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Is there a doctor on the plane? Tips for providing in-flight assistance
In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.
as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.
The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.
The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.
When a physician is faced with an in-flight emergency, the medical team includes the physician himself, medical ground control, and the flight attendants, said Dr. Ho. Requirements may vary among airlines, but all flight attendants will be trained in cardiopulmonary resuscitation (CPR) or basic life support, as well as use of automated external defibrillators (AEDs).
Physician call centers (medical ground control) can provide additional assistance remotely, she said.
The in-flight medical bag
Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.
The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.
An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.
Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
How to handle an in-flight emergency
Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.
Legal lessons
Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.
The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”
Dr. Ho disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.
as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.
The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.
The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.
When a physician is faced with an in-flight emergency, the medical team includes the physician himself, medical ground control, and the flight attendants, said Dr. Ho. Requirements may vary among airlines, but all flight attendants will be trained in cardiopulmonary resuscitation (CPR) or basic life support, as well as use of automated external defibrillators (AEDs).
Physician call centers (medical ground control) can provide additional assistance remotely, she said.
The in-flight medical bag
Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.
The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.
An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.
Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
How to handle an in-flight emergency
Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.
Legal lessons
Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.
The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”
Dr. Ho disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.
as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.
The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.
The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.
When a physician is faced with an in-flight emergency, the medical team includes the physician himself, medical ground control, and the flight attendants, said Dr. Ho. Requirements may vary among airlines, but all flight attendants will be trained in cardiopulmonary resuscitation (CPR) or basic life support, as well as use of automated external defibrillators (AEDs).
Physician call centers (medical ground control) can provide additional assistance remotely, she said.
The in-flight medical bag
Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.
The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.
An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.
Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
How to handle an in-flight emergency
Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.
Legal lessons
Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.
The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”
Dr. Ho disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACEP 2022
Imaging IDs brain activity related to dissociative symptoms
Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.
Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).
“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.
“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.
The findings were published online in Neuropsychopharmacology.
Detachment, discontinuity
Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.
Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.
“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”
Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.
She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.
In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.
Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
Filling the gap
The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.
This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.
The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.
Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.
They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.
This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).
Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
Connectivity alterations
Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.
Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.
Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.
“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.
“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.
She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”
In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
A first step?
Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”
Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.
He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”
The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.
Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).
“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.
“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.
The findings were published online in Neuropsychopharmacology.
Detachment, discontinuity
Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.
Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.
“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”
Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.
She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.
In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.
Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
Filling the gap
The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.
This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.
The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.
Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.
They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.
This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).
Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
Connectivity alterations
Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.
Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.
Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.
“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.
“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.
She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”
In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
A first step?
Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”
Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.
He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”
The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.
Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).
“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.
“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.
The findings were published online in Neuropsychopharmacology.
Detachment, discontinuity
Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.
Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.
“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”
Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.
She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.
In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.
Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
Filling the gap
The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.
This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.
The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.
Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.
They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.
This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).
Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
Connectivity alterations
Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.
Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.
Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.
“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.
“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.
She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”
In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
A first step?
Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”
Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.
He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”
The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROPSYCHOPHARMACOLOGY
Nutrition for cognition: A missed opportunity in U.S. seniors?
, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.
Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.
Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.
She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.
Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.
The study was published online in Neurology.
Memory preservation
Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.
At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.
Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.
The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.
One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.
While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.
Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.
The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.
“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
An underutilized program
In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.
Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.
“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.
The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.
Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.
Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.
She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.
Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.
The study was published online in Neurology.
Memory preservation
Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.
At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.
Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.
The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.
One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.
While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.
Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.
The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.
“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
An underutilized program
In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.
Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.
“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.
The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.
Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.
Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.
She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.
Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.
The study was published online in Neurology.
Memory preservation
Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.
At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.
Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.
The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.
One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.
While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.
Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.
The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.
“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
An underutilized program
In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.
Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.
“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.
The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Neurology
Traffic-related pollutant tied to increased dementia risk
Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed
Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.
While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.
“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.
The findings were published online in Neurology.
Conflicting results in past studies
Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.
Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.
After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m3 rise in PM2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).
The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.
The study did not examine how or if the duration of PM2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.
The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m3 to be safe. The World Health Organization sets that limit lower, at 5 mcg/m3.
Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.
“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”
Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.
Research also suggests that improving air quality PM2.5 by just 10% results in a 14% decreased risk for dementia.
‘Impressive’ pattern
Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.
He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.
