioning against over-resuscitation. He advised early oral feeds, without clear preference for nasogastric or nasojejunal administration. Dr. Gardner emphasized the importance of classifying type of fluid collection to optimize clinical decision making. Endoscopic techniques appear to be safer and as efficacious as surgical approaches. Regarding thrombosis, anticoagulation was recommended unless an absolute contraindication exists. He also recommended addressing symptomatic ductal disruptions.

Dr. Kim is an assistant professor of gastroenterology at Mount Sinai Hospital, acting director of endoscopy, and director of endoscopic ultrasound at Mount Sinai Hospital, New York. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

To improve patient care and outcomes, leading dermatologists offered their recommendations on athlete’s foot products. Consideration must be given to:

• Lamisil^AT Cream
  GlaxoSmithKline plc
  “I recommend Lamisil Cream twice daily for 2 to 4 weeks.”— Gary Goldenberg, MD, New York, New York
   
• Lamisil^AT Spray
  GlaxoSmithKline plc
  “This product is effective in treating fungus and allows for easy application with the ability of the spray to reach broad areas of the feet, including within the toe webs.”—Jeannette Graf, MD, New York, New York
   
• Tinactin Athlete’s Foot Powder Spray
  Bayer
  “I recommend all my patients with tinea pedis to spray this product in their shoes.”—Gary Goldenberg, MD, New York, New York
   
• Zeasorb Athlete’s Foot
  Stiefel Laboratories, Inc
  “I recommend this powder to treat tinea pedis and to prevent recurrences in patients who have been treated for onychomycosis.”—Shari Lipner, MD, PhD, New York, New York
   

Cutis invites readers to send us their recommendations. Postprocedural makeup, moisturizers for men, and wet skin moisturizer will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on athlete’s foot products. Consideration must be given to:

• Lamisil^AT Cream
  GlaxoSmithKline plc
  “I recommend Lamisil Cream twice daily for 2 to 4 weeks.”— Gary Goldenberg, MD, New York, New York
   
• Lamisil^AT Spray
  GlaxoSmithKline plc
  “This product is effective in treating fungus and allows for easy application with the ability of the spray to reach broad areas of the feet, including within the toe webs.”—Jeannette Graf, MD, New York, New York
   
• Tinactin Athlete’s Foot Powder Spray
  Bayer
  “I recommend all my patients with tinea pedis to spray this product in their shoes.”—Gary Goldenberg, MD, New York, New York
   
• Zeasorb Athlete’s Foot
  Stiefel Laboratories, Inc
  “I recommend this powder to treat tinea pedis and to prevent recurrences in patients who have been treated for onychomycosis.”—Shari Lipner, MD, PhD, New York, New York
   

Cutis invites readers to send us their recommendations. Postprocedural makeup, moisturizers for men, and wet skin moisturizer will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on athlete’s foot products. Consideration must be given to:

• Lamisil^AT Cream
  GlaxoSmithKline plc
  “I recommend Lamisil Cream twice daily for 2 to 4 weeks.”— Gary Goldenberg, MD, New York, New York
   
• Lamisil^AT Spray
  GlaxoSmithKline plc
  “This product is effective in treating fungus and allows for easy application with the ability of the spray to reach broad areas of the feet, including within the toe webs.”—Jeannette Graf, MD, New York, New York
   
• Tinactin Athlete’s Foot Powder Spray
  Bayer
  “I recommend all my patients with tinea pedis to spray this product in their shoes.”—Gary Goldenberg, MD, New York, New York
   
• Zeasorb Athlete’s Foot
  Stiefel Laboratories, Inc
  “I recommend this powder to treat tinea pedis and to prevent recurrences in patients who have been treated for onychomycosis.”—Shari Lipner, MD, PhD, New York, New York
   

Cutis invites readers to send us their recommendations. Postprocedural makeup, moisturizers for men, and wet skin moisturizer will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

I’m always surprised by how much I can learn in a few short weeks. I am now up to full speed with my project studying the utility of bone biopsies in the management of osteomyelitis.

This is a retrospective study, which means I’ll be collecting historical data from patient charts to be used for our analysis. My mentor – Ernie Esquivel, MD – has played an invaluable role in helping me get this project off the ground. He has worked with me on everything from project planning to successfully navigating the ever-confusing institutional review board (IRB) process. He has also provided advice in areas I thought I might actually have more experience, such as data collection and analysis methods.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

I’m always surprised by how much I can learn in a few short weeks. I am now up to full speed with my project studying the utility of bone biopsies in the management of osteomyelitis.

This is a retrospective study, which means I’ll be collecting historical data from patient charts to be used for our analysis. My mentor – Ernie Esquivel, MD – has played an invaluable role in helping me get this project off the ground. He has worked with me on everything from project planning to successfully navigating the ever-confusing institutional review board (IRB) process. He has also provided advice in areas I thought I might actually have more experience, such as data collection and analysis methods.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.

I’m always surprised by how much I can learn in a few short weeks. I am now up to full speed with my project studying the utility of bone biopsies in the management of osteomyelitis.

This is a retrospective study, which means I’ll be collecting historical data from patient charts to be used for our analysis. My mentor – Ernie Esquivel, MD – has played an invaluable role in helping me get this project off the ground. He has worked with me on everything from project planning to successfully navigating the ever-confusing institutional review board (IRB) process. He has also provided advice in areas I thought I might actually have more experience, such as data collection and analysis methods.

Cole Hirschfeld is originally from Phoenix. He received undergraduate degrees in finance and entrepreneurship from the University of Arizona and went on to work in the finance industry for 2 years before deciding to change careers and attend medical school. He is now a 4th year medical student at Cornell University, New York, and plans to apply for residency in internal medicine.

Click here to download the PDF.

Click here to download the PDF.

Click here to download the PDF.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

In a case series of 202 former football players whose brains were donated for research, 87% of the participants had neuropathologic evidence of chronic traumatic encephalopathy (CTE), according to a study published in the July 25 issue of JAMA. Among 111 players who played in the National Football League (NFL), 99% had CTE. A progressive clinical course was common in players with mild and severe CTE pathology. The results suggest that CTE may be related to prior participation in football, the researchers said.

The report by Jesse Mez, MD, MS, Assistant Professor of Neurology at Boston University, and colleagues describes the largest CTE case series to date. A limitation of the study, however, is that brain donation programs are associated with ascertainment bias. Awareness of a possible link between repetitive head trauma and CTE may have motivated players with signs of brain injury and their families to participate in the study. “Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample,” Dr. Mez and colleagues said.

Findings From a Brain Bank

CTE is a progressive neurodegenerative disease associated with repetitive head trauma. To study the neuropathology and clinical presentation of brain donors with exposure to repetitive head trauma, investigators in 2008 established the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank.

The present study assessed donors who participated in American football at any level of play. Outcomes included neuropathologic diagnoses of neurodegenerative diseases, including CTE; CTE neuropathologic severity; and informant-reported athletic history and clinical presentation.

Investigators conducted retrospective telephone clinical assessments with informants to determine participants’ clinical presentations, including timelines of behavior, mood, and cognitive symptoms. Neither the researchers nor the informants knew the participants’ neuropathology during the interview. Online questionnaires ascertained participants’ athletic and military histories. Pathologists were blinded to exposure data and clinical information.

Level of Play

Among the 202 former football players (median age at death, 66), CTE was neuropathologically diagnosed in 177 players. Participants with CTE had played football for a mean of 15.1 years.

Investigators diagnosed CTE in three of 14 players (21%) whose highest level of play was at the high school level, 48 of 53 players (91%) who played at the college level, nine of 14 players (64%) who played at the semiprofessional level, seven of eight players (88%) who played in the Canadian Football League, and 110 of 111 players (99%) who played in the NFL. Pathologists did not diagnose CTE in two participants whose highest level of play was before high school.

The three players with CTE whose highest level of play was in high school had mild CTE pathology (ie, stage I or II), whereas the majority of former college, semiprofessional, and professional players had severe pathology (ie, stage III or IV).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a progressive clinical course was reported in 85% of participants with mild CTE pathology and in 100% of participants with severe CTE pathology.