The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed
Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.
While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.
“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.
The findings were published online in Neurology.
Conflicting results in past studies
Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.
Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.
After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m3 rise in PM2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).
The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.
The study did not examine how or if the duration of PM2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.
The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m3 to be safe. The World Health Organization sets that limit lower, at 5 mcg/m3.
Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.
“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”
Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.
Research also suggests that improving air quality PM2.5 by just 10% results in a 14% decreased risk for dementia.
‘Impressive’ pattern
Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.
He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.
The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed
Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.
While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.
“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.
The findings were published online in Neurology.
Conflicting results in past studies
Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.
Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.
After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m3 rise in PM2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).
The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.
The study did not examine how or if the duration of PM2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.
The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m3 to be safe. The World Health Organization sets that limit lower, at 5 mcg/m3.
Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.
“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”
Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.
Research also suggests that improving air quality PM2.5 by just 10% results in a 14% decreased risk for dementia.
‘Impressive’ pattern
Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.
He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.
The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
In rheumatoid arthritis, reducing inflammation reduces dementia risk
The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.
The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.
Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”
In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.
In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.
Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.
“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”
He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”
In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
Prior research
Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.
Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.
Other past studies include:
- A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
- A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
- A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
- In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).
These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.
Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.
The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.
The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.
Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”
In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.
In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.
Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.
“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”
He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”
In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
Prior research
Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.
Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.
Other past studies include:
- A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
- A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
- A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
- In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).
These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.
Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.
The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.
The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.
Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”
In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.
In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.
Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.
“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”
He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”
In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
Prior research
Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.
Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.
Other past studies include:
- A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
- A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
- A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
- In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).
These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.
Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.
FROM SEMINARS IN ARTHRITIS AND RHEUMATISM
‘Lucid dying’: EEG backs near-death experience during CPR
“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.
Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.
He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
The AWARE II study
“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.
“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.
In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).
They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO2) monitoring into CPR.
Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.
These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.
“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said.
And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO2] 43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.
Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
‘Seismic shift’ in understanding of death
This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.
He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.
“Our understanding of death has gone through a seismic shift in the last few years,” he said.
“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.
Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”
The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.
“However, whether there is conscious perception or not is very hard to answer,” he cautioned.
“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.
Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.
Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.
He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
The AWARE II study
“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.
“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.
In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).
They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO2) monitoring into CPR.
Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.
These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.
“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said.
And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO2] 43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.
Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
‘Seismic shift’ in understanding of death
This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.
He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.
“Our understanding of death has gone through a seismic shift in the last few years,” he said.
“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.
Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”
The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.
“However, whether there is conscious perception or not is very hard to answer,” he cautioned.
“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.
Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.
Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.
He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
The AWARE II study
“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.
“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.
In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).
They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO2) monitoring into CPR.
Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.
These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.
“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said.
And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO2] 43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.
Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
‘Seismic shift’ in understanding of death
This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.
He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.
“Our understanding of death has gone through a seismic shift in the last few years,” he said.
“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.
Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”
The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.
“However, whether there is conscious perception or not is very hard to answer,” he cautioned.
“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.
Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AHA 2022
Sacral nerve stimulation may aid female sexual dysfunction
Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.
The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.
According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.
It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
Tested before implantation
In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.
The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
Systematic study analysis
To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”
According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.
The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
An experimental therapy
According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:
A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.
An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.
This article was translated from Univadis Germany and a version appeared on Medscape.com.
Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.
The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.
According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.
It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
Tested before implantation
In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.
The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
Systematic study analysis
To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”
According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.
The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
An experimental therapy
According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:
A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.
An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.
This article was translated from Univadis Germany and a version appeared on Medscape.com.
Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.
The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.
According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.
It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
Tested before implantation
In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.
The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
Systematic study analysis
To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”
According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.
The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
An experimental therapy
According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:
A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.
An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.
This article was translated from Univadis Germany and a version appeared on Medscape.com.
FROM DIE GYNÄKOLOGIE
Novel drug eases Parkinson’s-related constipation in early trial
The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.
The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.
The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.
Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.
“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
Constipation is an early PD symptom
Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.
According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.
In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.
Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.
In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).
There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.
No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.
The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.
Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.
The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.
Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
Targeting the underlying disease
Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.
According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).
In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).
The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.