Among the 27 players with mild CTE pathology, 96% had behavioral or mood symptoms or both, 85% had cognitive symptoms, and 33% had signs of dementia. Among the 84 players with severe CTE pathology, 89% had behavioral or mood symptoms or both, 95% had cognitive symptoms, and 85% had signs of dementia.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” Dr. Mez and colleagues said. “These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Future studies should assess how factors such as age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits may influence outcomes, the researchers said.

Opportunities for Symptomatic Treatment

The rate of symptomatic CTE may be lower in an unselected population of former football players, said Gil D. Rabinovici, MD, Professor of Neurology at the University of California, San Francisco, in an accompanying editorial.

“The prevalence of cognitive and behavioral symptoms in the autopsy cohort was 88% and 95%, respectively,” he said. “In contrast, questionnaire-based ascertainment of neuropsychiatric symptoms among retired NFL players found that the prevalence of memory symptoms and depression was 5% to 20%. Acknowledging that questionnaires are an insensitive method for detecting neurodegenerative disease, the large discrepancy suggests that the rates of symptomatic CTE may be lower in an unselected cohort of former players.”

In addition, this study and prior studies suggest that there may be opportunities to improve care of patients with CTE. “Potentially treatable contributing factors are found in many patients, including high rates of substance abuse, affective disorders, headaches, and sleep disturbances,” Dr. Rabinovici said. “Thus, at-risk patients may benefit from a multidisciplinary medical team to optimize symptomatic treatment and maximize patient function and quality of life.”

—Jake Remaly

Suggested Reading

Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017;318(4):360-370.

Rabinovici GD. Advances and gaps in understanding chronic traumatic encephalopathy: From pugilists to American football players. JAMA. 2017;318(4):338-340.

So often in clinical practice, guidelines and directives about psychiatric treatments lag behind the results we see every day in our offices. Such is the case with cognitive-behavioral therapy.

Earlier this summer, the departments of Veterans Affairs and Defense deemed trauma-focused psychotherapies, such as CBT, as first-line treatments for posttraumatic stress disorder over medication management. Was I surprised by these findings? Absolutely not. Likewise, last year, the American College of Physicians released a guideline recommending CBT as first-line treatment for chronic insomnia disorder in adults. Surprising? Again, not in the least.

copyright Andrea Danti/Thinkstock

Dr. London, a psychiatrist who practices in New York, developed and ran a short-term psychotherapy program for 20 years at NYU Langone Medical Center and has been writing columns for 35 years. His new book about helping people feel better fast is expected to be published in fall 2017. He has no disclosures.
 

So often in clinical practice, guidelines and directives about psychiatric treatments lag behind the results we see every day in our offices. Such is the case with cognitive-behavioral therapy.

Earlier this summer, the departments of Veterans Affairs and Defense deemed trauma-focused psychotherapies, such as CBT, as first-line treatments for posttraumatic stress disorder over medication management. Was I surprised by these findings? Absolutely not. Likewise, last year, the American College of Physicians released a guideline recommending CBT as first-line treatment for chronic insomnia disorder in adults. Surprising? Again, not in the least.

copyright Andrea Danti/Thinkstock

Dr. London, a psychiatrist who practices in New York, developed and ran a short-term psychotherapy program for 20 years at NYU Langone Medical Center and has been writing columns for 35 years. His new book about helping people feel better fast is expected to be published in fall 2017. He has no disclosures.
 

So often in clinical practice, guidelines and directives about psychiatric treatments lag behind the results we see every day in our offices. Such is the case with cognitive-behavioral therapy.

Earlier this summer, the departments of Veterans Affairs and Defense deemed trauma-focused psychotherapies, such as CBT, as first-line treatments for posttraumatic stress disorder over medication management. Was I surprised by these findings? Absolutely not. Likewise, last year, the American College of Physicians released a guideline recommending CBT as first-line treatment for chronic insomnia disorder in adults. Surprising? Again, not in the least.

copyright Andrea Danti/Thinkstock

Dr. London, a psychiatrist who practices in New York, developed and ran a short-term psychotherapy program for 20 years at NYU Langone Medical Center and has been writing columns for 35 years. His new book about helping people feel better fast is expected to be published in fall 2017. He has no disclosures.
 

BOSTON—Patients with migraine may have greater fluctuation in headache frequency than was previously understood. The rate of transition from episodic migraine to chronic migraine is higher than previously reported, and about three-quarters of people with chronic migraine have a period of episodic migraine during one year, according to a study described at the 59th Annual Scientific Meeting of the American Headache Society.

An Analysis of CaMEO Data

Epidemiologic research has provided information about the profiles of people with chronic migraine and people with episodic migraine. Investigators also have clarified the frequency with which people transition from episodic to chronic migraine. Comparatively little is known, however, about individual variation in headache frequency.

Dr. Lipton and colleagues conducted a study to assess the rates of transition between episodic and chronic migraine and to model the variation in headache days over the course of one year. The investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, which includes a representative sample of Americans with episodic migraine or chronic migraine.

Dr. Lipton’s group screened participants with an electronic version of the American Migraine Study/the American Migraine Prevalence and Prevention diagnostic module. They used modified International Classification of Headache Disorders 3-beta criteria to classify people as having episodic migraine, and modified Silberstein–Lipton criteria to classify patients as having chronic migraine. Every three months, the researchers asked participants how many days they had had headache during the previous quarter. Participants completed as many as five surveys during 2012 and 2013.

To examine within-person change in headache frequency over time, the investigators asked about chronic migraine onset in people with episodic migraine at baseline, and asked about transition to episodic migraine in people with chronic migraine at baseline. Finally, Dr. Lipton and colleagues plotted participants’ longitudinal data and modeled them using adjusted and unadjusted generalized linear mixed models.

High Variation in Headache Days

At baseline, 15,313 respondents had episodic migraine, and 32.4% of them had episodic migraine at baseline only. In addition, 1,476 had chronic migraine at baseline, and 62.3% of them had chronic migraine at baseline only. The investigators observed a “striking level of within-person variation in headache days,” said Dr. Lipton. The number of headache days per month ranged from none to 31.

In further analyses, the investigators examined subpopulations of participants who provided data most consistently throughout the study. Of the 5,464 patients with episodic migraine at baseline for whom at least four completed surveys were available, 92.4% had episodic migraine at every follow-up. In addition, 7.6% of these participants crossed the diagnostic threshold into chronic migraine during at least one quarter. “In the American Migraine Prevalence and Prevention study, the transition rate from episodic migraine to chronic migraine was about 2.5%,” said Dr. Lipton.

A total of 526 patients had chronic migraine at baseline and completed at least four surveys. Of this subpopulation, 26.6% had chronic migraine at every time point, and 73.4% had episodic migraine during at least one quarter. “My suspicion is that the patients that we see in our practices are the people with chronic migraine that remain chronic migraine,” said Dr. Liption, “or at least that our headache practices are enriched with these people whose chronic migraine persists until we make heroic efforts to cause their headache to abate.”

A model unadjusted for covariates, but adjusted for random effects, indicated that the rate of headache days increased by 19% per quarter for participants with chronic migraine, compared with those with episodic migraine. After the researchers adjusted the model for covariates and random effects, it indicated that headache days increased by 26% per quarter for participants with chronic migraine, compared with those with episodic migraine.

Results May Influence Future Investigations

An appropriate goal of future studies would be to clarify the concept of chronic migraine, said Dr. Lipton. Allodynia, comorbidity, and treatment refractoriness are essential components of this disease and may help clarify the border between episodic and chronic migraine. Research also could attempt to identify trait predictors of episodic migraine and chronic migraine.

Furthermore, the findings suggest that the methodology of future epidemiologic studies should be reconsidered. “More frequent sampling will likely identify higher rates of chronic migraine onset,” said Dr. Lipton. The results also suggest that enrolling people with 15 or more headache days per month into clinical trials may lead to reductions in headache frequency that are unrelated to treatment, which could contribute to a strong placebo response.