He added that, if findings are reproduced in a large study, the drug could have “a major impact” not just in treating constipation, for which there are no PD-specific drugs, but also in addressing neurological dysfunctions that are cardinal features of PD. “That is what is exciting to me, because we’re now talking about reversing the disease itself,” he said.
However, Dr. Barbut said it’s been difficult to get across to the medical community and to investors that a drug that acts on nerve cells in the gut might reverse neurologic symptoms by improving direct gut-brain communication. “That’s a concept that is alien to most people’s thinking,” she said.
Enterin funded the study and was responsible for the design, data collection and analysis. Its employees also participated in the interpretation of data, writing of the report, and the decision to submit the manuscript for publication. Dr. Barbut reported stock options in Enterin and patent interests in ENT-01. Fifteen other study investigators reported financial ties to Enterin and/or ENT-01 including employment, stock options, research funding, consulting fees and patent application ownership. Dr. Rao reported receiving honoraria from multiple companies that market drugs for general constipation.
The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.
The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.
The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.
Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.
“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
Constipation is an early PD symptom
Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.
According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.
In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.
Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.
In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).
There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.
No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.
The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.
Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.
The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.
Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
Targeting the underlying disease
Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.
According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).
In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).
The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.
He added that, if findings are reproduced in a large study, the drug could have “a major impact” not just in treating constipation, for which there are no PD-specific drugs, but also in addressing neurological dysfunctions that are cardinal features of PD. “That is what is exciting to me, because we’re now talking about reversing the disease itself,” he said.
However, Dr. Barbut said it’s been difficult to get across to the medical community and to investors that a drug that acts on nerve cells in the gut might reverse neurologic symptoms by improving direct gut-brain communication. “That’s a concept that is alien to most people’s thinking,” she said.
Enterin funded the study and was responsible for the design, data collection and analysis. Its employees also participated in the interpretation of data, writing of the report, and the decision to submit the manuscript for publication. Dr. Barbut reported stock options in Enterin and patent interests in ENT-01. Fifteen other study investigators reported financial ties to Enterin and/or ENT-01 including employment, stock options, research funding, consulting fees and patent application ownership. Dr. Rao reported receiving honoraria from multiple companies that market drugs for general constipation.
The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.
The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.
The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.
Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.
“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
Constipation is an early PD symptom
Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.
According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.
In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.
Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.
In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).
There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.
No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.
The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.
Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.
The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.
Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
Targeting the underlying disease
Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.
According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).
In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).
The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.
He added that, if findings are reproduced in a large study, the drug could have “a major impact” not just in treating constipation, for which there are no PD-specific drugs, but also in addressing neurological dysfunctions that are cardinal features of PD. “That is what is exciting to me, because we’re now talking about reversing the disease itself,” he said.
However, Dr. Barbut said it’s been difficult to get across to the medical community and to investors that a drug that acts on nerve cells in the gut might reverse neurologic symptoms by improving direct gut-brain communication. “That’s a concept that is alien to most people’s thinking,” she said.
Enterin funded the study and was responsible for the design, data collection and analysis. Its employees also participated in the interpretation of data, writing of the report, and the decision to submit the manuscript for publication. Dr. Barbut reported stock options in Enterin and patent interests in ENT-01. Fifteen other study investigators reported financial ties to Enterin and/or ENT-01 including employment, stock options, research funding, consulting fees and patent application ownership. Dr. Rao reported receiving honoraria from multiple companies that market drugs for general constipation.
FROM ANNALS OF INTERNAL MEDICINE
Combo thrombolytic approach fails to reduce ICH in stroke
A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).
However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.
“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.
The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center.
She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.
Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.
Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.
“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.
The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.
As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.
The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.
They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.
The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.
This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).
Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.
However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.
In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.
Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.
“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”
Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk.
They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.
Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.
Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”
The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”
The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
A version of this article first appeared on Medscape.com.
A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).
However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.
“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.
The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center.
She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.
Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.
Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.
“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.
The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.
As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.
The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.
They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.
The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.
This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).
Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.
However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.
In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.
Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.
“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”
Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk.
They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.
Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.
Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”
The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”
The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
A version of this article first appeared on Medscape.com.
A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).
However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.
“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.
The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center.
She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.
Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.
Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.
“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.
The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.
As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.
The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.
They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.
The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.
This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).
Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.
However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.
In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.
Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.
“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”
Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk.
They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.
Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.
Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”
The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”
The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM WSC 2022
Major depression treatments boost brain connectivity
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ECNP 2022