On July 13, the Italian Society for the Study of Headaches recognized Drs. Lipton, Serrano, and colleagues for their research with the 2017 Enrico Greppi Award. The manuscript will be published in the Journal of Headache and Pain.

—Erik Greb

Suggested Reading

Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 2015;35(7):563-578.

Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

BOSTON—Patients with migraine may have greater fluctuation in headache frequency than was previously understood. The rate of transition from episodic migraine to chronic migraine is higher than previously reported, and about three-quarters of people with chronic migraine have a period of episodic migraine during one year, according to a study described at the 59th Annual Scientific Meeting of the American Headache Society.

An Analysis of CaMEO Data

Epidemiologic research has provided information about the profiles of people with chronic migraine and people with episodic migraine. Investigators also have clarified the frequency with which people transition from episodic to chronic migraine. Comparatively little is known, however, about individual variation in headache frequency.

Dr. Lipton and colleagues conducted a study to assess the rates of transition between episodic and chronic migraine and to model the variation in headache days over the course of one year. The investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, which includes a representative sample of Americans with episodic migraine or chronic migraine.

Dr. Lipton’s group screened participants with an electronic version of the American Migraine Study/the American Migraine Prevalence and Prevention diagnostic module. They used modified International Classification of Headache Disorders 3-beta criteria to classify people as having episodic migraine, and modified Silberstein–Lipton criteria to classify patients as having chronic migraine. Every three months, the researchers asked participants how many days they had had headache during the previous quarter. Participants completed as many as five surveys during 2012 and 2013.

To examine within-person change in headache frequency over time, the investigators asked about chronic migraine onset in people with episodic migraine at baseline, and asked about transition to episodic migraine in people with chronic migraine at baseline. Finally, Dr. Lipton and colleagues plotted participants’ longitudinal data and modeled them using adjusted and unadjusted generalized linear mixed models.

High Variation in Headache Days

At baseline, 15,313 respondents had episodic migraine, and 32.4% of them had episodic migraine at baseline only. In addition, 1,476 had chronic migraine at baseline, and 62.3% of them had chronic migraine at baseline only. The investigators observed a “striking level of within-person variation in headache days,” said Dr. Lipton. The number of headache days per month ranged from none to 31.

In further analyses, the investigators examined subpopulations of participants who provided data most consistently throughout the study. Of the 5,464 patients with episodic migraine at baseline for whom at least four completed surveys were available, 92.4% had episodic migraine at every follow-up. In addition, 7.6% of these participants crossed the diagnostic threshold into chronic migraine during at least one quarter. “In the American Migraine Prevalence and Prevention study, the transition rate from episodic migraine to chronic migraine was about 2.5%,” said Dr. Lipton.

A total of 526 patients had chronic migraine at baseline and completed at least four surveys. Of this subpopulation, 26.6% had chronic migraine at every time point, and 73.4% had episodic migraine during at least one quarter. “My suspicion is that the patients that we see in our practices are the people with chronic migraine that remain chronic migraine,” said Dr. Liption, “or at least that our headache practices are enriched with these people whose chronic migraine persists until we make heroic efforts to cause their headache to abate.”

A model unadjusted for covariates, but adjusted for random effects, indicated that the rate of headache days increased by 19% per quarter for participants with chronic migraine, compared with those with episodic migraine. After the researchers adjusted the model for covariates and random effects, it indicated that headache days increased by 26% per quarter for participants with chronic migraine, compared with those with episodic migraine.

Results May Influence Future Investigations

An appropriate goal of future studies would be to clarify the concept of chronic migraine, said Dr. Lipton. Allodynia, comorbidity, and treatment refractoriness are essential components of this disease and may help clarify the border between episodic and chronic migraine. Research also could attempt to identify trait predictors of episodic migraine and chronic migraine.

Furthermore, the findings suggest that the methodology of future epidemiologic studies should be reconsidered. “More frequent sampling will likely identify higher rates of chronic migraine onset,” said Dr. Lipton. The results also suggest that enrolling people with 15 or more headache days per month into clinical trials may lead to reductions in headache frequency that are unrelated to treatment, which could contribute to a strong placebo response.

On July 13, the Italian Society for the Study of Headaches recognized Drs. Lipton, Serrano, and colleagues for their research with the 2017 Enrico Greppi Award. The manuscript will be published in the Journal of Headache and Pain.

—Erik Greb

Suggested Reading

Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 2015;35(7):563-578.

Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

BOSTON—Patients with migraine may have greater fluctuation in headache frequency than was previously understood. The rate of transition from episodic migraine to chronic migraine is higher than previously reported, and about three-quarters of people with chronic migraine have a period of episodic migraine during one year, according to a study described at the 59th Annual Scientific Meeting of the American Headache Society.

An Analysis of CaMEO Data

Epidemiologic research has provided information about the profiles of people with chronic migraine and people with episodic migraine. Investigators also have clarified the frequency with which people transition from episodic to chronic migraine. Comparatively little is known, however, about individual variation in headache frequency.

Dr. Lipton and colleagues conducted a study to assess the rates of transition between episodic and chronic migraine and to model the variation in headache days over the course of one year. The investigators examined data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, which includes a representative sample of Americans with episodic migraine or chronic migraine.

Dr. Lipton’s group screened participants with an electronic version of the American Migraine Study/the American Migraine Prevalence and Prevention diagnostic module. They used modified International Classification of Headache Disorders 3-beta criteria to classify people as having episodic migraine, and modified Silberstein–Lipton criteria to classify patients as having chronic migraine. Every three months, the researchers asked participants how many days they had had headache during the previous quarter. Participants completed as many as five surveys during 2012 and 2013.

To examine within-person change in headache frequency over time, the investigators asked about chronic migraine onset in people with episodic migraine at baseline, and asked about transition to episodic migraine in people with chronic migraine at baseline. Finally, Dr. Lipton and colleagues plotted participants’ longitudinal data and modeled them using adjusted and unadjusted generalized linear mixed models.

High Variation in Headache Days

At baseline, 15,313 respondents had episodic migraine, and 32.4% of them had episodic migraine at baseline only. In addition, 1,476 had chronic migraine at baseline, and 62.3% of them had chronic migraine at baseline only. The investigators observed a “striking level of within-person variation in headache days,” said Dr. Lipton. The number of headache days per month ranged from none to 31.

In further analyses, the investigators examined subpopulations of participants who provided data most consistently throughout the study. Of the 5,464 patients with episodic migraine at baseline for whom at least four completed surveys were available, 92.4% had episodic migraine at every follow-up. In addition, 7.6% of these participants crossed the diagnostic threshold into chronic migraine during at least one quarter. “In the American Migraine Prevalence and Prevention study, the transition rate from episodic migraine to chronic migraine was about 2.5%,” said Dr. Lipton.

A total of 526 patients had chronic migraine at baseline and completed at least four surveys. Of this subpopulation, 26.6% had chronic migraine at every time point, and 73.4% had episodic migraine during at least one quarter. “My suspicion is that the patients that we see in our practices are the people with chronic migraine that remain chronic migraine,” said Dr. Liption, “or at least that our headache practices are enriched with these people whose chronic migraine persists until we make heroic efforts to cause their headache to abate.”

A model unadjusted for covariates, but adjusted for random effects, indicated that the rate of headache days increased by 19% per quarter for participants with chronic migraine, compared with those with episodic migraine. After the researchers adjusted the model for covariates and random effects, it indicated that headache days increased by 26% per quarter for participants with chronic migraine, compared with those with episodic migraine.

Results May Influence Future Investigations

An appropriate goal of future studies would be to clarify the concept of chronic migraine, said Dr. Lipton. Allodynia, comorbidity, and treatment refractoriness are essential components of this disease and may help clarify the border between episodic and chronic migraine. Research also could attempt to identify trait predictors of episodic migraine and chronic migraine.

Furthermore, the findings suggest that the methodology of future epidemiologic studies should be reconsidered. “More frequent sampling will likely identify higher rates of chronic migraine onset,” said Dr. Lipton. The results also suggest that enrolling people with 15 or more headache days per month into clinical trials may lead to reductions in headache frequency that are unrelated to treatment, which could contribute to a strong placebo response.

On July 13, the Italian Society for the Study of Headaches recognized Drs. Lipton, Serrano, and colleagues for their research with the 2017 Enrico Greppi Award. The manuscript will be published in the Journal of Headache and Pain.

—Erik Greb

Suggested Reading

Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 2015;35(7):563-578.

Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

Participation in mental health courts appears to reduce some measures of recidivism among adults with mental illness – but the impact is modest, according to a meta-analysis conducted by Evan M. Lowder, PhD, and his associates.

“Our findings inform the overall effectiveness of [mental health courts] as a judicial strategy to reduce the number of adults with mental illnesses who are returning to the criminal justice system,” wrote Dr. Lowder, formerly with the department of psychology at North Carolina State University, Raleigh, and now with the school of public and environmental affairs at Indiana University, Indianapolis (Psychiatr Serv. 2017 Aug 15. doi: 10.1176/appi.ps.201700107).

The growing numbers of adults with mental illnesses in the U.S. criminal justice system led to the development of mental health courts in the 1990s. Mental health courts allow defendants to agree on a voluntary basis to mental health treatment in the community, “often in exchange for a reduced or dismissed index charge upon successful completion,” the investigators wrote. Previous research has shown that graduation from mental health courts, rather than participation, is tied to better outcomes (Law Hum Behav. 2016 Apr;40[2]:118-27) and (Int J Psychiatry. 2014 Sep-Oct;37[5]:448-54).

copyright Andrea Danti/Thinkstock

acruz@frontlinemedcom.com

On Twitter @ Abbbbeeeyyy

Participation in mental health courts appears to reduce some measures of recidivism among adults with mental illness – but the impact is modest, according to a meta-analysis conducted by Evan M. Lowder, PhD, and his associates.

“Our findings inform the overall effectiveness of [mental health courts] as a judicial strategy to reduce the number of adults with mental illnesses who are returning to the criminal justice system,” wrote Dr. Lowder, formerly with the department of psychology at North Carolina State University, Raleigh, and now with the school of public and environmental affairs at Indiana University, Indianapolis (Psychiatr Serv. 2017 Aug 15. doi: 10.1176/appi.ps.201700107).

The growing numbers of adults with mental illnesses in the U.S. criminal justice system led to the development of mental health courts in the 1990s. Mental health courts allow defendants to agree on a voluntary basis to mental health treatment in the community, “often in exchange for a reduced or dismissed index charge upon successful completion,” the investigators wrote. Previous research has shown that graduation from mental health courts, rather than participation, is tied to better outcomes (Law Hum Behav. 2016 Apr;40[2]:118-27) and (Int J Psychiatry. 2014 Sep-Oct;37[5]:448-54).

copyright Andrea Danti/Thinkstock

acruz@frontlinemedcom.com

On Twitter @ Abbbbeeeyyy

Participation in mental health courts appears to reduce some measures of recidivism among adults with mental illness – but the impact is modest, according to a meta-analysis conducted by Evan M. Lowder, PhD, and his associates.

“Our findings inform the overall effectiveness of [mental health courts] as a judicial strategy to reduce the number of adults with mental illnesses who are returning to the criminal justice system,” wrote Dr. Lowder, formerly with the department of psychology at North Carolina State University, Raleigh, and now with the school of public and environmental affairs at Indiana University, Indianapolis (Psychiatr Serv. 2017 Aug 15. doi: 10.1176/appi.ps.201700107).

The growing numbers of adults with mental illnesses in the U.S. criminal justice system led to the development of mental health courts in the 1990s. Mental health courts allow defendants to agree on a voluntary basis to mental health treatment in the community, “often in exchange for a reduced or dismissed index charge upon successful completion,” the investigators wrote. Previous research has shown that graduation from mental health courts, rather than participation, is tied to better outcomes (Law Hum Behav. 2016 Apr;40[2]:118-27) and (Int J Psychiatry. 2014 Sep-Oct;37[5]:448-54).

copyright Andrea Danti/Thinkstock

acruz@frontlinemedcom.com

On Twitter @ Abbbbeeeyyy

LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.